Type 1 Diabetes Mellitus early Detection

Romesh Khardori, MD, PhD, FACP (Retired) Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Eastern Virginia Medical School Chief Editor; George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine Type 1 Diabetes

Type 1 diabetes is a chronic illness characterized by the body’s inability to produce insulin due to the autoimmune destruction of the beta cells in the pancreas. Although onset frequently occurs in childhood, the disease can also develop in . 

Signs and symptoms

The classic symptoms of type 1 diabetes are as follows:

• Polyuria

• Polydipsia

• Polyphagia

• Unexplained weight loss

  Other symptoms may include fatigue, nausea, and blurred vision.

The onset of symptomatic disease may be sudden. It is not unusual for patients with type 1 diabetes to present with diabetic ketoacidosis (DKA).

Diagnosis

Diagnostic criteria by the American Diabetes Association (ADA) include the following  :

• A fasting plasma glucose (FPG) level ≥126 mg/dL (7.0 mmol/L), or

• A 2-hour plasma glucose level ≥200 mg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test (OGTT), or

• Type 1 diabetes mellitus (DM) is a multisystem disease with both biochemical and anatomic/structural consequences. It is a chronic disease of carbohydrate, fat, and protein metabolism caused by the lack of insulin, which results from the marked and progressive inability of the pancreas to secrete insulin because of autoimmune destruction of the beta cells. ^[1] (See Pathophysiology.) (See also Glucose Intolerance.).

  Type 1 DM can occur at any age. Although it frequently arises in juveniles, it can also develop in adults. (See Epidemiology.)

  Unlike people with type 2 DM, those with type 1 DM usually are not obese and usually present initially with diabetic ketoacidosis (DKA). The distinguishing characteristic of a patient with type 1 DM is that if his or her insulin is withdrawn, ketosis and eventually ketoacidosis develop. Therefore, these patients are dependent on exogenous insulin. (See Presentation.)

  Treatment of type 1 DM requires lifelong insulin therapy. A multidisciplinary approach by the physician, nurse, and dietitian, with regular specialist consultation, is needed to control glycemia, as well as to limit the development of its devastating complications and manage such complications when they do occur. (See Treatmentand Medication.)

  Despite the differences between type 1 and type 2 DM, the costs of the 2 conditions are often combined. In a study that focused on type 1 alone, Tao et al estimated that in the United States, type 1 DM is responsible for $14.4 billion in medical costs and lost income each year. ^[8]

  Pathophysiology

  Type 1 DM is the culmination of lymphocytic infiltration and destruction of insulin-secreting beta cells of the islets of Langerhans in the pancreas. As beta-cell mass declines, insulin secretion decreases until the available insulin no longer is adequate to maintain normal blood glucose levels. After 80-90% of the beta cells are destroyed, hyperglycemia develops and diabetes may be diagnosed. Patients need exogenous insulin to reverse this catabolic condition, prevent ketosis, decrease hyperglucagonemia, and normalize lipid and protein metabolism.

  Currently, autoimmunity is considered the major factor in the pathophysiology of type 1 DM. In a genetically susceptible individual, viral infection may stimulate the production of antibodies against a viral protein that trigger an autoimmune response against antigenically similar beta cell molecules.

  Approximately 85% of type 1 DM patients have circulating islet cell antibodies, and the majority also have detectable anti-insulin antibodies before receiving insulin therapy. The most commonly found islet cell antibodies are those directed against glutamic acid decarboxylase (GAD), an enzyme found within pancreatic beta cells.

  The prevalence of type 1 DM is increased in patients with other autoimmune diseases, such as Graves disease, Hashimoto thyroiditis, and Addison disease. Pilia et al found a higher prevalence of islet cell antibodies (IA2) and anti-GAD antibodies in patients with autoimmune thyroiditis. ^[9]

  A study by Philippe et al used computed tomography (CT) scans, glucagon stimulation test results, and fecal elastase-1 measurements to confirm reduced pancreatic volume in individuals with DM. ^[10] This finding, which was equally present in both type 1 and type 2 DM, may also explain the associated exocrine dysfunction that occurs in DM.

  Polymorphisms of the class II human leukocyte antigen (HLA) genes that encode DR and DQ are the major genetic determinants of type 1 DM. Approximately 95% of patients with type 1 DM have either HLA-DR3 or HLA-DR4. Heterozygotes for those haplotypes are at significantly greater risk for DM than homozygotes. HLA-DQs are also considered specific markers of type 1 DM susceptibility. In contrast, some haplotypes (eg, HLA-DR2) confer strong protection against type 1 DM. ^[11]

  Sensory and autonomic neuropathy

  Sensory and autonomic neuropathy in people with diabetes are caused by axonal degeneration and segmental demyelination. Many factors are involved, including the accumulation of sorbitol in peripheral sensory nerves from sustained hyperglycemia. Motor neuropathy and cranial mononeuropathy result from vascular disease in blood vessels supplying nerves.

  Angiopathy

  Using nailfold video capillaroscopy, Barchetta et al detected a high prevalence of capillary changes in patients with diabetes, particularly those with retinal damage. This reflects a generalized microvessel involvement in both type 1 and type 2 DM. ^[12]

  Microvascular disease causes multiple pathologic complications in people with diabetes. Hyaline arteriosclerosis, a characteristic pattern of wall thickening of small arterioles and capillaries, is widespread and is responsible for ischemic changes in the kidney, retina, brain, and peripheral nerves.

  Atherosclerosis of the main renal arteries and their intrarenal branches causes chronic nephron ischemia. It is a significant component of multiple renal lesions in diabetes.

  Vitamin D deficiency is an important independent predictor of development of coronary artery calcification in individuals with type 1 DM. ^[13] Joergensen et al determined that vitamin D deficiency in type 1 diabetes may predict all causes of mortality but not development of microvascular complications. ^[14]

  Nephropathy

  In the kidneys, the characteristic wall thickening of small arterioles and capillaries leads to diabetic nephropathy, which is characterized by proteinuria, glomerular hyalinization (Kimmelstiel-Wilson), and chronic renal failure. Exacerbated expression of cytokines such as tumor growth factor beta 1 is part of the pathophysiology of glomerulosclerosis, which begins early in the course of diabetic nephropathy.

  Genetic factors influence the development of diabetic nephropathy. Single-nucleotide polymorphisms affecting the factors involved in its pathogenesis appear to influence the risk for diabetic nephropathy in different people with type 1 DM. ^[15]

  Double diabetes

  In areas where rates of type 2 DM and obesity are high, individuals with type 1 DM may share genetic and environmental factors that lead to their exhibiting type 2 features such as reduced insulin sensitivity. This condition is termed double diabetes.

  In a study that included 207 patients with type 1 DM, Epstein et al used the estimated glucose disposal rate (eGDR) to assess insulin resistance and found that mean eGDR was significantly lower (and, thus, insulin resistance was higher) in black patients (5.66 mg/kg/min) than in either Hispanic patients (6.70 mg/kg/min) or white patients (7.20 mg/kg/min). In addition, low eGDR was associated with an increased risk of vascular complications of diabetes (eg, cardiovascular disease, diabetic retinopathy, or severe chronic kidney disease). ^[16, 17]

  Etiology

  Type 1A DM results from autoimmune destruction of the beta cells of the pancreas and involves both genetic predisposition and an environmental component.

  Genetic factors

  Although the genetic aspect of type 1 DM is complex, with multiple genes involved, there is a high sibling relative risk. ^[18] Whereas dizygotic twins have a 5-6% concordance rate for type 1 DM, ^[19] monozygotic twins will share the diagnosis more than 50% of the time by the age of 40 years. ^[20]

  For the child of a parent with type 1 DM, the risk varies according to whether the mother or the father has diabetes. Children whose mother has type 1 DM have a 2-3% risk of developing the disease, whereas those whose father has the disease have a 5-6% risk. When both parents are diabetic, the risk rises to almost 30%. In addition, the risk for children of parents with type 1 DM is slightly higher if onset of the disease occurred before age 11 years and slightly lower if the onset occurred after the parent’s 11th birthday.

  The genetic contribution to type 1 DM is also reflected in the significant variance in the frequency of the disease among different ethnic populations. Type 1 DM is most prevalent in European populations, with people from northern Europe more often affected than those from Mediterranean regions. ^[21] The disease is least prevalent in East Asians. ^[22]

  Genome-wide association studies have identified several loci that are associated with type 1 DM, but few causal relations have been established. The genomic region most strongly associated with other autoimmune diseases, the major histocompatibility complex (MHC), is the location of several susceptibility loci for type 1 DM—in particular, class II HLA DR and DQ haplotypes. ^{[23, 24, 25]}

  A hierarchy of DR-DQ haplotypes associated with increased risk for type 1 DM has been established. The most susceptible haplotypes are as follows ^[26] :

  • DRB1*0301 – DQA1*0501 – DQB1*0201 (odds ratio [OR] 3.64)

  • DRB1*0405 – DQA1*0301 – DQB1*0302 (OR 11.37)

  • DRB1*0401 – DQA1*0301 – DQB*0302 (OR 8.39)

  • DRB1*0402 – DQA1*0301 – DQB1*0302 (OR 3.63)

  • DRB1*0404 – DQA1*0301 – DQB1*0302 (OR 1.59)

  • DRB1*0801 – DQB1*0401 – DQB1*0402 (OR 1.25)

  Other haplotypes appear to offer protection against type 1 DM. These include the following ^[26] :

  • DRB1*1501 – DQA1*0102 – DQB1*0602 (OR 0.03)

  • DRB1*1401 – DQA1*0101 – DQB1*0503 (OR 0.02)

  • DRB1*0701 – DQA1*0201 – DQB1*0303 (OR 0.02)

  From 90% to 95% of young children with type 1 DM carry HLA-DR3 DQB1*0201, HLA-DR4 DQB1*0302, or both. Carriage of both haplotypes (ie, DR3/4 heterozygotes) confers the highest susceptibility.

  These high-risk haplotypes are found primarily in people of European descent; other ethnic groups are less well studied. In African Americans, the DRB1*07:01 – DQA1*03:01 -DQB1*02:01g haplotype is associated with increased risk (OR 3.96), whereas the DRB1*07:01-DQA1*02:01 – DQB1*02:01g haplotype appears to be protective (OR 0.34). ^[27]

  The insulin gene (INS), which encodes for the pre-proinsulin peptide, is adjacent to a variable number of tandem repeats (VNTR) polymorphism at chromosome 11p15.5. ^[28] Different VNTR alleles may promote either resistance or susceptibility to type 1 DM through their effect on INS transcription in the thymus; for example, protective VNTRs are associated with higher INS expression, which may promote deletion of insulin-specific T cells. ^[29]

  Other genes that have been reported to be involved in the mechanism of type 1 DM include CTLA4 (important in T-cell activation), PTPN22 (produces LYP, a negative regulator of T-cell kinase signaling), and IL2RA (encodes for CD25 which is involved with regulating T-cell function). UBASH3A (also known as STS2), may be involved in the increased risk not only of type 1 DM but also of other autoimmune disease and Down syndrome; it is located on locus chromosome 21q22.3. ^[30]

  In addition, genome-wide association studies have implicated numerous other genes, including the following ^[31] :

  • SH2B3

  • ERBB3

  • CLEC16A

  • IL18RAP

  • PTPN2

  • CCR5

  Environmental factors

  Extragenetic factors also may contribute. Potential triggers for immunologically mediated destruction of the beta cells include viruses (eg, enterovirus, ^[32] mumps, rubella, and coxsackievirus B4), toxic chemicals, exposure to cow’s milk in infancy, ^[33] and cytotoxins.

  Combinations of factors may be involved. Lempainen et al found that signs of an enterovirus infection by 12 months of age were associated with the appearance of type 1 DM–related autoimmunity among children who were exposed to cow’s milk before 3 months of age. These results suggest an interaction between the 2 factors and provide a possible explanation for the contradictory findings obtained in studies that examined these factors in isolation. ^[34]

  One meta-analysis found a weak but significant linear increase in the risk of childhood type 1 DM with increasing maternal age. ^[35] However, little evidence supports any substantial increase in childhood type 1 DM risk after pregnancy complicated by preeclampsia. ^[36]

  A study by Simpson et al found that neither vitamin D intake nor 25-hydroxyvitamin D levels throughout childhood were associated with islet autoimmunity or progression to type 1 DM. ^[37] This study was based in Denver, Colorado, and has been following children at increased risk of diabetes since 1993.

  Early upper respiratory infection may also be a risk factor for type 1 diabetes. In an analysis of data on 148 children considered genetically at risk for diabetes, upper respiratory infections in the first year of life were associated with an increased risk for type 1 diabetes . ^[38, 39] All children in the study who developed islet autoimmunity had at least 2 upper respiratory infections in the first year of life and at least 1 infection within 6 months before islet autoantibody seroconversion.

  Children with respiratory infections in the first 6 months of life had the greatest increased hazard ratio (HR) for islet autoantibody seroconversion (HR = 2.27), and the risk was also increased in those with respiratory infections at ages 6 to almost 12 months (HR = 1.32). ^[38, 39] The rate of islet autoantibody seroconversion was highest among children with more than 5 respiratory infections in the first year of year of life. Respiratory infections in the second year of life were not related to increased risk. ^[38, 39]

  Evidence exists that coronavirus disease 2019 (COVID-19) may actually lead to the development of type 1 and type 2 diabetes. One theory is that diabetes arises when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, binds “to angiotensin-converting enzyme 2 (ACE2) receptors in key metabolic organs and tissues, including pancreatic beta cells and kidneys.” The CoviDiab registry was established by an international group of diabetes researchers to gather data on COVID-19–related diabetes. ^[40]

  A report by Xie and Al-Aly found that among study patients who had survived the first 30 days of COVID-19, the risk for diabetes at 1 year was increased by about 40%. More specifically, the hazard ratios (HRs) for diabetes at 1 year among patients who, during the acute infection, were not hospitalized, were hospitalized, or were admitted to intensive care were 1.25, 2.73, and 3.76, respectively. The investigators stated that diabetes “should be considered as a facet of the multifaceted long COVID syndrome.” ^[41, 42]

  A study by Tang et al detected SARS-CoV-2 antigen in pancreatic beta cells, as taken from autopsy samples from individuals who had had COVID-19. The research indicated that insulin expression decreases in SARS-CoV-2–infected beta cells, with these cells possibly undergoing transdifferentiation. ^[43] A study by Wu et al also indicated that infected beta cells secrete less insulin, with the investigators finding evidence that SARS-CoV-2 can induce beta-cell apoptosis. ^[44]

  A study from the US Centers for Disease Control and Prevention (CDC) indicates that SARS-CoV-2 infection increases the likelihood of diabetes developing in children under age 18 years, more than 30 days post infection. The investigators, using two US health claims databases, reported that pediatric patients with COVID-19 in the HealthVerity database were 31% percent more likely than other youth to receive a new diabetes diagnosis, while those in the IQVIA database were 166% more likely. The study could not specify the type or types of diabetes specifically related to COVID-19, with the report saying that the disease could be causing both type 1 and type 2 diabetes but through differing mechanisms. The researchers suggested, however, that COVID-19 may induce diabetes by directly attacking pancreatic cells that express ACE2 receptors, that it may give rise to diabetes “through stress hyperglycemia resulting from the cytokine storm and alterations in glucose metabolism caused by infection,” or that COVID-19 may cause diabetes via the conversion of prediabetes to diabetes. Whether the diabetes is transient or chronic was also unknown. ^[45, 46]

  A study by Kendall et al found that compared with pediatric subjects with a non–SARS-CoV-2 respiratory infection, the proportion of children who were diagnosed with new-onset type 1 DM within 6 months after a SARS-CoV-2 infection was 72% greater. According to the investigators, who looked at patients aged 18 years or younger, the rate of new-onset type 1 DM among the two groups was 0.025% and 0.043%, respectively, at 6 months. ^[47]

  However, a study by Cromer et al looked at adult patients with newly diagnosed diabetes mellitus at the time of hospital admission for COVID-19, finding that a number of them subsequently regressed to a state of normoglycemia or prediabetes. The investigators reported that out of 64 survivors in the study with newly diagnosed diabetes (62 of whom had type 2 diabetes), 26 (40.6%) were known to undergo such regression (median 323-day follow-up). ^[48]

  Epidemiology

  United States statistics

  A 2011 report from the US Centers for Disease Control and Prevention (CDC) estimated that approximately 1 million Americans have type 1 DM. ^[49] The CDC estimated that each year from 2002 to 2005, type 1 DM was newly diagnosed in 15,600 young people. Among children younger than 10 years, the annual rate of new cases was 19.7 per 100,000 population; among those 10 years or older, the rate was 18.6 per 100,000 population. ^[49]

  Type 1 DM is the most common metabolic disease of childhood. About 1 in every 400-600 children and adolescents has type 1 DM. In adults, type 1 DM constitutes approximately 5% of all diagnosed cases of diabetes. ^[49]

  A study by Mayer-Davis et al indicated that between 2002 and 2012, the incidence of type 1 and type 2 DM saw a significant rise among youths in the United States. According to the report, after the figures were adjusted for age, sex, and race or ethnic group, the incidence of type 1 (in patients aged 0-19 years) and type 2 DM (in patients aged 10-19 years) during this period underwent a relative annual increase of 1.8% and 4.8%, respectively. The greatest increases occurred among minority youths. ^[50]

  International statistics

  Internationally, rates of type 1 DM are increasing. In Europe, the Middle East, and Australia, rates of type 1 DM are increasing by 2-5% per year. ^[51] The prevalence of type 1 DM is highest in Scandinavia (ie, approximately 20% of the total number of people with DM) and lowest in China and Japan (ie, fewer than 1% of all people with diabetes). Some of these differences may relate to definitional issues and the completeness of reporting.

  The 10th edition of the International Diabetes Federation Diabetes Atlas, published in December 2021, reported that worldwide, 1 in 10 adults has diabetes. The data predicted that there would be a global increase in the number of adults with diabetes from 537 million in 2021 to 786 million by 2045, a 46% rise. Although increases are expected throughout the world, Africa, the Middle East, and Southeast Asia are predicted to have the greatest expansion. ^[52]

  Age-related demographics

  Previously referred to as juvenile-onset diabetes, type 1 DM is typically diagnosed in childhood, adolescence, or early adulthood. Although the onset of type 1 DM often occurs early in life, 50% of patients with new-onset type 1 DM are older than 20 years of age.

  Type 1 DM usually starts in children aged 4 years or older, appearing fairly abruptly, with the peak incidence of onset at age 11-13 years (ie, in early adolescence and puberty). There is also a relatively high incidence in people in their late 30s and early 40s, in whom the disease tends to present less aggressively (ie, with early hyperglycemia without ketoacidosis and gradual onset of ketosis). This slower-onset adult form of type 1 DM is referred to as latent autoimmune diabetes of the adult (LADA). ^[49]

  A study by Thomas et al, using data from the UK Biobank, determined that in 42% of type 1 DM cases reviewed, disease onset occurred in patients aged 31 to 60 years. The report also found that because type 2 DM is far more common than type 1 in individuals in the 31- to 60-year age group, with type 1 DM making up only 4% of all diabetes cases in this population, identification of type 1 DM is difficult in patients over age 30 years. The presence of type 1 DM was identified in the study using a genetic risk score that employed 29 common genetic variants. ^[53, 54]

  The risk of development of antibodies (anti-islet) in relatives of patients with type 1 DM decreases with increasing age. This finding supports annual screening for antibodies in relatives younger than 10 years and 1 additional screening during adolescence. ^[4]

  Sex- and race-related demographics

  Type 1 DM is more common in males than in females. In populations of European origin, the male-to-female ratio is greater than 1.5:1.

  Type 1 DM is most common among non-Hispanic whites, followed by African Americans and Hispanic Americans. It is comparatively uncommon among Asians.

  Prognosis

  Type 1 DM is associated with a high morbidity and premature mortality. More than 60% of patients with type 1 DM do not develop serious complications over the long term, but many of the rest experience blindness, end-stage renal disease (ESRD), and, in some cases, early death. The risk of ESRD and proliferative retinopathy is twice as high in men as in women when the onset of diabetes occurred before age 15 years. ^[55]

  Patients with type 1 DM who survive the period 10-20 years after disease onset without fulminant complications have a high probability of maintaining reasonably good health. Other factors affecting long-term outcomes are the patient’s education, awareness, motivation, and intelligence level. The 2012 American Diabetes Association (ADA) standard of care emphasizes the importance of long-term, coordinated care management for improved outcomes and suggests structural changes to existing systems of long-term care delivery. ^[5]

  The morbidity and mortality associated with diabetes are related to the short- and long-term complications. Such complications include the following:

  • Hypoglycemia from management errors

  • Increased risk of infections

  • Microvascular complications (eg, retinopathy and nephropathy)

  • Neuropathic complications

  • Macrovascular disease

    A random plasma glucose ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis

    Lab studies

    A fingerstick glucose test is appropriate for virtually all patients with diabetes. All fingerstick capillary glucose levels must be confirmed in serum or plasma to make the diagnosis. All other laboratory studies should be selected or omitted on the basis of the individual clinical situation.

    An international expert committee appointed by the ADA, the European Association for the Study of Diabetes (EASD), and the International Diabetes Association recommended the HbA_1c assay for diagnosing type 1 diabetes only when the condition is suspected but the classic symptoms are absent. 

    Screening

    Screening for type 1 diabetes in asymptomatic low-risk individuals is not recommended. ^[2] However, in patients at high risk (eg, those who have first-degree relatives with type 1 diabetes), it may be appropriate to perform annual screening for anti-islet antibodies before the age of 10 years, along with 1 additional screening during adolescence. 

    Management

    Glycemic control

    The ADA recommends using patient age as one consideration in the establishment of glycemic goals, with different targets for preprandial, bedtime/overnight, and hemoglobin A_1c (HbA_1c) levels in patients aged 0-6, 6-12, and 13-19 years. ^[5] Benefits of tight glycemic control include not only continued reductions in the rates of microvascular complications but also significant differences in cardiovascular events and overall mortality.

    Self-monitoring

    Optimal diabetic control requires frequent self-monitoring of blood glucose levels, which allows rational adjustments in insulin doses. All patients with type 1 diabetes should learn how to self-monitor and record their blood glucose levels with home analyzers and adjust their insulin doses accordingly.

    Real-time continuous monitoring of glucose—using continuous glucose monitors (CGMs)—can help patients improve glycemic control. ^[6, 7] CGMs contain subcutaneous sensors that measure interstitial glucose levels every 1-5 minutes, providing alarms when glucose levels are too high or too low or are rapidly rising or falling.

    Insulin therapy 

    Patients with type 1 diabetes require lifelong insulin therapy. Most require 2 or more injections of insulin daily, with doses adjusted on the basis of self-monitoring of blood glucose levels. Insulin replacement is accomplished by giving a basal insulin and a preprandial (premeal) insulin. The basal insulin is either long-acting (glargine or detemir) or intermediate-acting (NPH). The preprandial insulin is either rapid-acting (lispro, aspart, insulin inhaled, or glulisine) or short-acting (regular).

    Common insulin regimens include the following:

    • Split or mixed: NPH with rapid-acting (eg, lispro, aspart, or glulisine) or regular insulin before breakfast and supper

    • Split or mixed variant: NPH with rapid-acting or regular insulin before breakfast, rapid-acting or regular insulin before supper, and NPH before bedtime (the idea is to reduce fasting hypoglycemia by giving the NPH later in the evening)

    • Multiple daily injections (MDI): A long-acting insulin (eg, glargine or detemir) once a day in the morning or evening (or twice a day in about 20% of patients) and a rapid-acting insulin before meals or snacks (with the dose adjusted according to the carbohydrate intake and the blood glucose level)

    • Continuous subcutaneous insulin infusion (CSII): Rapid-acting insulin infused continuously 24 hours a day through an insulin pump at 1 or more basal rates, with additional boluses given before each meal and correction doses administered if blood glucose levels exceed target levels

    Diet and activity

    All patients on insulin should have a comprehensive diet plan, created with the help of a professional dietitian, that includes the following:

    • A daily caloric intake prescription

    • Recommendations for amounts of dietary carbohydrate, fat, and protein

    • Instructions on how to divide calories between meals and snacks

    Exercise is also an important aspect of diabetes management. Patients should be encouraged to exercise regularly.

    Background

  These complications result in increased risk for ischemic heart disease, cerebral vascular disease, peripheral vascular disease with gangrene of lower limbs, chronic renal disease, reduced visual acuity and blindness, and autonomic and peripheral neuropathy. Diabetes is the major cause of blindness in adults aged 20-74 years, as well as the leading cause of nontraumatic lower-extremity amputation and ESRD.

  In both diabetic and non-diabetic patients, coronary vasodilator dysfunction is a strong independent predictor of cardiac mortality. In diabetic patients without coronary artery disease, those with impaired coronary flow reserve have event rates similar to those with prior coronary artery disease, while patients with preserved coronary flow reserve have event rates similar to non-diabetic patients. ^[56]

  A study by Bode et al indicated that among patients with coronavirus disease 2019 (COVID-19), the US in-hospital death rate for individuals living with diabetes, patients with an HbA_1c of 6.5% or higher, and those with hyperglycemia throughout their stay is 29%, a figure over four times greater than that for patients without diabetes or hyperglycemia. Moreover, the in-hospital death rate for patients with no evidence of preadmission diabetes who develop hyperglycemia while admitted was found to be seven times higher (42%). ^[57, 58]

  A whole-population study from the United Kingdom (UK) reported that the risk of in-hospital death for patients with COVID-19 was 2.0 times greater for those with type 2 diabetes and 3.5 times higher for individuals with type 1 diabetes. However, patients under age 40 years with either type of diabetes were at extremely low risk for death. ^[59, 60]

  A French study, by Wargny et al, indicated that among patients with diabetes who are hospitalized with COVID-19, approximately 20% will die within 28 days. Individuals particularly at risk for mortality over this 4-week period include patients of advanced age, as well as those with a history of microvascular complications (especially those who have had kidney or eye damage), who have dyspnea on admission or inflammatory markers (increased white blood cell [WBC] count, raised C-reactive protein, elevated aspartate transaminase), or who have undergone routine insulin and statin treatment. It should be kept in mind, however, that the data was gathered between March 10 and April 10, 2020, with a statement from Diabetes UK explaining that in people with diabetes, COVID-19–associated mortality has decreased over time as treatment has improved. ^[61, 62]

  Another study, by Barrera et al, looking at 65 observational reports (15,794 participants), found that among COVID-19 patients with diabetes, the unadjusted relative risk for admission to an intensive care unit (ICU) was 1.96, and for mortality, 2.78. ^[63, 64]

  Another study from the United Kingdom found that risk factors for mortality in COVID-19 patients with type 1 or type 2 diabetes include male sex, older age, renal impairment, non-White ethnicity, socioeconomic deprivation, and previous stroke and heart failure. Moreover, patients with type 1 or type 2 diabetes had a significantly greater mortality risk with an HbA_1c level of 86 mmol/mol or above, compared with persons with an HbA_1c level of 48-53 mmol/mol. In addition, an HbA_1c of 59 mmol/mol or higher in patients with type 2 diabetes increased the risk as well. The study also found that in both types of diabetes, body mass index (BMI) had a U-shaped relationship with death, the mortality risk being increased in lower BMI and higher BMI but being reduced between these (25.0-29.9 kg/m²). ^[65, 60]

  A literature review by Schlesinger et al strengthened the association between severe diabetes and COVID-19–related mortality, finding that among study patients with diabetes, the likelihood of death from COVID-19 was 75% greater in chronic insulin users. The study also indicated that the chance of death from COVID-19 is 50% less in individuals undergoing metformin therapy than in other patients with diabetes. The investigators suggested that the medications themselves did not impact survival but were indicators of the severity of diabetes in each group, with the prognosis being poorer among those with more severe diabetes. ^[66, 67]

  However, a Belgian study, by Vangoitsenhoven et al, indicated that in most people, the presence of type 1 diabetes mellitus is not associated with a greater risk of hospitalization for COVID-19. The investigators found that during the first 3 months of the pandemic in Belgium, the COVID-19 hospitalization rate was similar between individuals with type 1 diabetes and those without (0.21% vs 0.17%, respectively). Among the patients with type 1 diabetes, older persons had a greater tendency toward COVID-19–related hospitalization, although glucose control, comorbidity profile, and angiotensin-converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARB) therapy did not significantly differ between the hospitalized and non-hospitalized groups. This and other research suggest that in persons with type 1 diabetes, an increased risk of death from COVID-19 is found primarily in particularly vulnerable individuals instead of in such patients overall. ^[68, 69]

  A retrospective, multicenter study by Carrasco-Sánchez et al indicated that among noncritical patients with COVID-19, the presence of hyperglycemia on hospital admission independently predicts progression to critical status, as well as death, whether or not the patient has diabetes. The in-hospital mortality rate in persons with a blood glucose level of higher than 180 mg/dL was 41.1%, compared with 15.7% for those with a level below 140 mg/dL. Moreover, the need for ventilation and intensive care unit admission were also greater in the presence of hyperglycemia. The report involved over 11,000 patients with confirmed COVID-19, only about 19% of whom had diabetes. ^[70, 71]

  In contrast to the above study, a report by Klonoff et al on over 1500 US patients with COVID-19 found no association between hyperglycemia on hospital admission and mortality, in non-ICU patients. However, the in-hospital mortality rate was significantly greater in such patients if they had a blood glucose level above 13.88 mmol/L on the second or third hospital day, compared with those with a level below 7.77 mmol/L. Findings for patients admitted directly to the ICU differed from these, with the investigators determining that mortality was associated with the presence of hyperglycemia on admission but was not significantly linked with a high glucose level on the second hospital day. ^[72, 73]

  Type 1 diabetic patients also have a high prevalence of small-fiber neuropathy. ^[74, 75] In a prospective study of 27 patients who had type 1 diabetes with a mean disease duration of 40 years, almost 60% of the subjects showed signs or symptoms of neuropathy, including sensory neuropathy symptoms (9 patients), pain (3 patients), and carpal-tunnel symptoms (5 patients). ^[74, 75] Of the 27 patients, 22 were diagnosed with small-fiber dysfunction by means of quantitative sensory testing.

  Abnormal results on intraepidermal nerve-fiber density measurement (IENFD) were seen in 19 patients. ^[75] IENFD was negatively correlated with HbA_1c, but this relation was no longer significant after adjustment for age, body mass index, and height. N-ε-(carboxymethyl) lysine (CML), which is linked to painful diabetic neuropathy, remained independently associated with IENFD even after adjustment for these variables. Large-fiber neuropathy was also common, being found in 16 patients.

  Although ESRD is one of the most severe complications of type 1 DM, its incidence is relatively low: 2.2% at 20 years after diagnosis and 7.8% at 30 years after diagnosis. ^[76] A greater risk is that mild diabetic nephropathy in type 1 diabetic persons appears to be associated with an increased likelihood of cardiovascular disease. ^[77] Moreover, the long-term risk of an impaired glomerular filtration rate (GFR) is lower in persons treated with intense insulin therapy early in the course of disease than in those given conventional therapy. ^[78]

  Although mortality from early-onset type 1 DM (onset age, 0-14 y) has declined, the same may not be true for late-onset type 1 DM (onset age, 15-29 y). One study suggest that women tend to fare worse in both cohorts and that alcohol and drug use account for more than one third of deaths. ^[79]

  Control of blood glucose, hemoglobin A_1c (HbA_1c), lipids, blood pressure, and weight significantly affects prognosis. Excess weight gain with intensified diabetes treatment is associated with hypertension, insulin resistance, dyslipidemia and extensive atherosclerotic cardiovascular disease. ^[80]

  Patients with diabetes face a lifelong challenge to achieve and maintain blood glucose levels as close to the normal range as possible. With appropriate glycemic control, the risk of both microvascular and neuropathic complications is decreased markedly. In addition, aggressive treatment of hypertension and hyperlipidemia decreases the risk of macrovascular complications.

  A study by Zheng et al indicated that HbA_1c levels in persons with diabetes are longitudinally associated with long-term cognitive decline, as found using a mean 4.9 cognitive assessments of diabetes patients over a mean 8.1-year follow-up period. The investigators saw a significant link between each 1 mmol/mol rise in HbA_1c and an increased rate of decline in z scores for global cognition, memory, and executive function. Patients in the study had a mean age of 65.6 years. The report cited a need for research into whether optimal glucose control in people with diabetes can affect their cognitive decline rate. ^[81, 82]

  A study indicated that children with type 1 DM who have an HbA_1c level of 9% or above are at greater risk of mortality, intubation, and sepsis due to COVID-19 than are children without type 1 DM. However, the report also found evidence that such risk is not greater in children with an HbA_1c level at or below 7%. The investigators found the COVID-19 mortality rates in children without type 1 DM, those with type 1 DM, and those with type 1 DM with an HbA_1c of 7% or lower to be 0.047%, 0.328%, and 0%, respectively. ^[83]

  The benefits of glycemic control and control of comorbidities in type 1 DM must be weighed against the risk of hypoglycemia and the short-term costs of providing high-quality preventive care. However, studies have shown cost savings due to a reduction in acute diabetes-related complications within 1-3 years of starting

  Patient Education

  Education is a vital aspect of diabetes management. Patients with new-onset type 1 DM require extensive education if they are to manage their disease safely and effectively and to minimize long-term complications. Such education is best coordinated by the patient’s long-term care providers.

  At every encounter, the clinician should educate the patient—and, in the case of children, the parents—about the disease process, management, goals, and long-term complications. In particular, clinicians should do the following:

  • Make patients aware of the signs and symptoms of hypoglycemia and knowledgeable about ways to manage it

  • Help patients understand and acknowledge the course of diabetes (eg, by teaching patients that they have a chronic condition that requires lifestyle modification and that they are likely to have chronic complications if they do not take control of their disease)

  • Reassure patients about the prognosis in properly managed type 1 DM

  ADA guidelines urge that attention be paid to older adolescent patients who may be leaving their home and their current health care providers. At the transition between pediatric and adult health care, older teens can become detached from the health care system, putting their medical care and their glycemic control at risk. ^[5] The guidelines identify the National Diabetes Education Program (NDEP) as a source of materials that can help smooth the transition to adult health care.

  Education about an appropriate treatment plan and encouragement to follow the plan are especially important in patients with diabetes. Physicians must ensure that the care for each patient with diabetes includes all necessary laboratory tests, examinations (eg, foot and neurologic examinations), and referrals to specialists (eg, an ophthalmologist or podiatrist).

  A dietitian should provide specific diet control education to the patient and family. A nurse should educate the patient about self–insulin injection and performing fingerstick tests for blood glucose level monitoring.

  Physical Examination

  In new cases of diabetes, physical examination findings are usually normal. Patients with DKA, however, will have Kussmaul respiration, signs of dehydration, hypotension, and, in some cases, altered mental status.

  In established cases, patients should be examined every 3 months for macrovascular and microvascular complications. They should undergo funduscopic examination for retinopathy and monofilament testing for peripheral neuropathy.

  Diabetes-focused examination

  A diabetes-focused physical examination includes assessment of vital signs, funduscopic examination, limited vascular and neurologic examinations, and foot examination. Other organ systems should be assessed as indicated by the patient’s clinical situation. A comprehensive examination is not necessary at every visit.

  Assessment of vital signs

  Patients with established diabetes and autonomic neuropathy may have orthostatic hypotension. Orthostatic vital signs may be useful in assessing volume status and in suggesting the presence of an autonomic neuropathy. Measurement of the pulse is important, in that relative tachycardia is a typical finding in autonomic neuropathy, often preceding the development of orthostatic hypotension. If the respiratory rate and pattern suggest Kussmaul respiration, DKA must be considered immediately, and appropriate tests must be ordered.

  Funduscopic examination

  The funduscopic examination should include a careful view of the retina. Both the optic disc and the macula should be visualized. If hemorrhages or exudates are seen, the patient should be referred to an ophthalmologist as soon as possible. Examiners who are not ophthalmologists tend to underestimate the severity of retinopathy, which cannot be evaluated accurately unless the patients’ pupils are dilated.

  Foot examination

  The dorsalis pedis and posterior tibialis pulses should be palpated and their presence or absence noted. This is particularly important in patients who have foot infections: poor lower-extremity blood flow can delay healing and increase the risk of amputation.

  Documenting lower-extremity sensory neuropathy is useful in patients who present with foot ulcers because decreased sensation limits the patient’s ability to protect the feet and ankles. If peripheral neuropathy is found, the patient should be made aware that foot care (including daily foot examination) is very important for the prevention of foot ulcers and lower-extremity amputation. (See Diabetic Foot and Diabetic Foot Infections.)

  Complications

  Infections

  Infections cause considerable morbidity and mortality in patients with diabetes. Infection may precipitate metabolic derangements, and conversely, the metabolic derangements of diabetes may facilitate infection. (See Infections in Patients with Diabetes Mellitus.)

  Patients with long-standing diabetes tend to have microvascular and macrovascular disease with resultant poor tissue perfusion and increased risk of infection. The ability of the skin to act as a barrier to infection may be compromised when the diminished sensation of diabetic neuropathy results in unnoticed injury.

  Diabetes increases susceptibility to various types of infections. The most common sites are the skin and urinary tract. Dermatologic infections that occur with increased frequency in patients with diabetes include staphylococcal follicular skin infections, superficial fungal infections, cellulitis, erysipelas, and oral or genital candidal infections. Both lower urinary tract infections and acute pyelonephritis are seen with greater frequency.

  A few infections, such as malignant otitis externa, rhinocerebral mucormycosis, and emphysematous pyelonephritis, occur almost exclusively in patients with diabetes, though they are fairly rare even in this population. Infections such as staphylococcal sepsis occur more frequently and are more often fatal in patients with diabetes than in others. Infections such as pneumococcal pneumonia affect patients with diabetes and other patients with the same frequency and severity. ^[84]

  COVID-19

  A study reported that out of 178 adult patients hospitalized with coronavirus disease 2019 (COVID-19), at least one underlying condition was found in 89.3%, the most common being hypertension (49.7%), obesity (48.3%), chronic lung disease (34.6%), diabetes mellitus (28.3%), and cardiovascular disease (27.8%). ^[85]

  According to a report by Stokes et al, out of 287,320 US cases of COVID-19 in which the patient’s underlying health status was known, diabetes was the second most common underlying condition (30%), after cardiovascular disease (32%), which in this study included hypertension. ^[86, 87]

  The aforementioned study by Barrera et al found the overall prevalence of diabetes in patients with COVID-19 to be 12%, with the prevalence being 18% in severe COVID-19. ^[63, 64]

  In patients with type 1 DM who were diagnosed with COVID-19, a study by Ebekozien et al found that high blood glucose (48.5%), elevated temperature (45.5%), dry cough (39.4%), excess fatigue (33.3%), vomiting (33.3%), shortness of breath (30.3), nausea (30.2%), and body aches/headaches (21.2%) were the most prevalent presenting symptoms reported. Moreover, diabetic ketoacidosis was the most prevalent adverse outcome (45.5%) among these patients. ^[88, 89]

  The Centers for Disease Control and Prevention (CDC) includes type 2 DM in the list of conditions that increase the likelihood of severe illness in persons with COVID-19, and type 1 DM in the list of conditions that may increase this likelihood. ^[90]

  Ophthalmologic complications

  Diabetes can affect the lens, vitreous, and retina, causing visual symptoms that may prompt the patient to seek emergency care. Visual blurring may develop acutely as the lens changes shape with marked changes in blood glucose concentrations.

  This effect, which is caused by osmotic fluxes of water into and out of the lens, usually occurs as hyperglycemia increases, but it also may be seen when high glucose levels are lowered rapidly. In either case, recovery to baseline visual acuity can take up to a month, and some patients are almost completely unable to read small print or do close work during this period.

  Patients with diabetes tend to develop senile cataracts at a younger age than persons without diabetes. Rarely, patients with type 1 DM that is very poorly controlled (eg, those with frequent episodes of DKA) can acutely develop a “snowflake” (or “metabolic”) cataract. Named for their snowflake or flocculent appearance, these cataracts can progress rapidly and create total opacification of the lens within a few days.

  Whether diabetes increases the risk of glaucoma remains controversial; epidemiologic studies have yielded conflicting results. ^[91] Glaucoma in diabetes relates to the neovascularization of the iris (ie, rubeosis iridis diabetica).

  Diabetic retinopathy is the principal ophthalmologic complication of DM. (See Diabetic Retinopathy.) Diabetic retinopathy is the leading cause of blindness in the United States in people younger than 60 years and affects the eyes in the following different ways:

  • Background retinopathy involves retinal small vessel abnormality leading to hard exudates, hemorrhages, and microaneurysms; it does not affect acuity

  • Proliferative retinopathy involves extensive proliferation of new retinal small blood vessels; a sudden loss of vision can occur because of vitreous hemorrhage from proliferating new vessels or retinal detachment

  • Maculopathy involves edema and hard exudate or retinal ischemia; it causes a marked reduction of acuity

  Whether patients develop diabetic retinopathy depends on the duration of their diabetes and on the level of glycemic control. ^{[92, 93, 94]} The following are the 5 stages in the progression of diabetic retinopathy:

  1. Dilation of the retinal venules and formation of retinal capillary microaneurysms
  2. Increased vascular permeability
  3. Vascular occlusion and retinal ischemia
  4. Proliferation of new blood vessels on the surface of the retina
  5. Hemorrhage and contraction of the fibrovascular proliferation and the vitreous

  The first 2 stages of diabetic retinopathy are jointly referred to as background or nonproliferative retinopathy. Initially, the retinal venules dilate, then microaneurysms (tiny red dots on the retina that cause no visual impairment) appear. The microaneurysms or retinal capillaries become more permeable, and hard exudates appear, reflecting leakage of plasma.

  Rupture of intraretinal capillaries results in hemorrhage. If a superficial capillary ruptures, a flame-shaped hemorrhage appears. Hard exudates are often found in partial or complete rings (circinate pattern), which usually include multiple microaneurysms. These rings usually mark an area of edematous retina.

  The patient may not notice a change in visual acuity unless the center of the macula is involved. Macular edema can cause visual loss; therefore, all patients with suspected macular edema must be referred to an ophthalmologist for evaluation and possible laser therapy. Laser therapy is effective in decreasing macular edema and preserving vision but is less effective in restoring lost vision. (See Macular Edema in Diabetes .)

  Preproliferative (stage 3) and proliferative diabetic retinopathy (stages 4 and 5) are the next phases in the progression of the disease. Cotton-wool spots can be seen in preproliferative retinopathy. These represent retinal microinfarcts from capillary occlusion and appear as off-white to gray patches with poorly defined margins.

  Proliferative retinopathy is characterized by neovascularization, or the development of networks of fragile new vessels that often are seen on the optic disc or along the main vascular arcades. The vessels undergo cycles of proliferation and regression. During proliferation, fibrous adhesions develop between the vessels and the vitreous. Subsequent contraction of the adhesions can result in traction on the retina and retinal detachment. Contraction also tears the new vessels, which hemorrhage into the vitreous.

  Diabetic nephropathy

  About 20–30% of patients with type 1 DM develop evidence of nephropathy, ^[95] and all patients with diabetes should be considered to have the potential for renal impairment unless proven otherwise. Chronically elevated blood pressure contributes to the decline in renal function. The use of contrast media can precipitate acute renal failure in patients with underlying diabetic nephropathy. Although most recover from contrast medium–induced renal failure within 10 days, some have irreversible renal failure. (See Diabetic Nephropathy.)

  Diabetic neuropathy

  In the peripheral nerves, diabetes causes peripheral neuropathy. (See Diabetic Lumbosacral Plexopathy and Diabetic Neuropathy.) The 4 types of diabetic neuropathy are as follows:

  • Peripheral distal symmetrical polyneuropathy, predominantly sensory

  • Autonomic neuropathy

  • Proximal painful motor neuropathy

  • Cranial mononeuropathy (ie, cranial nerve III, IV, or VI)

  Of these 4 types, distal symmetric sensorimotor polyneuropathy (in a glove-and-stocking distribution) is the most common. ^[96] Besides causing pain in its early stages, this type of neuropathy eventually results in the loss of peripheral sensation. The combination of decreased sensation and peripheral arterial insufficiency often leads to foot ulceration and eventual amputation.

  Acute-onset mononeuropathies in diabetes include acute cranial mononeuropathies, mononeuropathy multiplex, focal lesions of the brachial or lumbosacral plexus, and radiculopathies. Of the cranial neuropathies, the third cranial nerve (oculomotor) is most commonly affected, followed by the sixth nerve (abducens) and the fourth nerve (trochlear).

  Patients can present with diplopia and eye pain. In diabetic third-nerve palsy, the pupil is usually spared, whereas in third-nerve palsy due to intracranial aneurysm or tumor, the pupil is affected in 80-90% of cases.

  It is important to consider nondiabetic causes of cranial nerve palsies, including intracranial tumors, aneurysms, and brainstem stroke. ^[97] Therefore, evaluation should include nonenhanced and contrast-enhanced compute4d tomography (CT) or, preferably, magnetic resonance imaging (MRI). Neurologic consultation is recommended. Acute cranial-nerve mononeuropathies usually resolve in 2-9 months. Acute thrombosis or ischemia of the blood vessels supplying the structure involved is thought to cause these neuropathies.

  Macrovascular complications

  People with diabetes experience accelerated atherosclerosis, affecting the small arteries of the heart, brain, lower extremity, and kidney. Coronary atherosclerosis often occurs at a younger age and is more severe and extensive than in those without diabetes, increasing the risk of ischemic heart disease. Atherosclerosis of the internal carotid and vertebrobasilar arteries and their branches predisposes to cerebral ischemia.

  Severe atherosclerosis of the iliofemoral and smaller arteries of the lower legs predisposes to gangrene. Ischemia of a single toe or ischemic areas on the heel are characteristic of diabetic peripheral vascular disease; these result from the involvement of much smaller and more peripheral arteries.

  Atherosclerosis of the main renal arteries and their intrarenal branches causes chronic nephron ischemia, which is a significant component of multiple renal lesions in diabetes. However, not all people with type 1 DM are at risk for nephropathy, because there are some polymorphisms in the various factors involved in its pathogenesis, which can modulate the course of this disease from one person to the other.

  Risk factors for macrovascular disease

  Macrovascular disease is the leading cause of death in patients with diabetes, causing 65-75% of deaths in this group, compared with approximately 35% of deaths in people without diabetes. Diabetes by itself increases the risk of myocardial infarction (MI) 2-fold in men and 4-fold in women, and many patients have other risk factors for MI as well.

  The HbA1c value per se, rather than self-reported diabetes status or other established risk factors, robustly predicts MI odds. Each 1% increment in HbA1c independently predicts 19% higher odds for MI. ^[98] The risk of stroke in people with diabetes is double that of nondiabetic people, and the risk of peripheral vascular disease is 4 times that of people without diabetes.

  Patients with diabetes may have an increased incidence of silent ischemia. ^[99] Diastolic dysfunction is common in patients with diabetes and should be considered in patients who have symptoms of congestive heart failure and a normal ejection fraction.

  Diagnostic Considerations

  The following conditions and factors should be taken into account in considering a diagnosis of type 1 diabetes mellitus (DM):

  • Type 2 DM

  • Monogenic DM, ^[100] previously known as maturity-onset diabetes of youth (MODY), a rare autosomal dominant condition found primarily in whites

  • Secondary hyperglycemia

  • Disorders of target tissues (liver, muscles, adipose tissue)

  • Endocrine disorders – Endocrine tumor causing increased production of growth hormone, glucocorticoids, catecholamines, glucagon, and somatostatin; Addison disease; Graves disease; Hashimoto thyroiditis; acanthosis nigricans (genetic disorders with insulin resistance)

  • Drugs – Thiazide diuretics, phenytoin, and glucocorticoids

  • Chronic pancreatitis

  • Cystic fibrosis

  • Prader-Willi syndrome – Intellectual disability, muscular hypotonia, obesity, short stature, and hypogonadism associated with DM

  • Nondiabetic glycosuria

  • Renal glycosuria – Glucose appears in urine despite normal glucose concentration in blood; this may occur because of an autosomal genetic disorder or dysfunction of the proximal renal tubule (eg, Fanconi syndrome or chronic renal failure), or it may occur during pregnancy as a consequence of the increased glucose load placed on tubules by the elevated glucose filtration rate

  • Peripheral neuropathy from alcohol abuse or vitamin B-12 deficiency

  Type 1 versus type 2 diabetes

  Determining whether a patient has type 1 or type 2 DM is an important diagnostic and therapeutic concern because patients with type 1 DM depend on continuous exogenous insulin for survival. A patient whose diabetes is controlled with diet or an oral antidiabetic agent clearly has type 2 DM. A lean patient who has had diabetes since childhood, who has always been dependent on insulin, or who has a history of diabetic ketoacidosis (DKA) almost certainly has type 1 DM.

  Distinguishing the type of diabetes can be difficult in (1) patients who are treated with insulin and who are younger but clinically appear to have type 2 DM and (2) older patients with late-onset diabetes who nonetheless take insulin and seem to share characteristics of patients with type 1 DM. (This latter group is now said to have latent autoimmune diabetes of the adult [LADA].) It should be noted that for many patients, it will not be possible to fully distinguish type 1 DM from type 2.

  When in doubt, treat the patient with insulin and close monitoring of glucose levels. It is not unusual for adolescents or young adults, particularly Hispanic or African-American patients, to present with DKA and subsequently be found to have type 2 DM.

  Monogenic diabetes

  Although monogenic diabetes syndromes are not very common, representing fewer than 5% of pediatric diabetes cases, it is important to avoid misdiagnosis of monogenic DM as type 1 or type 2 DM. The American Diabetes Association (ADA) advises considering a diagnosis of monogenic diabetes when the following criteria are present ^[5] :

  • Diabetes is diagnosed within 6 months of birth

  • A strong family history of diabetes is present, without type 2 features (eg, obesity or higher-risk ethnicity)

  • Mild fasting hyperglycemia is observed, especially in young, nonobese children

  • Diabetes is present, but islet cell autoantibodies, obesity, and insulin resistance are absent

  If a form of monogenic diabetes is suspected, it is increasingly feasible to obtain a true genetic diagnosis through commercially available genetic testing. For further information about the diagnosis and management of monogenic diabetes, the ADA suggests consulting the 2009 clinical practice consensus guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD) at the ISPAD website. ^[5, 101]

  Differential Diagnoses

  • Diabetic Ketoacidosis (DKA)

  • Diabetic Nephropathy

  • Diabetic Foot Ulcers

  • Insulin Resistance

  • Lead Nephropathy

  • Type 2 Diabetes Mellitus

    Laboratory Studies

    Plasma glucose

    Patients with type 1 diabetes mellitus (DM) typically present with symptoms of uncontrolled hyperglycemia (eg, polyuria, polydipsia, polyphagia). In such cases, the diagnosis of DM can be confirmed with a random (nonfasting) plasma glucose concentration of 200 mg/dL or a fasting plasma glucose concentration of 126 mg/dL (6.99 mmol/L) or higher. ^[2, 100]

    A fingerstick glucose test is appropriate in the emergency department (ED) for virtually all patients with diabetes. All fingerstick capillary glucose levels must be confirmed in serum or plasma to make the diagnosis. All other laboratory studies should be selected or omitted on the basis of the individual clinical situation. Intravenous (IV) glucose testing may be considered for possible early detection of subclinical diabetes.

    Individually measured glucose levels may differ considerably from estimated glucose averages calculated from measured hemoglobin A_1c (HbA_1c) levels. ^[102] Therefore, caution is urged when the decision is made to estimate rather than actually measure glucose concentration; the difference between the 2 has a potential impact on decision making.

    Hemoglobin A

    HbA_1c is the stable product of nonenzymatic irreversible glycation of the beta chain of hemoglobin by plasma glucose and is formed at rates that increase with increasing plasma glucose levels. HbA_1c levels provide an estimate of plasma glucose levels during the preceding 1-3 months. The reference range for nondiabetic people is 6% in most laboratories. Glycated hemoglobin levels also predict the progression of diabetic microvascular complications.

    American Diabetes Association (ADA) guidelines recommend measuring HbA_1c at least every 6 months in patients with diabetes who are meeting treatment goals and who have stable glycemic control. For patients whose therapy has changed or who are not meeting glycemic goals, the guidelines recommend HbA_1c testing every 3 months. ^[5]

    In the past, HbA_1c measurements were not considered useful for the diagnosis of DM. Drawbacks included a lack of international standardization and insensitivity for the detection of milder forms of glucose intolerance.

    In a 2009 report, however, an international expert committee appointed by the ADA, the European Association for the Study of Diabetes (EASD), and the International Diabetes Association recommended the HbA_1c assay for diagnosing type 1 and type 2 DM. ^[3] In the case of type 1 DM, however, the committee recommended using the test only when the condition is suspected but the classic symptoms of type 1 DM—polyuria, polydipsia, polyphagia, a random glucose level of 200 mg/dL, and unexplained weight loss—are absent.

    The committee noted the improvement in standardization and cited the following advantages of HbA_1c testing over glucose measurement:

    • Ability to capture long-term glucose exposure

    • Less biologic variability

    • No requirement for fasting or timed samples

    • Current use in guiding management decisions

    Consequently, since 2010 the ADA has included an HbA_1c level of 6.5% or higher as a criterion for diabetes diagnosis, with confirmation from repeat testing (unless clinical symptoms are present and the glucose level exceeds 200 mg/dL). HbA_1c testing cannot be used in patients with abnormal red blood cell (RBC) turnover (as in hemolytic or iron-deficiency anemia). In children with rapidly evolving type 1 DM, HbA_1c may not be significantly elevated despite frank diabetes. ^[2]

    One study found seasonal variability in HbA_1c levels of school-age children with higher levels (0.44%) coinciding with colder outdoor temperatures, fewer hours of sunlight, and lower levels of solar irradiance. ^[103] This effect was seen in school-aged children but not preschoolers and may hold importance for studies using HbA_1c as a primary endpoint and HbA_1c -based diagnosis of diabetes.

    HbA_1c cannot be used as an indicator of glycemic control in patients with neonatal diabetes mellitus (NDM) because of the high levels of fetal hemoglobin (HbF) remaining in the blood. A study by Suzuki et al found that glycated albumin, which is not affected by HbF levels, more strongly correlated with 1-month average postprandial blood glucose and was therefore a better marker of diabetes in neonates. This finding is important to neonatologist and those caring for newborns. ^[104]

    Moreover, the overall efficacy of HbA_1c testing in diabetes diagnosis remains uncertain. A study presented in 2019, using data derived from 9000 adults, reported diabetes diagnosis with the HbA_1c blood test to be unreliable. The investigators found evidence that in comparison with the oral glucose tolerance test, HbA_1c testing would lead to a 42% overdiagnosis of glucose tolerance and a 73% underdiagnosis of diabetes, in adults. ^[105]

    ADA guidelines recommend measuring HbA_1c at least every 6 months year in patients who are meeting treatment goals and who have stable glycemic control. For patients whose therapy has changed or who are not meeting glycemic goals, the guidelines recommend HbA_1c testing every 3 months. ^[5]

    Other laboratory studies

    Fructosamine levels also test for glucose levels. Fructosamine is formed by a chemical reaction of glucose with plasma protein and reflects glucose control in the previous 1-3 weeks. This assay, therefore, may show a change in control before HbA_1c and often is helpful when applying intensive treatment and in short-term clinical trials.

    A white blood cell (WBC) count and blood and urine cultures may be performed to rule out infection.

    Urine ketones are not reliable for diagnosing or monitoring diabetic ketoacidosis (DKA), although they may be useful in screening to see whether a hyperglycemic individual may have some degree of ketonemia. The plasma acetone level—specifically, the beta-hydroxybutyrate level—is a more reliable indicator of DKA, along with measurement of plasma bicarbonate or arterial pH as clinically required. (See the Medscape Reference Laboratory Medicine article Ketones.)

    Screening for type 1 DM in asymptomatic low-risk individuals is not recommended. ^[2] However, in patients at high risk (eg, those who have first-degree relatives with type 1 DM), it may be appropriate to perform annual screening for anti-islet antibodies before the age 10 years, along with 1 additional screening during adolescence. ^[4]

    Tests to Differentiate Type 1 from Type 2 Diabetes

    Although the oral glucose tolerance test with insulin levels is usually considered unnecessary for diagnosing type 1 DM, the dramatic increase of type 2 DM in the young suggests that assessment of insulin secretion may become more important. The 2011 American Association of Clinical Endocrinologists (AACE) guidelines note that to help distinguish between the 2 types in children, physicians should measure insulin and C-peptide levels and immune markers (eg, glutamic acid decarboxylase [GAD] autoantibodies), as well as obtain a detailed family history. ^[100]

    C-peptide is formed during conversion of proinsulin to insulin. An insulin or C-peptide level below 5 µU/mL (0.6 ng/mL) suggests type 1 DM; a fasting C-peptide level greater than 1 ng/dL in a patient who has had diabetes for more than 1-2 years is suggestive of type 2 (ie, residual beta-cell function). An exception is the individual with type 2 DM who presents with a very high glucose level (eg, >300 mg/dL) and a temporarily low insulin or C-peptide level but who will recover insulin production once normal glucose is restored.

    Most patients who present with undiagnosed type 1 DM have the classic symptoms of uncontrolled hyperglycemia, including polyuria, polydipsia, nocturia, fatigue, and weight loss. In these patients, a confirmatory random plasma glucose level of greater than 200 mg/dL is adequate to establish the diagnosis of DM. On occasion, a patient who is ultimately found to have type 1 DM presents with subtle symptoms because of residual insulin secretion.

    Islet-cell (IA2), anti-GAD65, and anti-insulin autoantibodies can be present in early type 1 but not type 2 DM. Measurements of IA2 autoantibodies within 6 months of diagnosis can help differentiate between type 1 and type 2 DM. These titers decrease after 6 months. Anti-GAD65 antibodies can be present at diagnosis of type 1 DM and are persistently positive over time. (See also Type 2 Diabetes Mellitus.)

    Testing for islet autoantibodies can substitute for expensive genetic testing in those patients suspected of having maturity-onset diabetes of the young (MODY). The prevalence of these antibodies is the same in patients with MODY as in the healthy population. A positive test for positive islet autoantibodies makes MODY highly unlikely. ^[106]

    ADA/EASD consensus statement

    A consensus statement published in 2021 by the ADA and the EASD provided an algorithm meant to aid in avoiding the misdiagnosis of adult-onset type 1 DM. In the algorithm, which was devised using data from White European populations, an islet autoantibody test is first carried out; if positive, type 1 diabetes is diagnosed. A negative test in a patient younger than 35 years and with no signs of type 2 diabetes means that C-peptide testing is advised. A C-peptide level below 200 pmol/L points to a diagnosis of type 1 diabetes, while a level above 200 pmol/L indicates that genetic testing for monogenic diabetes should be carried out. If signs of type 2 diabetes exist and/or the patient is over age 35 years, the individual most likely has type 2 diabetes. ^{[107, 108, 109, 110]}

    Approach Considerations

    Patients with type 1 diabetes mellitus (DM) require lifelong insulin therapy. Most require 2 or more injections of insulin daily, with doses adjusted on the basis of self-monitoring of blood glucose levels. Long-term management requires a multidisciplinary approach that includes physicians, nurses, dietitians, and selected specialists.

    In some patients, the onset of type 1 DM is marked by an episode of diabetic ketoacidosis (DKA) but is followed by a symptom-free “honeymoon period” in which the symptoms remit and the patient requires little or no insulin. This remission is caused by a partial return of endogenous insulin secretion, and it may last for several weeks or months (sometimes for as long as 1-2 years). Ultimately, however, the disease recurs, and patients require insulin therapy.

    Often, the patient with new-onset type 1 DM who presents with mild manifestations and who is judged to be compliant can begin insulin therapy as an outpatient. However, this approach requires close follow-up and the ability to provide immediate and thorough education about the use of insulin; the signs, symptoms, and treatment of hypoglycemia; and the need to self-monitor blood glucose levels.

    The American Diabetes Association (ADA) recommends using patient age as one consideration in the establishment of glycemic goals, with targets for preprandial, bedtime/overnight, and hemoglobin A_1c (HbA_1c) levels. ^[5] In 2014, the ADA released a position statement on the diagnosis and management of type 1 diabetes in all age groups. The statement includes a new pediatric glycemic control target of HbA1c of less than 7.5% across all pediatric age groups, replacing earlier guidelines that specified different glycemic control targets by age. The adult HbA1c target of less than 7% did not change. Individualized lower or higher targets may be used based on patient need. ^[111, 112]

    In addition to diagnosis and management, the new statement also covers screening for long-term complications, workplace management, diabetes in older patients, and diabetes in pregnancy, and recommends unimpeded access to glucose test strips for blood glucose testing and use of continuous glucose monitoring. ^[111, 112]

    Although patients with type 1 DM have normal incretin response to meals, administration of exogenous glucagonlike peptide 1 (GLP-1) reduces peak postprandial glucose by 45%. Long-term effects of exogenously administered GLP-1 analogues warrant further studies. ^[113]

    Pancreatic transplantation for patients with type 1 DM is a possibility in some referral centers. It is performed most commonly with simultaneous kidney transplantation for end-stage renal disease (ESRD).

    Transplantation of pancreatic islet cells into patients with type 1 DM, as a means of enabling these individuals to produce their own insulin, has been under investigation.

    Allogeneic pancreatic islet cellular therapy produced from deceased donor pancreatic cells received FDA approval in June 2023. The first treatment of its kind, donislecel (Lantidra) is indicated for adults with type 1 diabetes who, owing to current, repeated episodes of severe hypoglycemia, have been unable to approach target HbA1c, even with intensive diabetes management and education. It is meant for concomitant use with immunosuppression. ^[114]

    In two nonrandomized, single-arm studies that together evaluated the safety and effectiveness of donislecel in a total of 30 adults with type 1 diabetes and hypoglycemic unawareness, 21 participants needed no posttreatment insulin intake for at least a year. Eleven individuals required no insulin for 1-5 years, and 10 participants required none for more than 5 years. In five persons, no insulin independence was achieved. Patients received between one and three infusions of donislecel. ^[115]

    The American Diabetes Association’s Standards of Medical Care in Diabetes for type 1 and 2 diabetes highlight recommendations most relevant to primary care. ^[116] (See Guidelines.)

    The care of patients with type 1 diabetes mellitus is summarized below.

    Tight glycemic control

    The association between chronic hyperglycemia and increased risk of microvascular complications in patients with type 1 DM was demonstrated in the Diabetes Control and Complications Trial (DCCT). ^[117] In that trial, intensive therapy designed to maintain normal blood glucose levels greatly reduced the development and progression of retinopathy, microalbuminuria, proteinuria, and neuropathy, as assessed over 7 years.

    The DCCT ended in 1993. However, the Epidemiology of Diabetes Interventions and Complications Study (EDIC), an observational study that continues to follow the patients previously enrolled in the DCCT, has demonstrated continued benefit from intensive treatment. ^[118, 119]

    Benefits

    Benefits of tight glycemic control include not only continued reductions in the rates of microvascular complications but also significant differences in cardiovascular events and overall mortality. These benefits occurred even though subjects in the intensively treated group and those in the standard treatment group maintained similar HbA_1c levels (about 8%), starting 1 year after the DCCT ended. It is postulated that a “metabolic memory” exists and that better early glycemic control sets the stage for outcomes many years in the future.

    Increasing HbA_1c levels correlated with increasing risk of developing heart failure in a study of 20,985 patients with type 1 DM. Thus, improved glycemic control should prevent heart failure as well. ^[120]

    Risks

    For many patients, the HbA_1c target should be less than 7%, with a premeal blood glucose level of 80–130 mg/dL. However, targets should be individualized.

    Individuals with recurrent episodes of severe hypoglycemia, cardiovascular disease, advanced complications, substance abuse, or untreated mental illness may require higher targets, such as an HbA_1c of less than 8% and preprandial glucose levels of 100-150 mg/dL. The 2011 American Association of Clinical Endocrinologists (AACE) guidelines support the creation of individualized targets that consider these factors as part of a comprehensive treatment plan. ^[121]

    Although tight glycemic control is beneficial, an increased risk of severe hypoglycemia accompanies lower blood glucose levels. The 2011 AACE guidelines for developing a comprehensive care plan emphasize that hypoglycemia should be avoided. ^[100]

    In patients with type 1 DM, recurrent and chronic hypoglycemia has been linked to cognitive dysfunction. ^[122] This has important implications in the management of children with type 1 DM. ^[123]

    An 18-year follow-up of the DCCT by Jacobson et al found that HbA_1c levels and retinal and renal complications were independently linked to cognitive declines. No relation with macrovascular risk factors or severe hypoglycemic events was found. A smoking history was modestly associated with decrements in learning, memory, spatial information processing, and psychomotor efficiency. This information is useful in advising patients with type 1 DM interested in preserving cognitive function.

    Continuous Glucose Monitoring

    Continuous glucose monitors (CGMs) contain transcutaneous or subcutaneous sensors—depending on whether the devices are externally worn or fully implantable, respectively—that measure interstitial glucose levels every 1-5 minutes, providing alarms when glucose levels are too high or too low or are rapidly rising or falling. ^[124] CGMs transmit to a receiver, which either is a pagerlike device or is integral to an insulin pump. Looking at the continuous glucose graph and responding to the alarms can help patients avoid serious hyperglycemia or hypoglycemia.

    CGMs have several drawbacks. First, there is a lag between glucose levels in the interstitial space and levels in capillary blood, so that the levels recorded by the CGM may differ from a fingerstick (capillary) glucose reading. For that reason, the trends (ie, whether the glucose levels are rising or falling) tend to be more helpful.

    Second, patients may overtreat hyperglycemia (repeatedly giving insulin because the glucose levels do not fall rapidly enough—a phenomenon known as stacking), as well as overtreat low glucose levels (because the glucose levels rise slowly with ingestion of carbohydrate).

    Use of CGMs may help to prevent significant glucose variability in patients receiving either multiple daily injection therapy or continuous insulin infusion therapy. ^[125] Additionally, continuous glucose monitoring is associated with reduced time spent in hypoglycemia. ^[126] Whether glucose variability is detrimental in the absence of hypoglycemia remains an unresolved question; in any event, variability leads to the expense of frequent testing.

    Guidelines from the Endocrine Society ^[127] recommend the use of real-time CGMs in adult patients with type 1 DM who have demonstrated that they are able to use these devices on a nearly daily basis. The guidelines suggest the intermittent use of CGM systems for short-term retrospective analysis in the following cases ^[127] :

    • Patients with suspected nocturnal hypoglycemia, dawn phenomenon, or postprandial hyperglycemia

    • Patients with hypoglycemic unawareness

    • Patients experimenting with important changes to their diabetes regimen (eg, instituting new insulin or switching from multiple daily injections to pump therapy)

    The 2018 edition of the ADA’s Standards of Medical Care in Diabetes recommends that continuous glucose monitoring be used in all persons aged 18 years or older with type 1 DM (down from the previously recommended age of 25 years or above) in whom glycemic targets are unmet. ^[128]

    A study comparing the performance of three CGM devices—Navigator (Abbott Diabetes Care), Seven Plus (Dexcom), and Guardian (Medtronic)—found the Navigator to be the most accurate. ^[6, 7] For commercial reasons, however, this device is no longer on the market in the United States, though it remains available in Europe, Israel, Australia, and other areas; the other two CGM devices are still available in the United States.

    In September 2013, the US Food and Drug Administration (FDA) approved a sensor-augmented insulin pump system that includes an automated low-glucose suspend safety feature (Medtronic’s MiniMed 530G with Enlite) for use by patients aged 16 years and older with type 1 DM. ^[129, 130] When the continuous glucose sensor detects that blood sugar has fallen below a preset threshold (60-90 mg/dL) and the patient fails to respond to a first alarm, the pump automatically stops insulin delivery. The manufacturer indicates the Elite sensor is 31% more accurate than previous-generation sensors, as well as being 69% smaller and simpler to insert. ^[129, 130]

    In December 2016, Dexcom’s G5 Mobile Continuous Glucose Monitoring System became the first CGM to win FDA approval as a replacement for finger-stick testing for determination of insulin doses, although twice-daily finger-stick testing was still required for calibration. ^[131]

    In March 2018, the FDA approved Medtronic’s stand-alone CGM, Guardian Connect, which eschews use of a receiver and makes data viewable via a smartphone display alone. Receiving CGM data through its smartphone app, the device works with an artificial intelligence app to assess glucose level response to various factors, including an individual’s food intake, insulin dosages, and daily routines. The approval was made for patients with diabetes aged 14-75 years. ^[132]

    In June 2018, the FDA approved the Eversense Continuous Glucose Monitoring system (Senseonics), the first continuous glucose monitoring system with a fully implantable glucose sensor, for persons aged 18 years or older with diabetes. Using a fluorescence-based sensor that a physician implants subcutaneously in the patient’s upper arm (via an office procedure), the device has a transmitter that is worn above the sensor, with the CGM employing a mobile app to show glucose values and trends. In addition, the app alerts the patient to high and low glucose values, with the transmitter also emitting on-body vibration alerts. The device is intended for adjunctive use, with fingerstick monitoring and twice-daily calibrations required. The implant lasts for up to 3 months before needing replacement. ^[133, 134]

    Flash glucose monitoring

    Another technology, flash glucose monitoring, stores data in a wearable sensor that can be scanned for this information via a dedicated receiver or smartphone. ^[124] The FreeStyle Libre Flash Glucose Monitoring System (Abbott Diabetes Care), approved by the FDA in September 2017, allows patients to reduce the number of required finger-stick tests by measuring glucose levels using a self-applied sensor inserted into the back of the upper arm. ^[135]

    Artificial pancreas

    Closed-loop systems, also known as artificial pancreases, are in development for use in improving glycemic control in type 1 diabetes. These systems include a CGM that is in constant communication with an infusion pump, with a blood glucose device (eg, a glucose meter) utilized for CGM calibration. An external processor, such as a cell phone, runs control algorithm software, receiving data from the CGM. The data is used to perform a series of calculations, producing dosing instructions that are sent to the infusion pump. ^[136]

    The artificial pancreases are being developed to administer either insulin or glucagon or a combination of the two agents. ^[137] A 1-month study in 20 patients indicated that, with regard to keeping blood glucose levels in the target range over a 24-hour period, round-the-clock use of closed-loop glucose control is more effective than use of a patient-controlled sensor-augmented pump. ^[138, 139]

    In September 2016, the FDA approved the first artificial pancreas, Medtronic’s MiniMed 670G, for persons aged 14 years or older with type 1 diabetes. A hybrid closed-loop system, it still requires patients to determine the number of carbohydrates in their food and input that data into the system, manually requesting the insulin dose needed for meals. ^[140]  In June 2018, the FDA extended the MiniMed 670G’s approval to children aged 7-13 years with type 1 diabetes. ^[141]

    In 2020, the FDA approved Medtronic’s MiniMed 770G, a Bluetooth-enabled, hybrid closed-loop device, for use in children aged 2-6 years. ^[142]

    Insulin Therapy

    Types of insulin

    Rapid-, short-, intermediate-, and long-acting insulin preparations are available. Various pork, beef, and beef-pork insulins were previously used; however, in the United States, recombinant human insulin is now used almost exclusively. Commercially prepared mixtures of insulin are also available.

    Rapid-acting insulins include lispro, glulisine, and aspart insulin. Lispro insulin is a form of regular insulin that is genetically engineered with the reversal of the amino acids lysine and proline at B28,29 in the B chain. Glulisine insulin substitutes glutamic acid for lysine in position B29. Aspart insulin substitutes aspartic acid for proline in position 28 of the B chain.

    These insulins are absorbed more quickly and have a rapid onset of action (5-10 minutes), a short interval to peak action (45-75 minutes), and a short duration of action (2-4 hours). Therefore, they can be administered shortly before eating. In addition, neutral protamine Hagedorn (NPH) insulin will not inhibit the action of insulin lispro when the 2 agents are mixed together right before injection; this is not true of regular insulin.

    A rapid-acting inhaled insulin powder (Afrezza) for types 1 and 2 diabetes mellitus was approved by the FDA in June 2014. It is regular insulin but is considered rapid-acting because it peaks at 12-15 minutes and returns to baseline levels at about 160 minutes. Approval was based on a study involving over 3,000 patients over a 24-week period. In persons with type 1 diabetes, the inhaled insulin was found to be noninferior to standard injectable insulin when used in conjunction with basal insulin at reducing hemoglobin A1c. In persons with type 2 diabetes, the inhaled insulin was compared to placebo inhalation in combination with oral diabetic agents and showed a statistically significant lower hemoglobin A1c. ^[143, 144]

    Short-acting insulin includes regular insulin. Regular insulin is a preparation of zinc insulin crystals in solution. When it is administered subcutaneously, its onset of action occurs in 0.5 hours, its peak activity comes at 2.5-5 hours, and its duration of action is 4-12 hours.

    The standard strength of regular insulin is 100 U/mL (U-100), but 500 U/mL (U-500) insulin is increasingly used, albeit mostly in type 2 DM. Accidental prescribing of U-500 rather than U-100 is a potential safety issue. ^[145] A study by de la Pena et al found that although the overall insulin exposure and effects of 500 U/mL insulin are similar to those of 100 U/mL insulin, peak concentration was significantly lower with U-500, and the effect after the peak was prolonged; areas under the curve were similar for the 2 strengths. ^[146]

    Both regular human insulin and rapid-acting insulin analogues are effective at lowering postprandial hyperglycemia in various basal bolus insulin regimens used in type 1 DM. Rapid-acting insulin analogues may be slightly better at lowering HbA_1c and are preferred by most US diabetologists, but the differences are clinically insignificant. ^[147]

    In September 2017, the FDA approved the rapid-acting insulin aspart Fiasp for the treatment of adults with diabetes. This human insulin analog is formulated with niacinamide, which aids in speeding the initial absorption of insulin. Dosing can occur at the beginning of a meal or within 20 minutes after the meal commences. In a study of adult patients with type 1 DM, Fiasp could be detected in the circulation about 2.5 minutes after it was administered. Maximum insulin levels occurred approximately 63 minutes after the drug’s administration. ^[148, 149]

    Semilente insulin is like regular insulin and is a rapid-acting insulin with a slightly slower onset of action. It contains zinc insulin microcrystals in an acetate buffer. It is not readily available in the United States.

    Intermediate-acting insulins include NPH insulin, a crystalline suspension of human insulin with protamine and zinc. NPH provides a slower onset of action and longer duration of action than regular insulin does. The onset of action usually occurs at 1-2 hours, the peak effect is noted at 4-12 hours, and the duration of action is normally 14–24 hours.

    Lente insulin is a suspension of insulin in buffered water that is modified by the addition of zinc chloride. This insulin zinc suspension is equivalent to a mixture of 30% prompt insulin zinc (Semilente) and 70% extended insulin zinc (Ultralente). It is not used in the United States.

    Long-acting insulins used in the United States include insulin glargine (Lantus, Toujeo) and insulin detemir (Levemir). Insulin glargine has no peak and produces a relatively stable level lasting more than 24 hours. In some cases, it can produce a stable basal serum insulin concentration with a single daily injection, though patients requiring lower doses typically are given twice-daily injections. Insulin detemir has a duration of action that may be substantially shorter than that of insulin glargine but longer than those of intermediate-acting insulins.

    Toujeo 300 U/mL is a newer dosage strength and form of insulin glargine than Lantus 100 U/mL, having been approved by the FDA in February 2016. Compared with those of Lantus 100 U/mL, the pharmacokinetic and pharmacodynamic profiles of Toujeo are more stable and prolonged; the duration of action exceeds 24 hours. Clinical trials showed comparable glycemic control between Lantus and Toujeo, although the trials noted the need for higher daily basal insulin doses (ie, 12-17.5%) with Toujeo. The risk for nocturnal hypoglycemia was lower with Toujeo in insulin-experienced patients with type 2 diabetes, but this was not the case for insulin-naïve patients with type 1 DM or for patients with type 2 DM. ^[150]

    With its March 2018 approval by the FDA, Toujeo Max SoloStar became the highest capacity long-acting insulin pen on the market. Toujeo Max necessitates fewer refills and, for some diabetes patients, fewer injections to deliver the required Toujeo dosage. ^[151]

    A new ultralong-acting basal insulin, insulin degludec (Tresiba), which has a duration of action beyond 42 hours, has also been approved by the FDA. It is indicated for diabetes mellitus types 1 and 2. A combination product of insulin degludec and the rapid-acting insulin aspart was also approved (Ryzodeg 70/30). Approval was based on results from the BEGIN trial ^{[152, 153, 154]} that showed noninferiority to comparator productions. The cardiovascular outcomes trial (DEVOTE) comparing cardiovascular safety of insulin degludec to that of insulin glargine in patients with type 2 DM is ongoing.

    Mixtures of insulin preparations with different onsets and durations of action frequently are administered in a single injection by drawing measured doses of 2 preparations into the same syringe immediately before use. The exceptions are insulin glargine and insulin detemir, which should not be mixed with any other form of insulin. Preparations that contain a mixture of 70% NPH and 30% regular human insulin (eg, Novolin 70/30, Humulin 70/30, Ryzodeg 70/30) are available, but the fixed ratios of intermediate-acting or long-acting to rapid-acting insulin may restrict their use.

    An ultrafast-acting insulin aspart formulation for mealtimes (Fiasp), for adult patients with type 1 or 2 DM, was approved in January 2017 for use in Canada and the Europe Union. The drug contains conventional mealtime insulin aspart in combination with two ingredients—vitamin B₃ and the amino acid L-arginine—that are meant to allow faster insulin absorption so the medication can better mimic natural physiologic insulin. Unlike in the European Union, however, the new formulation is not approved for insulin pumps in Canada. The product has not yet been approved for use in the United States. ^[155]

    Insulin glargine and cancer

    Controversy has arisen over a disputed link between insulin glargine and cancer. On July 1, 2009, the FDA issued an early communication regarding a possible increased risk of cancer in patients using insulin glargine (Lantus). ^[156] The FDA communication was based on 4 observational studies that evaluated large patient databases and found some association between insulin glargine (and other insulin products) and various types of cancer.

    The validity of the link remains in question, however. The duration of these observational studies was shorter than that considered necessary to evaluate for drug-related cancers. Additionally, findings were inconsistent within and across the studies, and patient characteristics differed across treatment groups.

    In a study by Suissa et al, insulin glargine use was not associated with an increased risk of breast cancer during the first 5 years of use. The risk tended to increase after 5 years, however, and significantly so for the women who had taken other forms of insulin before starting insulin glargine. ^[157]

    A study by Johnson et al found the same incidences for all cancers in patients receiving insulin glargine as in those not receiving insulin glargine. Overall, no increase in breast cancer rates was associated with insulin glargine use, although patients who used only insulin glargine had a higher rate of cancer than those who used another type of insulin. This finding was attributed to allocation bias and differences in baseline characteristics. ^[158]

    Common insulin regimens

    The goal of treatment in type 1 DM is to provide insulin in as physiologic a manner as possible. Insulin replacement is accomplished by giving a basal insulin and a preprandial (premeal) insulin. The basal insulin is either long-acting (glargine or detemir) or intermediate-acting (NPH). The preprandial insulin is either rapid-acting (lispro, aspart, or glulisine) or short-acting (regular). Currently, NPH insulin is being used less frequently, whereas insulin glargine and insulin detemir are being used more frequently.

    For patients on intensive insulin regimens (multiple daily injections or insulin pumps), the preprandial dose is based on the carbohydrate content of the meal (the carbohydrate ratio) plus a correction dose if their blood glucose level is elevated (eg, an additional 2 U of rapid-acting insulin to correct the blood glucose from a level of 200 mg/dL to a target of 100 mg/dL). This method allows patients more flexibility in caloric intake and activity, but it requires more blood glucose monitoring and closer attention to the control of their diabetes.

    Common insulin regimens include the following:

    • Split or mixed – NPH with rapid-acting (eg, lispro, aspart, or glulisine) or regular insulin before breakfast and supper

    • Split or mixed variant – NPH with rapid-acting or regular insulin before breakfast, rapid-acting or regular insulin before supper, and NPH before bedtime (the idea is to reduce fasting hypoglycemia by giving the NPH later in the evening)

    • Multiple daily injections (MDI) – A long-acting insulin (eg, glargine or detemir) once a day in the morning or evening (or twice a day in about 20% of patients) and a rapid-acting insulin before meals or snacks (with the dose adjusted according to the carbohydrate intake and the blood glucose level)

    • Continuous subcutaneous insulin infusion (CSII) – Rapid-acting insulin infused continuously 24 hours a day through an insulin pump at 1 or more basal rates, with additional boluses given before each meal and correction doses administered if blood glucose levels exceed target levels

    Insulin is sensitive to heat and exposure to oxygen. Once a bottle of insulin is open, it should be used for no more than 28 days and then discarded; even if there is still some insulin in the bottle, it may have lost its clinical effectiveness. Insulin kept in a pump reservoir for longer than 3 days may lose its clinical effectiveness (though insulin aspart has now been approved for use for as long as 6 days in a pump).

    Sometimes, insulin distributed from the pharmacy has been exposed to heat or other environmental factors and therefore may be less active. If a patient is experiencing unexplained high blood sugar levels, new insulin vials should be opened and used.

    Initiation of insulin therapy

    The initial daily insulin dose is calculated on the basis of the patient’s weight. This dose is usually divided so that one half is administered before breakfast, one fourth before dinner, and one fourth at bedtime. After selecting the initial dose, adjust the amounts, types, and timing according to the plasma glucose levels. Adjust the dose to maintain preprandial plasma glucose at 80-150 mg/dL (ie, 4.44-8.33 mmol/L).

    The insulin dose is often adjusted in increments of 10% at a time, and the effects are assessed over about 3 days before any further changes are made. More frequent adjustments of regular insulin can be made if a risk of hypoglycemia is present.

    Carbohydrate counting may be used to determine the meal-time insulin dose. Because patients may experience hyperglycemic episodes despite strict adherence to carbohydrate counting, particularly after meals that are high in protein or fat, Australian researchers developed an algorithm for estimating the mealtime insulin dose on the basis of measurements of physiologic insulin demand evoked by foods in healthy adults. The researchers showed that use of this algorithm improved glycemic control. ^[159]

    Initiation of insulin therapy in children

    Children with moderate hyperglycemia but without ketonuria or acidosis may be started with a single daily subcutaneous injection of 0.3-0.5 U/kg of intermediate-acting insulin alone. Children with hyperglycemia and ketonuria but without acidosis or dehydration may be started on 0.5-0.7 U/kg of intermediate-acting insulin and subcutaneous injections of 0.1 U/kg of regular insulin at 4- to 6-hour intervals.

    Multiple daily injections

    Multiple subcutaneous insulin injections are administered to control hyperglycemia after meals and to maintain normal plasma glucose levels throughout the day. This may increase the risks of hypoglycemia. Therefore, patients should be well educated about their disease and about self-monitoring of plasma glucose levels.

    About 25% of the total daily dose is administered as intermediate-acting insulin at bedtime, with additional doses of rapid-acting insulin before each meal (4-dose regimen). Where available, a basal insulin such as glargine or detemir is preferred to NPH. These patients may need additional intermediate- or long-acting insulin in the morning for all-day coverage.

    Patients should adjust their daily dosage(s) on the basis of their self-monitoring of glucose levels before each meal and at bedtime. Patients should also assess their plasma glucose levels at 2:00-4:00 AM at least once per week during the first few weeks of treatment and thereafter as indicated.

    Continuous subcutaneous insulin infusion

    A small battery-operated infusion pump that administers a continuous subcutaneous infusion of rapid-acting insulin can provide selected, programmed basal rate(s) of insulin and a manually administered bolus dose before each meal. The patient self-monitors preprandial glucose levels to adjust the bolus dose(s).

    The CSII method provides better control than the MDI method does. Initially, hypoglycemia is common with pump therapy, but once metabolic control is achieved, the risk is the same as with MDI. Bergenstal et al determined that sensor-augmented pump therapy led to better glycemic control and that more patients reached targets with this technology than with injection therapy. ^[160]

    An Australian observational case-control study involving 690 children with type 1 diabetes found that CSII, in comparison with insulin injection therapy, yielded a long-term improvement in glycemic control, as well as a reduction in complications such as severe hypoglycemia and hospitalization for diabetic ketoacidosis (DKA). ^[161, 162] HbA_1c improvement remained significant in the pump therapy cohort throughout 7 years of follow-up.

    The rate of severe hypoglycemic events per 100 patient-years dropped from 14.7 to 7.2 with pump therapy but jumped from 6.8 to 10.2 events per 100 patient-years with injection therapy. ^[161, 162] Hospitalization rates for DKA were lower in children receiving pump therapy (2.3 per 100 patient-years) compared with those receiving injection therapy (4.7 per 100 patient-years) over 1160 patient-years of follow-up.

    Increased bedtime doses of hypoglycemic agents with nighttime peaks in action may correct early morning hyperglycemia but may be associated with undesirable nocturnal hypoglycemia. Targeted CSII programming can facilitate the prevention of early-morning hyperglycemia in selected patients.

    Changes in altitude may affect delivery from insulin pumps. During the flight of a commercial airliner (200 mm Hg pressure decrease), excess insulin delivery of 0.623% of cartridge volume was demonstrated as a result of bubble formation and expansion of preexisting bubbles. ^[163]

    The American Association of Clinical Endocrinologists and American College of Endocrinology released a consensus statement on insulin pump management: ^[164]

    • Based on currently available data, continuous subcutaneous insulin infusion (CSII) is justified for basal-bolus insulin therapy in patients with type 1 diabetes mellitus.

    • Only providers whose practice can assume full responsibility for a comprehensive pump management program should offer this technology.

    • The ideal CSII candidate is a patient with type 1 diabetes mellitus or intensively management insulin-dependent type 2 diabetes mellitus who is currently performing 4 or more insulin injections and 4 or more self-monitored blood glucose measurements daily; is motivated to achieve optima blood glucose control; is willing and able to carry out the tasks that are required to use this complex and time-consuming therapy safely and effectively; and is willing to maintain frequent contact with their health care team.

    • Adult patients

      • At CSII initiation, the patient should have daily contact with the pump trainer. a return visit with the endocrinologist/diabetologist/advanced practice nurse is advised within 3-7 days after CSII initiation.
      • Educational consults should be scheduled weekly or biweekly at first, then periodically as needed.
      • Specialist follow-up visits should be scheduled at least monthly until the pump regimen is stabilized, then at least once every 3 mo.

    • Pediatric patients

      • CSII is indicated for pediatric patients with elevated hemoglobin A1C (HbA1C) levels on injection therapy; frequent, severe hypoglycemia; widely fluctuating glucose levels; a treatment regimen that compromises lifestyle; and microvascular complications and/or risk factors for macrovascular complications.
      • Ideal pediatric candidates are those with motivated families who are committed to monitoring blood glucose 4 or more times per day and have a working understanding of basic diabetes management.
      • Patient age and duration of diabetes should not be factors in determining the transition from injections to CSII.

    Local allergic reactions

    Generalized insulin allergy is rare. Symptoms occur immediately after the injection and include urticaria, angioedema, pruritus, bronchospasm, and, rarely, circulatory shock. As a rule, allergy may be treated with antihistamines. Some cases may require epinephrine and intravenous (IV) steroids.

    Local allergic reactions can occur at the site of insulin injections and can cause pain, burning, local erythema, pruritus, and induration. These complications are less common with the human insulins now in use than with the animal insulins once widely employed. Such reactions usually resolve spontaneously without any intervention.

    Local fat atrophy or hypertrophy at injection sites was common with animal insulins but is rare with human insulin and insulin analogues. Patients do not require any specific treatment of local fat hypertrophy, but injection sites should be rotated. Changing to a different insulin preparation may be necessary. ^[165]

    Management of Hypoglycemia

    Hypoglycemia may result from a change in insulin dose, a small or missed meal, or strenuous exercise. Regular insulin doses may cause hypoglycemia if the patient becomes anorectic or has another cause for reduced food intake, has gastroparesis, or is vomiting.

    Common symptoms of hypoglycemia are light-headedness, dizziness, confusion, shakiness, sweating, and headache. Patients should be made aware of these symptoms and educated to respond rapidly with sugar intake. They should be advised to carry candy or sugar cubes. Family members can be taught to administer a subcutaneous injection of glucagon. In an emergency situation, initial treatment consists of a bolus injection of 25 mL of 50% glucose solution followed by a continuous glucose infusion.

    Repeated hypoglycemia may be an aggravating factor in preclinical atherosclerosis. Thus, in the process of designing treatment plans aimed at reducing the glycemic burden and minimizing vascular complications, hypoglycemic episodes might negate some benefits. ^[166]

    Controversy surrounds the question of whether severe hypoglycemia in youths with type 1 DM has lasting cognitive consequences. In a follow-up to the DCCT, recurrent and chronic hypoglycemia was linked to cognitive dysfunction. ^[122] In another study, however, electroencephalography (EEG) and cognition studies were performed at baseline and 16 years later in patients with type 1 DM, and no association between early severe hypoglycemia and subsequent reduced adult cognition or EEG changes was found. ^[167]

    Management of Hyperglycemia

    Acute hyperglycemia, even when not associated with DKA (or hyperosmolar hyperglycemic state [HHS], which occurs most commonly in type 2 DM), is harmful for a number of reasons. If the blood glucose level exceeds the renal threshold for glucose (which is typically 240 mg/dL in a healthy person but is lower in older patients, those with renal insufficiency, and pregnant women), an osmotic diuresis ensues, with loss of glucose, electrolytes, and water.

    In addition, hyperglycemia impairs leukocyte function through a variety of mechanisms. Patients with diabetes have an increased rate of wound infection, and hyperglycemia impairs wound healing.

    In patients with known, poorly controlled type 1 DM, no absolute level of blood glucose elevation mandates admission to the hospital or administration of insulin in the emergency department (ED). In general, lowering the patient’s glucose level in the ED does not correct the underlying cause and has no long-term effect on the patient’s glucose levels. Therefore, a plan for lowering and monitoring the patient’s glucose levels is needed.

    Adequacy of follow-up is extremely important. Whether insulin is given in the ED is of less consequence and can be decided on an individual basis.

    Patients with type 1 DM can have coexisting illnesses that aggravate hyperglycemia, such as infection, coronary artery disease (CAD), or fever. Additionally, certain medications can aggravate the condition.

    Diabetic ketoacidosis

    DKA involves acute metabolic changes in the body that develop as a result of lack of insulin or poor response to insulin arising from stress or illness. DKA is characterized by hyperglycemia, ketosis, and acidosis, leading to osmotic diuresis and dehydration. Volume repletion, insulin therapy, and specific metabolic corrections are the keys to treatment of DKA. (See Diabetic Ketoacidosis.)

    Dawn and Somogyi phenomena

    The dawn phenomenon is the normal tendency of the blood glucose to rise in the early morning before breakfast. This rise, which may result from the nocturnal spikes in growth hormone that cause insulin resistance, is probably enhanced by increased hepatic gluconeogenesis secondary to the diurnal rise in serum cortisol.

    Augmented hepatic gluconeogenesis and glycogen cycling are known to occur in patients with type 1 DM. However, both abnormalities, regardless of the duration of diabetes, can be corrected with intensified insulin therapy. ^[168]

    In some patients, however, nocturnal hypoglycemia may be followed by a marked increase in fasting plasma glucose with an increase in plasma ketones (the Somogyi phenomenon). Thus, both the dawn phenomenon and the Somogyi phenomenon are characterized by morning hyperglycemia, but the latter is considered to be rebound (counterregulation) hyperglycemia.

    The existence of a true Somogyi phenomenon is a matter of debate. Most endocrinologists now believe this phenomenon reflects waning of insulin action with consequent hyperglycemia.

    In cases of the dawn phenomenon, the patient should check blood glucose levels at 2:00-4:00 AM. The dawn and Somogyi phenomena can be ameliorated by administering intermediate insulin at bedtime.

    Use of insulin

    The insulin coverage, with a sliding scale for insulin administration, should not be the only intervention for correcting hyperglycemia, because it is reactive rather than proactive. Also, insulin may be used inappropriately when hyperglycemia reflects hepatic gluconeogenesis in response to previously uncorrected hypoglycemia.

    Continue intermediate-acting (ie, NPH or Lente) insulin at 50-70% of the daily dose divided into 2 or, occasionally, 3-4 daily doses. Administer supplemental regular insulin on a sliding scale. Blood glucose should be monitored before meals and at bedtime.

    Diet

    One of the first steps in managing type 1 DM is diet control. According to ADA policy, dietary treatment is based upon nutritional assessment and treatment goals. Dietary recommendations should take into account the patient’s eating habits and lifestyle. For example, patients who participate in Ramadan may be at higher risk of acute diabetic complications. Although these patients do not eat during the annual observance, they should be encouraged to actively monitor their glucose, alter the dosage and timing of their medication, and seek dietary counseling and patient education to counteract these complications. ^[169]

    Diet management includes education about how to adjust the timing, size, frequency, and composition of meals so as to avoid hypoglycemia or postprandial hyperglycemia. All patients on insulin should have a comprehensive diet plan, created with the help of a professional dietitian, that includes the following:

    • A daily caloric intake prescription

    • Recommendations for amounts of dietary carbohydrate, fat, and protein

    • Instructions on how to divide calories between meals and snacks

    Caloric distribution is an important aspect of dietary planning in these patients. A recommended distribution consists of 20% of daily calories for breakfast, 35% for lunch, 30% for dinner, and 15% for a late-evening snack.

    The minimum protein requirement for good nutrition is 0.9 g/kg/day (usual range, 1-1.5 g/kg/day), but a reduced protein intake is indicated in cases of nephropathy. Fat intake should be limited to no more than 30% of the total calories, and a low-cholesterol diet is recommended. Patients should minimize consumption of sugars and ensure that they have adequate fiber intake. In some cases, midmorning and midafternoon snacks are important to avoid hypoglycemia.

    Activity

    Exercise is an important aspect of diabetes management. Patients should be encouraged to exercise regularly.

    Educate the patients about the effects of exercise on the blood glucose level. If patients participate in rigorous exercise for more than 30 minutes, they may develop hypoglycemia unless they either decrease the preceding insulin injection by 10-20% or have an extra snack. Patients must also make sure to maintain their hydration status during exercise.

    Management of Complications

    Infections

    Diabetes predisposes patients to a number of infectious diseases (see Infections in Patients with Diabetes Mellitus). These include the following:

    • Malignant otitis externa

    • Rhinocerebral mucormycosis

    • Bacteriuria

    • Pyuria

    • Cystitis

    • Upper urinary tract infection

    • Intrarenal bacterial infection

    • Skin and soft tissue infections

    • Osteomyelitis

    Ophthalmologic complications

    Patients with preproliferative or proliferative retinopathy must immediately be referred for ophthalmologic evaluation. Laser therapy is effective in this condition, especially if it is provided before hemorrhage occurs.

    Often, the first hemorrhage is small and is noted by the patient as a fleeting dark area (or “floater”) in the field of vision. Because subsequent hemorrhages can be larger and more serious, the patient should immediately be referred to an ophthalmologist for possible laser therapy. Patients with retinal hemorrhage should be advised to limit their activity and keep their head upright (even while sleeping), so that the blood settles to the inferior portion of the retina and thus obscures less of the central visual area.

    Multifactorial intervention is important for slowing the progression of diabetic retinopathy. Metabolic control, smoking cessation, and blood pressure control are all protective. Patients with active proliferative diabetic retinopathy are at increased risk for retinal hemorrhage if they receive thrombolytic therapy; therefore, this condition is a relative contraindication to the use of thrombolytic agents. (See Diabetic Retinopathy and Macular Edema in Diabetes.)

    Diabetic nephropathy

    Extreme care should be exercised whenever any nephrotoxic agent is used in a patient with diabetes. Potentially nephrotoxic drugs should be avoided whenever possible. Renally excreted or potentially nephrotoxic drugs should be given at reduced doses appropriate to the patient’s serum creatinine level. (See Diabetic Nephropathy.)

    In particular, caution should be exercised when contrast-enhanced radiologic studies are being considered in patients with diabetes who have a creatinine level higher than 2 mg/dL. Indeed, such studies should absolutely be avoided in patients with a creatinine level higher than 3 mg/dL.

    Patients with diabetes who must undergo such studies should be well hydrated before, during, and after the study, and their renal function should be carefully monitored. ^[170] A better solution is to seek equivalent clinical information by using an alternative modality that does not require the use of contrast material (eg, ultrasonography, noncontrast computed tomography [CT], or magnetic resonance imaging [MRI]).

    Current ADA guidelines recommend annual screening for nephropathy. ^[5] All adults with diabetes should have serum creatinine measured at least annually. In adults (and children aged 10 years or older) who have had type 1 DM for 5 or more years, annual assessment of urine albumin excretion is appropriate.

    Microalbuminuria and macroalbuminuria are not permanent features in most diabetic children and adolescents. ^[171] Regression of microalbuminuria is common; female gender, absence of retinopathy, better glucose control, lower blood pressure, and better lipid control favor this outcome. ^[172] In patients with persistent microalbuminuria, the use of angiotensin-converting enzyme (ACE) inhibitors and good metabolic control can usually induce remission.

    Progression and regression of kidney disease are common even after development of persistent microalbuminuria. Tight glycemic control, lower blood pressure, and a favorable lipid profile are associated with improved outcome. ^[172]

    When chronic kidney disease is present, reduction of protein intake may improve renal function. If kidney disease is advanced or difficult to manage or its etiology is unclear, consider referral to a physician with experience in kidney disease patient care.

    Control of blood pressure is a critical element of care. An ACE inhibitor or an angiotensin II receptor blocker (ARB) should be used because these classes of agents decrease proteinuria and slow the decline in renal function independent of the effect on blood pressure. ^[173] ACE inhibitors and ARBs tend to increase the serum potassium levels and therefore should be used with caution in patients with renal insufficiency or elevated serum potassium levels.

    Diabetic neuropathy

    Autonomic dysfunction can involve any part of the sympathetic or parasympathetic chains and produce myriad manifestations. ^[96, 174] Patients likely to seek care in the ED are those with diabetic gastroparesis and vomiting, severe diarrhea, bladder dysfunction and urinary retention, or symptomatic orthostatic hypotension. Treatment of gastroparesis is symptomatic, and symptoms tend to wax and wane. Patients with gastroparesis may benefit from metoclopramide or erythromycin.

    Before these therapies are started, the degree of dehydration and metabolic imbalance must be assessed, and other serious causes of vomiting must be excluded. In severe cases, gastric pacing has been used. Patients with disabling orthostatic hypotension may be treated with salt tablets, support stockings, or fludrocortisone. Alleviating the functional abnormalities associated with the autonomic neuropathy is often difficult and frustrating for both doctor and patient. (See Diabetic Neuropathy and Diabetic Lumbosacral Plexopathy.)

    Diabetic foot disease

    Patients with diabetes who present with wounds, infections, or ulcers of the foot should be treated intensively. ^[175] In addition to appropriate use of antibiotics, the use of crutches, wheelchairs, or bed rest is mandatory for preventing further trauma to the healing foot. Patients should be treated by a podiatrist or an orthopedist with experience in the care of diabetic foot disease. (See Diabetic Foot and Diabetic Foot Infections.)

    If bone or tendon is visible, osteomyelitis is present, and hospitalization for IV antibiotic therapy is often necessary. Many patients need a vascular evaluation in conjunction with local treatment of the foot ulcer because a revascularization procedure may be required to provide adequate blood flow for wound healing.

    Because ulcers and foot infections are difficult to cure, their prevention is extremely important. ^[176] At one clinic, the rate of amputation was halved after patients were required to remove their shoes and socks at every visit. The emergency physician can facilitate this practice by briefly inspecting the feet of patients with diabetes and by educating them about the need for proper foot care.

    Referral to a podiatrist is indicated for diabetic patients with any of the following:

    • Distal sensory neuropathy with inability to feel a pinprick or light touch

    • Decreased peripheral pulses

    • Moderate-to-severe onychomycosis

    • Impending skin breakdown

    Charcot joint, a type of arthropathy observed in people with diabetes, is a progressive deterioration of foot joints caused by underlying neuropathy. Tarsometatarsal and midtarsal joints are affected most commonly. Other neuromuscular foot deformities also may be present. Early diagnosis and treatment are important for preventing further joint degeneration.

    Macrovascular disease

    Hypercholesterolemia and hypertension increase the risk of specific late complications and require special attention and appropriate treatment. Although physicians can safely use beta blockers (eg, propranolol) in most patients, these agents can mask the adrenergic symptoms of insulin-induced hypoglycemia and can impair the normal counterregulatory response. ACE inhibitors are the drugs of choice for hypertension because of their renal protective action, especially early in the course of the disease.

    The ADA advises that a systolic blood pressure below 130 mm Hg is an appropriate goal for most patients with diabetes and hypertension, but it also recommends modifying systolic blood pressure targets in accordance with individual patient characteristics. Diastolic blood pressure should be less than 80 mm Hg. ^[5]

    Subtle differences in the pathophysiology of atherosclerosis in patients with diabetes result in both earlier development and a more malignant course. Therefore, lipid abnormalities must be treated aggressively to reduce the risk of serious atherosclerosis. ^[177] This is important from an epidemiologic point of view and has a bearing on the treatment strategies that must be used to mitigate the risk. ^[178]

    Prediction of cardiovascular risk in diabetic patients on the basis of the lipid profile is not affected by the timing of blood specimen. Therefore, it may be unnecessary to insist on using fasting blood samples to determine the lipid profile. ^[179]

    In a study involving diabetic adolescents and children, nocturnal hypertension was significantly associated with higher daytime blood pressure and carotid intima-media thickness, which could be precursors of atherosclerotic cardiovascular disease later in life; these findings warrant confirmation and longitudinal follow-up. ^[180]

    Patients with diabetes may have increased incidence of silent ischemia. ^[99] However, silent ischemia is common in many patients with CAD, and the apparent increase in its incidence may come about because patients with diabetes are more likely than others to have CAD to begin with. Nevertheless, it is prudent to perform electrocardiography (ECG) in patients who have diabetes and a serious illness or who present with generalized weakness, malaise, or other nonspecific symptoms that are not usually expected to result from myocardial ischemia.

    Persistent lipid abnormalities remain in patients with diabetes, despite evidence supporting the benefits of lipid-modifying drugs. Up-titration of the statin dose and addition of other lipid-modifying agents are needed. ^[181] Although metformin is used principally in type 2 DM because of its lipid-lowering effect, a placebo-controlled study by Lund et al found that metformin (1000 mg orally twice daily) significantly reduced total cholesterol and low-density lipoprotein (LDL) cholesterol in patients with type 1 DM. ^[182]

    The American Diabetes Association (ADA) provided recommendations on the use of statins in patients with diabetes to align with those of the American College of Cardiology and the American Heart Association. ^[183]

    • The ADA recommends statin use for nearly everyone with diabetes.

    • The ADA guidelines divide diabetes patients by 3 age groups:

      • Younger than 40 years: No statins for those with no cardiovascular disease (CVD) risk factors other than diabetes; moderate intensity or high-intensity statin doses for those with additional CVD risk factors (baseline LDL cholesterol 100 or greater, high blood pressure, smoking, and overweight/obesity); and high-intensity statin doses for those with overt CVD (including previous cardiovascular events or acute coronary syndrome).
      • Age 40-75 years: Moderate-intensity statins for those with no additional risk factors, and high-intensity statins for those with either CVD risk factors or overt CVD.
      • Older than 75 years: Moderate-intensity statins for those with CVD risk factors; and high-intensity statins for those with overt CVD.

    • Lipid monitoring for adherence is recommended as needed, and annual monitoring is advised for patients younger than 40 years who have not yet started on statins.

    • There is a new BMI cut point of 23 kg/m² (instead of 25 kg/m²) for screening Asian Americans for prediabetes and diabetes, based on evidence that Asian populations are at increased risk at lower BMIs relative to the general population.

    • The premeal glucose target of 70-130 mg/dL was changed to 80-130 mg/dL to better reflect new data that compared average glucose levels with HbA _1c targets.

    • The goal for diastolic blood pressure was raised to 90 mm Hg from 80 mm Hg to better reflect data from randomized clinical trials. (This follows ADA’s 2013 shift from a systolic target of 130 mm Hg to 140 mm Hg.)  In the ADA’s Standards of Care in Diabetes—2023, however, these numbers were again reduced, with the the target blood pressure for people with diabetes advised to be below 130/80 mm Hg, if it can be safely achieved. ^[184, 185]

    • With regard to physical activity, the document now advises limiting the time spent sitting to no longer than 90 min.

    • The ADA does not support e-cigarettes as alternatives to smoking or to facilitate smoking cessation.

    • Immunization against pneumococcal disease is recommended.

    • A new HbA _1c target of less than 7.5% for children is now recommended.

      Glycemic Control During Pregnancy

      Because pregnant patients with type 1 DM are at risk for multiple poor maternal and fetal outcomes, it is essential to provide these patients with prepregnancy counseling, good glycemic control before and during pregnancy, and a complete medical evaluation. (See Diabetes Mellitus and Pregnancy.) High-risk possibilities include exacerbation of existing hypertension, renal insufficiency, retinopathy, and more frequent congenital anomalies. These patients should be referred to obstetricians specializing in high-risk pregnancies.

      Despite advanced age, multiparity, obesity, and social disadvantage, patients with type 2 DM were found to have better glycemic control, fewer large-for-gestational-age infants, fewer preterm deliveries, and fewer neonatal care admissions than patients with type 1 DM. ^[191] This finding suggests that better tools are needed to improve glycemic control in patients with type 1 DM.

      Prevention

      Significant improvements in the prediction of type 1 DM have led to several trials of prevention. These include the Diabetes Prevention Trial–Type 1 (DPT-1) in the United States and the European Nicotinamide Diabetes Intervention Trial (ENDIT) in Europe and North America. Both trials have reported disappointing results.

      In DPT-1, parenteral insulin failed to delay or prevent type 1 DM in subjects at elevated risk (as indicated by family history and the presence of islet cell antibodies). These subjects received low-dose subcutaneous Ultralente insulin twice daily, plus annual 4-day continuous IV infusions of insulin. ^[192] DPT-1 subjects who received oral insulin experienced considerable delays in the onset of diabetes, but once therapy was stopped, their rate of developing diabetes increased to a rate similar to that seen in the placebo group. ^[193]

      In the ENDIT study, nicotinamide (which prevents autoimmune diabetes in animal models) did not prevent or delay the clinical onset of diabetes in people with a first-degree family history of type 1 DM. Subjects in the treatment arm received oral modified-release nicotinamide in a dose of 1.2 g/m². ^[194]

      Slowing progress of recent-onset type 1 DM

      Teplizumab

      Teplizumab is a humanized monoclonal antibody (mAb) that targets the cluster of differentiation 3 (CD3) antigen, which is coexpressed with the T-cell receptor on the surface of T lymphocytes. It is indicated to delay the onset of stage 3 type 1 DM in adults and in children aged 8 years or older.

      FDA approval was based a phase 2, randomized, placebo-controlled trial involving 76 at-risk children and adults. The study demonstrated that a single 14-day regimen of daily intravenous (IV) infusions of teplizumab in 44 patients delayed clinical type 1 DM by a median of 2 years compared with 32 participants who received placebo. ^[195]

      Data from an extended follow-up (median 923 days) showed that 50% of the teplizumab group remained diabetes free, compared with 22% of the placebo group. ^[196]

      n animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. However, a trial of antigen-based immunotherapy with 2 or 3 doses of glutamic acid decarboxylase formulated with aluminum hydroxide (GAD-alum) vaccine for 4-12 weeks in patients with newly diagnosed type 1 DM did not alter the course of loss of insulin secretion during the first year. ^[197]

      A study by Orban et al found that costimulation modulation of activated T cells with abatacept slowed reduction in beta-cell function over a 2-year period of administration. However, this effect was reduced after 6 months of treatment, suggesting that T-cell activation lessens over time. Further studies are needed. ^[198]

      Consultations

      Patients with type 1 DM should be referred to an endocrinologist for multidisciplinary management. They should also undergo a complete retinal examination by an ophthalmologist at least once a year. Those patients with significant proteinuria or a reduced creatinine clearance should be referred to a nephrologist. Patients with significant foot involvement should see a podiatrist.

      Guidelines Summary

      ADA: Position statement on type 1 diabetes in children and adolescents

      In August 2018, the American Diabetes Association released a position statement on type 1 diabetes in children and adolescents, which included the following guidelines ^[199, 200] :

      • Consult a pediatric endocrinologist before diagnosing type 1 diabetes when isolated glycosuria or hyperglycemia is discovered in patients with acute illness in the absence of classic symptoms
      • Differentiating type 1 diabetes, type 2 diabetes, monogenic diabetes, and other forms of diabetes is based on patient history and characteristics, as well as on laboratory tests, such as an islet autoantibody panel
      • The majority of children with type 1 diabetes should be treated with intensive insulin regimens using multiple daily injections of prandial insulin and basal insulin or continuous subcutaneous insulin infusion
      • A _1C should be measured every 3 months
      • Blood glucose levels should be monitored up to 6-10 times daily
      • Continuous glucose monitors (CGM) should be considered in all children and adolescents with type 1 diabetes; the benefits of CGM correlate with adherence to ongoing use of the device
      • Blood or urine ketone levels should be monitored in children with type 1 diabetes in the presence of prolonged/severe hyperglycemia or acute illness
      • Individualized medical nutrition therapy is recommended for children and adolescents
      • Exercise is recommended, with a goal of 60 minutes a day of moderate to vigorous aerobic activity, along with vigorous muscle-strengthening and bone-strengthening activities at least 3 days a week
      • It is important to frequently monitor glucose before, during, and after exercise (with or without CGM use) to prevent, detect, and treat hypoglycemia and hyperglycemia
      • All individuals with type 1 diabetes should have access to an uninterrupted supply of insulin; lack of access and insulin omissions are major causes of diabetic ketoacidosis
      • Glucagon should be prescribed for all individuals with type 1 diabetes, and caregivers or family members should be instructed regarding administration
      • Once the child has had diabetes for 5 years, annual screening for albuminuria, using a random spot urine sample (morning sample preferred to avoid effects of exercise) to assess the albumin-to-creatinine ratio, should be considered at puberty or at age greater than 10 years, whichever occurs earlier
      • Once the youth has had diabetes for 3-5 years, an initial dilated and comprehensive eye examination is recommended at age 10 years or after puberty has started, whichever is earlier, and an annual routine follow-up is generally recommended
      • For adolescents who have had type 1 diabetes for 5 years, consider an annual comprehensive foot exam at the start of puberty or at age 10 years, whichever is earlier
      • Blood pressure should be measured at each routine visit; children who have high-normal blood pressure (systolic blood pressure [SBP] or diastolic blood pressure [DBP] at 90th percentile for age, sex, and height) or hypertension (SBP or DBP at 95th percentile for age, sex, and height) should have blood pressure confirmed on 3 separate days
      • Initial treatment of high-normal blood pressure (SBP or DBP consistently at the 90th percentile for age, sex, and height) includes dietary modification and increased exercise for weight control; if target blood pressure is not reached within 3-6 months after lifestyle intervention, consider pharmacologic treatment
      • Because of their potential teratogenic effects, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) should be considered for initial pharmacologic treatment of hypertension after reproductive counseling
      • The blood pressure treatment goal is consistently less than the 90th percentile for age, sex, and height
      • If low-density lipoprotein (LDL) cholesterol is within an acceptable risk level (< 100 mg/dL [2.6 mmol/L]), a lipid profile every 3-5 years is reasonable
      • If lipid levels are abnormal, initial therapy should consist of optimizing glucose control and initiating a Step 2 American Heart Association diet (restricting saturated fat to 7% of total calories and dietary cholesterol to 200 mg/day)
      • After age 10 years, consider adding a statin if, despite 6 months of medical nutrition therapy and lifestyle changes, LDL cholesterol remains greater than 160 mg/dL (4.1 mmol/L) or LDL cholesterol remains greater than 130 mg/dL (3.4 mmol/L) with one or more cardiovascular disease (CVD) risk factors present (after reproductive counseling because of the potential teratogenic effects of statins)
      • The LDL therapy goal is less than 100 mg/dL (2.6 mmol/L)
      • In children with type 1 diabetes, consider testing for antithyroid peroxidase and antithyroglobulin antibodies soon after diagnosis
      • In children and adolescents with type 1 diabetes, an A _1C target of less than 7.5% should be considered but individualized
      • Glucose (15 g) is preferred treatment for conscious individuals with hypoglycemia (blood glucose < 70 mg/dL [3.9 mmol/L]), but any form of carbohydrate may be used; treatment should be repeated if self-monitoring blood glucose (SMBG) 15 minutes after treatment shows hypoglycemia is still present; when blood glucose concentration returns to normal, consider a meal or snack and/or reduce insulin to prevent recurrence of hypoglycemia
      • In patients with classic symptoms, blood glucose measurement is sufficient to diagnose diabetes (symptoms of hyperglycemia or hyperglycemic crisis and random plasma glucose ≥200 mg/dL [11.1 mmol/L])
      • Measure thyroid-stimulating hormone concentrations when the patient is clinically stable or once glycemic control has been established; if normal, suggest rechecking every 1-2 years (or sooner if the patient develops symptoms or signs that suggest thyroid dysfunction, thyromegaly, an abnormal growth rate, or unexplained glycemic variability)
      • Screen children for celiac disease by measuring IgA tissue transglutaminase antibodies
      • Criteria for diagnosis of diabetes is fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L)
      • In asymptomatic children and adolescents at high risk for diabetes, if FPG ≥126 mg/dL (7 mmol/L), if 2-hr PG ≥200 mg/dL (11.1 mmol/L), or if A _1C ≥6.5%, testing should be repeated on a separate day to confirm the diagnosis

      ADA: Standards of Medical Care in Diabetes

      The American Diabetes Association’s Standards of Medical Care in Diabetes-2018 include the following A-grade recommendations, ie, recommendations based on “[c]lear evidence from well-conducted, generalizable randomized controlled trials that are adequately powered” ^[116] :

      • Align approaches to diabetes management with the Chronic Care Model, emphasizing productive interactions between a prepared, proactive care team and an informed, activated patient
      • Providers should assess social factors that can affect patients with diabetes, such as potential food insecurity, housing stability, and financial barriers, and apply that information to treatment decisions
      • Provide patients with self-management support from lay health coaches, navigators, or community health workers, when available
      • Effective diabetes self-management education and support should be patient centered, may be given in group or individual settings or using technology, and should help guide clinical decisions
      • Psychosocial care should be integrated with a collaborative, patient-centered approach and provided to all people with diabetes, with the goal of optimizing health outcomes and health-related quality of life
      • A reasonable A _1C goal for many nonpregnant adults is below 7% (53 mmol/mol)
      • Insulin-treated patients with hypoglycemia unawareness or an episode of clinically significant hypoglycemia should be advised to raise their glycemic targets to strictly avoid hypoglycemia for at least several weeks in order to partially reverse hypoglycemia unawareness and reduce risk of future episodes
      • Most people with type 1 diabetes should be treated with a multiple daily injection regimen of prandial insulin and basal insulin or continuous subcutaneous insulin infusion
      • Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk
      • These guidelines state that most patients with diabetes and hypertension should be treated to a systolic blood pressure goal of less than 140 mm Hg and a diastolic blood pressure goal of under 90 mmHg; however, the ADA’s Standards of Care in Diabetes—2023 advised that the target blood pressure for people with diabetes be below 130/80 mmHg, if it can be safely achieved ^[184, 185]
      • Patients with a confirmed office-based blood pressure of 160/100 mmHg or above should, in addition to lifestyle therapy, have prompt initiation and timely titration of two drugs or a single-pill combination of drugs demonstrated to reduce cardiovascular events in patients with diabetes
      • Treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes (angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], thiazide-like diuretics, or dihydropyridine calcium channel blockers)
      • Multiple-drug therapy is generally required to achieve blood pressure targets; however, combinations of ACE inhibitors and ARBs and combinations of ACE inhibitors or ARBs with direct renin inhibitors should not be used
      • Lifestyle modifications focusing on weight loss (if indicated); the reduction of saturated fat, trans fat, and cholesterol intake; an increase in dietary omega-3 fatty acids, viscous fiber, and plant stanol/sterol intake; and increased physical activity should be recommended to improve the lipid profile in patients with diabetes
      • High-intensity statin therapy should be added to lifestyle therapy for patients of all ages with diabetes and atherosclerotic cardiovascular disease (ASCVD)
      • For patients aged 40-75 years who have diabetes but do not have ASCVD, use moderate-intensity statin treatment in addition to lifestyle therapy
      • For patients with diabetes and ASCVD, if the low-density lipoprotein (LDL) cholesterol level is 70 mg/dL (3.9 mmol/L) or above on maximally tolerated statin dose, consider adding additional LDL-lowering therapy (such as ezetimibe or a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor) after evaluating the potential for further ASCVD risk reduction, drug-specific adverse effects, and patient preferences; ezetimibe may be preferred due to lower cost
      • Combination therapy (statin/fibrate) has not been shown to improve ASCVD outcomes and is generally not recommended
      • Combination therapy (statin/niacin) has not been shown to provide additional cardiovascular benefit above statin therapy alone, may increase the risk of stroke with additional side effects, and is generally not recommended
      • Use aspirin therapy (75-162 mg/day) as a secondary prevention strategy in patients with diabetes and a history of ASCVD
      • In asymptomatic patients, routine screening for coronary artery disease is not recommended as it does not improve outcomes as long as ASCVD risk factors are treated
      • Optimize glucose control to reduce the risk or slow the progression of diabetic kidney disease
      • Optimize blood pressure control to reduce the risk or slow the progression of diabetic kidney disease
      • Patients should be referred for evaluation for renal replacement treatment if they have an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m ²
      • Optimize glycemic control to reduce the risk or slow the progression of diabetic retinopathy
      • Optimize blood pressure and serum lipid control to reduce the risk or slow the progression of diabetic retinopathy
      • Promptly refer patients with any level of macular edema, severe nonproliferative diabetic retinopathy (a precursor of proliferative diabetic retinopathy), or any proliferative diabetic retinopathy to an ophthalmologist who is knowledgeable and experienced in the management of diabetic retinopathy
      • The traditional standard treatment, panretinal laser photocoagulation therapy, is indicated to reduce the risk of vision loss in patients with high-risk proliferative diabetic retinopathy and, in some cases, severe nonproliferative diabetic retinopathy
      • Intravitreous injections of the vascular endothelial growth factor inhibitor ranibizumab are not inferior to traditional panretinal laser photocoagulation and are also indicated to reduce the risk of vision loss in patients with proliferative diabetic retinopathy
      • Intravitreous injections of vascular endothelial growth factor inhibitor are indicated for central-involved diabetic macular edema, which occurs beneath the foveal center and may threaten reading vision
      • The presence of retinopathy is not a contraindication to aspirin therapy for cardioprotection, as aspirin does not increase the risk of retinal hemorrhage
      • Either pregabalin or duloxetine is recommended as initial pharmacologic treatment for neuropathic pain in diabetes

      In the 2022 edition of the ADA’s Standards of Medical Care in Diabetes, changes include the following ^[201] :

      • It is recommended that, in a research study setting or perhaps in first-degree family members of a proband with type 1 diabetes, screening tests that detect autoantibodies to insulin, glutamic acid decarboxylase (GAD), islet antigen 2, or zinc transporter 8 be used to screen for presymptomatic type 1 diabetes
      • A risk factor for clinical diabetes, the development and persistence of multiple islet autoantibodies may indicate the need “for intervention in the setting of a clinical trial or screening for stage 2 type 1 diabetes”

      Numerous guideline changes were made in the ADA’s Standards of Care in Diabetes-2024. Revisions include, but are not limited to, the following ^[202] :

      • An added recommendation emphasizes that monitoring persons at risk of developing type 1 diabetes is important owing to the faster progression to clinical type 1 diabetes associated with younger age at seroconversion (especially when it occurs before age 3 years), the number of diabetes-associated autoantibodies found, and the formation of autoantibodies against islet antigen 2 (IA-2)
      • An early start to continuous glucose monitoring, even beginning at diagnosis, as a means of reaching glycemic goals early is recommended for patients with type 1 diabetes
      • For patients with type 2 diabetes, individualized evaluations of body fat mass and distribution are encouraged through incorporation, in addition to BMI, of waist circumference, waist-to-hip ratio, and/or waist-to-height ratio measurements
      • In persons with type 2 diabetes, pharmacotherapy with glucagon-like peptide 1 (GLP-1) receptor agonists or a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist is recommended for obesity management
      • A recommendation was updated to reflect the “growing evidence of the long-term benefits of metabolic surgery treatment in people with obesity and type 2 diabetes”
      • A recommendation was updated to indicate that, as a means of minimizing the risk of hypoglycemia, insulin analogs or inhaled insulin are preferred over injectable human insulin in the majority of adults with type 1 diabetes
      • An added recommendation advises that if individualized glycemic goals are not being achieved in an adult with type 2 diabetes, additional glucose-lowering agents be considered
      • An added recommendation advises that in adults with type 2 diabetes who have heart failure, glycemic management and the prevention of hospitalization for heart failure be achieved using sodium-glucose cotransporter-2 (SGLT2) inhibitors
      • A revised recommendation advises that the serum creatinine/eGFR rate and potassium be monitored within 7-14 days after treatment with an ACE inhibitor, ARB, mineralocorticoid receptor agonist, or diuretic has begun
      • It is recommended that, to help prevent the development of the symptomatic stages of heart failure, adults with diabetes be screened for asymptomatic heart failure via measurement of the natriuretic peptide level
      • An updated recommendation advises that to lessen the risk of worsening heart failure and cardiovascular death, persons with diabetes and established heart failure with preserved or reduced ejection fraction undergo treatment with either an SGLT2 inhibitor or an SGLT1/2 inhibitor
      • An updated recommendation now takes into account “the role of ACE inhibitors or angiotensin receptor blockers in preventing the progression of kidney disease and reducing cardiovascular events”

      ADA: hypertension guidelines

      Guidelines published in 2017 by the American Diabetes Association on managing hypertension in patients with diabetes state the following ^[203, 204] :

      • Blood pressure should be measured at every routine clinical care visit; patients found to have an elevated blood pressure (≥140/90 mm Hg) should have blood pressure confirmed using multiple readings, including measurements on a separate day, to diagnose hypertension; in the ADA’s  Standards of Care in Diabetes—2023, hypertension was redefined as a blood pressure ≥130/80 mm Hg ^[184, 185]
      • All hypertensive patients with diabetes should have home blood pressure monitored to identify white-coat hypertension
      • Orthostatic measurement of blood pressure should be performed during initial evaluation of hypertension and periodically at follow-up, or when symptoms of orthostatic hypotension are present, and regularly if orthostatic hypotension has been diagnosed
      • These guidelines state that most patients with diabetes and hypertension should be treated to a systolic blood pressure goal of < 140 mm Hg and a diastolic blood pressure goal of < 90 mm Hg; however, in the ADA’s  Standards of Care in Diabetes—2023, these numbers were reduced, with the the target blood pressure for people with diabetes advised to be below 130/80 mm Hg, if it can be safely achieved ^[184, 185]
      • For patients with systolic blood pressure >120 mm Hg or diastolic blood pressure >80 mm Hg, lifestyle intervention consists of weight loss if the patients are overweight or obese; a Dietary Approaches to Stop Hypertension (DASH)–style dietary pattern, including reduced sodium and increased potassium intake, increased fruit and vegetable consumption, moderation of alcohol intake, and increased physical activity
      • Patients with confirmed office-based blood pressure ≥160/100 mm Hg should, in addition to lifestyle therapy, have prompt initiation and timely titration of two drugs or a single-pill combination of drugs demonstrated to reduce cardiovascular events in patients with diabetes
      • Treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes: angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), thiazide-like diuretics, or dihydropyridine calcium channel blockers; multiple-drug therapy is generally required to achieve blood pressure targets (but not a combination of ACE inhibitors and ARBs)
      • An ACE inhibitor or ARB, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and a urine albumin-to-creatinine ratio of ≥300 mg/g creatinine or 30–299 mg/g creatinine; if one class is not tolerated, the other should be substituted
      • For patients treated with an ACE inhibitor, ARB, or diuretic, serum creatinine/estimated glomerular filtration rate and serum potassium levels should be monitored
      • Pregnant women with diabetes and preexisting hypertension or mild gestational hypertension with systolic blood pressure < 160 mm Hg, diastolic blood pressure < 105 mm Hg, and no evidence of end-organ damage do not need to be treated with pharmacologic antihypertensive therapy
      • In pregnant patients with diabetes and preexisting hypertension who are treated with antihypertensive therapy, systolic or diastolic blood pressure targets of 120-160/80-105 mm Hg are suggested in the interest of optimizing long-term maternal health and fetal growth

      ISPAD: Diabetic vascular complications in children and adolescents

      In August 2018, the International Society for Pediatric and Adolescent Diabetes (ISPAD) released clinical practice consensus guidelines on diabetic microvascular and macrovascular complications in children and adolescents. These include the following ^[205] :

      • Commence screening for microvascular complications at age 11 years
      • Screening for microvascular disease should be performed preconception and during each trimester of pregnancy
      • Intensive education and treatment should be provided to children and adolescents to prevent or delay the onset and progression of vascular complications
      • Achievement of target glycemic control will reduce the risk for onset and progression of diabetic vascular complications
      • Prevention or cessation of smoking will reduce progression of albuminuria and cardiovascular disease
      • Screening for diabetic retinopathy should start at age 11 years with 2 to 5 years’ diabetes duration
      • Screening for diabetic retinopathy should be performed by an ophthalmologist or optometrist or a trained, experienced observer, through dilated pupils, with assessment carried out via biomicroscopic examination or fundal photography
      • Laser treatment and intravitreal injections of anti–vascular endothelial growth factor (VEGF) agents reduce the rate of vision loss for individuals in vision-threatening stages of retinopathy (severe nonproliferative retinopathy or worse and/or diabetic macular edema)
      • Screen for renal disease using first morning albumin/creatinine ratio as the preferred method.
      • Blood pressure (BP) should be measured at least annually; hypertension is defined as average systolic BP (SBP) and/or diastolic BP (DBP) that is at or above the 95th percentile for gender, age, and height on three or more occasions
      • Angiotensin-converting enzyme (ACE) inhibitors are recommended for use in children with diabetes and hypertension; they have been effective and safe in children in short-term studies but are not safe during pregnancy
      • Screen for lipid abnormalities in the nonfasting state
      • With regard to macrovascular disease, screening of BP and lipids is recommended, as above; the benefit of routine screening for other markers of macrovascular complications outside the research setting is unclear

      ISPAD: Glycemic control targets and glucose monitoring in children, adolescents, and young adults

      In July 2018, the ISPAD released clinical practice consensus guidelines on glycemic control targets and glucose monitoring in children, adolescents, and young adults with diabetes. These include the following ^[206] :

      • Glycemic control of children and adolescents must be assessed by both quarterly hemoglobin A1c (HbA1c) measurements and by regular home glucose monitoring; these permit achievement of optimal health in the following ways: (1) by determining with accuracy and precision an individual’s glycemic control, including through assessment of each individual’s glycemic determinants; (2) by reducing the risks of acute and chronic disease complications; and (3) by minimizing the effects of hypoglycemia and hyperglycemia on brain development, cognitive function, and mood
      • Regular self-monitoring of glucose (using accurate finger-stick blood glucose [BG] measurements, with or without continuous glucose monitoring [CGM] or intermittently scanned CGM [isCGM]), is essential for diabetes management for all children and adolescents with diabetes
      • Each child should have access to technology and materials for self-monitoring of glucose measurements to provide for enough testing for optimized diabetes care
      • When finger-stick BG measurements are used, testing may need to be performed 6-10 times per day to optimize intensive control; regular review of these BG values should be performed with adjustments to medication/nutritional therapies to optimize control
      • Real-time CGM data particularly benefit children who cannot articulate symptoms of hypoglycemia or hyperglycemia and those with hypoglycemic unawareness
      • Intermittently scanned CGM can complement finger-stick BG assessments. Although isCGM provides some benefits similar to those of CGM, it does not alert users to hypoglycemia or hyperglycemia in real time, nor does it permit calibration. Without robust pediatric use efficacy data, it cannot fully replace BG monitoring
      • For children, adolescents, and young adults aged 25 years or younger, ISPAD recommends individualized targets, aiming for the lowest achievable HbA1c without undue exposure to severe hypoglycemia, balanced with quality of life and burden of care
      • For children, adolescents, and young adults aged 25 years or younger who have access to comprehensive care, a target HbA1c of less than 53 mmol/mol (7.0%) is recommended
      • A higher HbA1c goal (in most cases below 58 mmol/mol [7.5%]) is appropriate in the following contexts: (1) inability to articulate symptoms of hypoglycemia; (2) hypoglycemia unawareness/history of severe hypoglycemia; (3) lack of access to analog insulins, advanced insulin delivery technology, and CGM, and lack of ability to regularly check BG; and (4) individuals who are “high glycators,” in whom an at-target HbA1c would reflect a significantly lower mean glucose level than 8.6 mmoL/L (155 mg/dL)
      • A lower goal (6.5%) or 47.5 mmol/mol may be appropriate if achievable without excessive hypoglycemia, impairment of quality of life, and undue burden of care
      • A lower goal may be appropriate during the honeymoon phase of type 1 diabetes
      • For patients who have elevated HbA1c, a stepwise approach to improve glycemic control is advised, including individualized attention to the following: (1) dose adjustments, (2) personal factors limiting achievement of the target, (3) assessment of the psychological effect of goal setting on the individual, and (4) incorporation of available technology to improve glucose monitoring and insulin delivery modalities
      • HbA1c measurement should be available in all centers caring for persons with diabetes
      • HbA1c measurements should be performed at least every 3 months
      • Examining variations in HbA1c between centers can assist in evaluating the care provided by health-care centers, including compliance with agreed-to standards to improve therapies and delivery of pediatric diabetes care

      Endocrine Society guidelines on diabetes management in older adults

      In 2019, the Endocrine Society released the following clinical practice guidelines on the diagnosis and management of diabetes and its comorbidities in older adults ^[207, 208] :

      • Screening for diabetes or prediabetes with the fasting plasma glucose test or HbA1c analysis is recommended for patients aged 65 years or older without known diabetes
      • A 2-hour glucose post–oral glucose tolerance test is suggested for patients aged 65 years or older without known diabetes in whom results from fasting plasma glucose or HbA1c analysis have indicated that prediabetes is present
      • To delay the onset of diabetes, it is recommended that patients aged 65 years or older with prediabetes adopt a lifestyle in line with that presented in the Diabetes Prevention Program
      • It is recommended that patients aged 65 years or older with diabetes participate in outpatient regimens specifically conceived to minimize hypoglycemia
      • Lifestyle modification is recommended as the first-line treatment for hyperglycemia in ambulatory individuals aged 65 years or older with diabetes
      • Nutritional status assessment for the detection and management of malnutrition is recommended in patients aged 65 years or older with diabetes
      • It is recommended that along with lifestyle changes, patients aged 65 years or older with diabetes undergo initial oral drug treatment with metformin, for glycemic management; significant kidney function impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m ²) or gastrointestinal intolerance should preclude implementation of this recommendation
      • If metformin therapy and lifestyle changes have not led a patient aged 65 years or older with diabetes to achieve his/her glycemic target, it is recommended that metformin treatment be combined with therapy employing other oral or injectable agents and/or insulin
      • To reduce the risk of cardiovascular disease outcomes, stroke, and progressive chronic kidney disease, it is recommended that the target blood pressure in patients aged 65-85 years with diabetes be 140/90 mm Hg
      • It is recommended that an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker be administered as first-line therapy in patients aged 65 years or older with diabetes and hypertension
      • Statin therapy and an annual lipid profile are recommended in patients aged 65 years or older with diabetes to reduce absolute cardiovascular disease events and all-cause mortality
      • For detection of retinal disease, annual comprehensive eye examinations are recommended for patients aged 65 years or older with diabetes
      • It is recommended that patients aged 65 years or older with diabetes who are not on dialysis be screened annually for chronic kidney disease, with determination of the estimated glomerular filtration rate and urine albumin-to-creatinine ratio

      Expert panel: management of diabetes in patients with coronavirus disease 2019 (COVID-19)

      Recommendations for the management of diabetes in patients with COVID-19 were published on April 23, 2020, by an international panel of diabetes experts. ^[209, 210]

      Regarding infection prevention and outpatient care:

      • Patients with diabetes, particularly those with type I diabetes mellitus, should be sensitized to the importance of optimal metabolic control
      • Current therapy should, if appropriate, be optimized
      • Telemedicine and connected health models should be used, if possible, to maintain maximal self-containment

      All patients hospitalized with COVID-19 should be monitored for new-onset diabetes.

      Regarding management in the intensive care unit (ICU) of infected patients with diabetes:

      • Plasma glucose monitoring, electrolytes, pH, blood ketones, or β-hydroxybutyrate
      • There is liberal indication for early intravenous insulin therapy in severe disease courses (acute respiratory distress syndrome, hyperinflammation) for exact titration, with variable subcutaneous resorption avoided, and management of commonly encountered very high insulin consumption

      Therapeutic goals include the following:

      • Plasma glucose concentration: 4-8 mmol/L (72-144 mg/dL) for outpatients or 4-10 mmol/L (72-180 mg/dL) for inpatients/intensive care, with, for frail individuals, the lower value possibly adjusted upward to 5 mmol/L (90 mg/dL)
      • A _1c< 53 mmol/mol (7%)
      • Continuous glucose monitoring/flash glucose monitoring targets: Time-in-range (3.9-10 mmol/L) >70% of time (or >50% in frail and older patients)
      • Hypoglycemia < 3.9 mmol/L (< 70 mg/dL): < 4% (< 1% in frail and older patients)

      The panel advises stopping administration of metformin and sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with COVID-19 and type 2 diabetes in order to lower the risk of acute metabolic decompensation.

      Fluid balance requires considerable care, “as there is a risk that excess fluid can exacerbate pulmonary edema in the severely inflamed lung.”

      Potassium balance requires careful consideration in the context of insulin treatment, “as hypokalemia is a common feature in COVID-19,” with initiation of insulin possibly exacerbating it.

      The panel recommends screening for hyperinflammation, owing to the possibility of increased risk for cytokine storm and severe COVID-19 in patients with type 2 diabetes and fatty liver disease.

      AACE guidelines for use of advanced technology

      In May 2021, the American Association of Clinical Endocrinology (AACE) released guidelines on the use of advanced technologies in diabetes management. The following recommendations are among those published. ^[211, 212]

      The percentage of time in range (%TIR) and below range (%TBR) should serve as a starting point for the evaluation of the quality of glycemic control and form the basis for therapy adjustment.

      For all persons with diabetes who are undergoing intensive insulin therapy (ie, three or more injections of insulin per day or treatment with an insulin pump), continuous glucose monitoring (CGM) is strongly recommended. For individuals on insulin therapy for whom success with CGM has been limited (or for those who are unable or unwilling to use CGM), structured self-monitoring of blood glucose (SMBG) is recommended. CGM is recommended for all individuals with problematic hypoglycemia (frequent/severe hypoglycemia, nocturnal hypoglycemia, hypoglycemia unawareness), for children/adolescents with type 1 diabetes; for pregnant women with type 1 or type 2 diabetes treated with intensive insulin therapy, and for women with gestational diabetes mellitus (GDM) on insulin therapy. CGM may be recommended for women with GDM who are not undergoing insulin treatment and for individuals with type 2 diabetes who are undergoing less intensive insulin therapy.

      For persons with diabetes who have problematic hypoglycemia (frequent/severe hypoglycemia, nocturnal hypoglycemia, hypoglycemia unawareness) and need predictive alarms/alerts, real-time CGM (rtCGM) should be recommended over intermittently scanned CGM (isCGM). Consideration should also be given, however, to a patient’s lifestyle and to other factors.

      The management of persons with diabetes who meet one or more of the following criteria should entail the use of diagnostic/professional CGM:

      • Newly diagnosed with diabetes mellitus
      • Not using CGM
      • No access to personal CGM, despite having problematic hypoglycemia
      • Persons with type 2 diabetes who, although undergoing non-insulin therapy, would derive educational benefit from episodic use of CGM
      • Persons who, before committing to daily use of CGM, wish to know more about it

      Importantly, continued adjunctive use of SMBG must be employed by patients who are using “masked” or “blinded” diagnostic/professional CGM, to assist in daily diabetes self-care.

      Persons with diabetes in whom glycemic targets are being reached with minimal TBR, infrequent episodes of symptomatic hypoglycemia are being reported, and SMBG is being used on a regular basis (at least 4 times daily for persons with type 1 diabetes) could employ an insulin pump without CGM.

      In all persons with diabetes who are undergoing intensive insulin management but who prefer to forgo the use of automated insulin suspension/dosing systems or have no access to them, use of an insulin pump with CGM or a sensor-augmented pump (SAP) is recommended.

      To reduce hypoglycemia’s severity and duration in persons with type 1 diabetes, low-glucose suspend (LGS) is strongly recommended; for mitigation of hypoglycemia in these patients, predictive low-glucose suspend (PLGS) is strongly recommended.

      It is strongly recommended that all persons with type 1 diabetes use automated insulin dosing (AID) systems; these have been shown to raise the TIR, especially in the overnight period, without increasing the hypoglycemia risk.

      In persons with diabetes who are hospitalized but are suffering no cognitive impairment, consideration should be given to the continuation of CGM and/or continuous subcutaneous insulin injection (CSII) (insulin pump, SAP, LGS/PLGS). The presence of a family member who is knowledgeable and educated in the use of these devices or the availability of a specialized inpatient diabetes team for advice and support is ideal in such situations.

      To enable persons aged 65 years or older with insulin-requiring diabetes to improve glycemic control, reduce episodes of severe hypoglycemia, and improve quality of life, use of rtCGM is recommended. Owing, however, to this population’s increased comorbidities and lowered capacity to detect and counter-regulate against severe hypoglycemia, glycemic goals should be individualized.

      As a means of tracking glucose before, during, and after exercise in persons with diabetes; monitoring the glycemic response to exercise; and helping to direct insulin and carbohydrate consumption to prevent the development of hypoglycemia and hyperglycemia, clinicians should prescribe CGM.

      It is strongly recommended that telemedicine be used in the treatment of diabetes, provision of diabetes education, remote monitoring of glucose and/or insulin data, and improvement of diabetes-related outcomes/control.

      As a means of teaching/reinforcing diabetes self-management skills, encouraging engagement, and supporting/encouraging desired health behaviors, clinically validated smartphone applications should be recommended to persons with diabetes.

      Comprehensive training in the proper use and care of insulin delivery technology should be provided to all persons with diabetes using that equipment.

      It is strongly recommended that, in the absence of pump therapy, FDA-cleared and clinically validated smartphone bolus calculators be used to reduce the frequency of hypoglycemia or severe postprandial hyperglycemia.

      Medication Summary

      Insulin injected subcutaneously is the first-line treatment of type 1 diabetes mellitus (DM). The different types of insulin vary with respect to onset and duration of action. Short-, intermediate-, and long-acting insulins are available. Short-acting and rapid-acting insulins are the only types that can be administered intravenously (IV). Human insulin currently is the only species of insulin available in the United States; it is less antigenic than the previously used animal-derived varieties.

      Antidiabetics, Insulins

      Class Summary

      Rapid-acting insulins are used whenever a rapid onset and short duration are appropriate (eg, before meals or when the blood glucose level exceeds target and a correction dose is needed). Rapid-acting insulins are associated with less hypoglycemia than regular insulin.

      Currently, short-acting insulins are less commonly used than the rapid-acting insulins in patients with type 1 DM. They are used when a slightly slower onset of action or a greater duration of action is desired.

      Intermediate-acting insulins have a relatively slow onset of action and a relatively long duration of action. They are usually combined with faster-acting insulins to maximize the benefits of a single injection.

      Long-acting and ultralong-acting insulins have a very long duration of action and, when combined with faster-acting insulins, provide better glucose control for some patients. In patients with type 1 DM, they must be used in conjunction with a rapid-acting or short-acting insulin given before meals.

      Premixed insulins contain a fixed ratio of rapid-acting insulins with longer-acting insulin, which can restrict their use. Premixed insulin is usually not recommended in type 1 DM patients, because of their need for frequent adjustments of premeal insulin doses.

      Insulin aspart (NovoLog, Fiasp)

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      Insulin aspart has a rapid onset of action, 5-15 minutes. The peak effect occurs within 30-90 minutes, and the usual duration of action is 2-4 hours. Insulin aspart is approved by the US Food and Drug Administration (FDA) for use in insulin pumps.

      Fiasp also has a rapid onset of action, with its first measurable effect occurring within 16-20 minutes. The peak effect occurs within 91-133 minutes, and the usual duration of action is 5-7 hours.

      Insulin glulisine (Apidra)

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      Insulin glulisine has a rapid onset of action, 5-15 minutes. The peak effect occurs within 30-90 minutes, and the usual duration of action is 2-4 hours. Insulin glulisine is FDA-approved for use in insulin pumps.

      Insulin lispro (Humalog, Admelog, insulin lispro-aabc, Lyumjev)

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      Insulin lispro has a rapid onset of action, 5-15 minutes. The peak effect occurs within 30-90 minutes, and the usual duration of action is 2-4 hours.

      Insulin inhaled (Afrezza)

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      Orally inhaled rapid-acting insulin in powder form. When 8 units were administered, maximum serum insulin concentration was reached by 12-15 minutes and declined to baseline by about 180 minutes.

      Regular insulin (Humulin R, Novolin R, Myxredlin)

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      Regular insulin has a short onset of action, 0.5 hour. Its peak effect occurs within 2-4 hours, and its usual duration of action is 5-8 hours. Preparations that contain a mixture of 70% neutral protamine Hagedorn (NPH) insulin and 30% regular human insulin (eg, Novolin 70/30 and Humulin 70/30) are available, but the fixed ratios of intermediate-acting to rapid-acting insulin may restrict their use.

      Insulin detemir (Levemir)

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      Insulin detemir is indicated for once-daily or twice-daily subcutaneous administration in individuals with type 1 DM who require long-acting basal insulin for hyperglycemia control. Its duration of action ranges from 5.7 hours (low dose) to 23.2 hours (high dose). The prolonged action results from slow systemic absorption of detemir molecules from the injection site. Its primary activity is regulation of glucose metabolism.

      Insulin detemir binds to insulin receptors and lowers blood glucose levels by facilitating cellular uptake of glucose into skeletal muscle and fat; it also inhibits glucose output from the liver. The drug inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.

      Insulin degludec (Tresiba)

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      Ultralong-acting basal insulin indicated to improve glycemic control in adults with diabetes mellitus who require basal insulin. It is highly protein bound, and following SC, the protein-binding provides a depot effect. The elimination half-life is 25 h and its duration of action is beyond 42 h.

      Insulin aspart protamine/insulin aspart (NovoLog 70/30)

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      The combination of insulin aspart protamine with insulin aspart includes 30% rapid-onset insulin (ie, insulin aspart) and 70% intermediate-acting insulin (ie, insulin aspart protamine). Insulin aspart is absorbed more rapidly than regular human insulin, and insulin aspart protamine has a prolonged absorption profile after injection.

      Insulin lispro protamine/insulin lispro (Humalog 75/25)

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      The combination of insulin lispro protamine with insulin lispro includes 75% insulin lispro protamine, which has a prolonged duration of action, and 25% insulin lispro, which is a rapid-onset insulin.

      Insulin degludec/insulin aspart (Ryzodeg)

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      Combines the ultralong-acting basal insulin (degludec 70 units) and a rapid-acting insulin (aspart 30 units). It is indicated to improve glycemic control in adults with diabetes mellitus.

      Insulin glargine (Lantus, Lantus SoloStar, Toujeo, Toujeo Max, Basaglar)

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      Insulin glargine stimulates proper utilization of glucose by the cells and reduces blood sugar levels. It has no pronounced peaks of action, because a small amount of insulin is gradually released at a constant rate over 24 hours. The amount of insulin in Toujeo and Toujeo Max SoloStar is three times greater (300 Units/mL) than in Lantus or Basaglar (100 Units/mL).

      Antidiabetics, Amylinomimetics

      Class Summary

      These amylinomimetic agents elicit endogenous amylin effects by delaying gastric emptying, decreasing postprandial glucagon release, and modulating appetite.

      Pramlintide acetate (Symlin)

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      Pramlintide acetate is a synthetic analogue of human amylin, a naturally occurring hormone made in pancreatic beta cells that is deficient in people with type 1 DM. It slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake through centrally mediated appetite modulation.

      Hypoglycemia Antidotes

      Class Summary

      Pancreatic alpha cells of the islets of Langerhans produce glucagon, a polypeptide hormone. Glucagon increases blood glucose levels by promoting hepatic glycogenolysis and gluconeogenesis.

      Glucagon (GlucaGen, Gvoke)

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      Glucagon elevates blood glucose levels by inhibiting glycogen synthesis and enhancing the formation of glucose from noncarbohydrate sources such as proteins and fats (gluconeogenesis). It increases hydrolysis of glycogen to glucose in the liver and accelerates hepatic glycogenolysis and lipolysis in adipose tissue. Glucagon also increases the force of contraction in the heart and has a relaxant effect on the gastrointestinal tract. It is available in a reconstitutable powder form. Glucagon is also available as a ready-to-use subcutaneous (SC) solution in prefilled syringes or an autoinjector.

      Glucagon intranasal (Baqsimi)

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      This agent activates hepatic glucagon receptors, which stimulate cyclic adenosine monophosphate (cAMP) synthesis. Hepatic glycogenolysis and gluconeogenesis are thus accelerated, with blood glucose levels consequently increasing. Glucagon requires preexisting hepatic glycogen stores to effectively treat hypoglycemia. Glucagon intranasal is indicated for severe hypoglycemic reactions in adults and children (aged 4 years or older) with diabetes.

      Monoclonal Antibodies

      Class Summary

      Teplizumab is a humanized monoclonal antibody (mAb) that targets the CD3 antigen, which is coexpressed with the T-cell receptor on the surface of T lymphocytes.

      Teplizumab (Tzield)

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      Indicated to delay onset of stage 3 type 1 DM in adults and in children aged 8 years or older.

      Allogeneic Islet Cells

      Class Summary

      Pancreatic islets regulate blood glucose levels through highly regulated, pulsatile secretion of multiple hormones in response to fluctuations in blood glucose. Insulin, glucagon, somatostatin, pancreatic peptide, and ghrelin are released by endocrine cells within pancreatic islets. It is believed that insulin secretion by infused (transplanted) beta cells is donislecel’s primary mechanism of action.

      Donislecel (Lantidra)

      • View full drug information

      Indicated for adults with type 1 diabetes who, owing to current, repeated episodes of severe hypoglycemia, have been unable to approach target HbA1c, even with intensive diabetes management and education. It is meant for concomitant use with immunosuppression.

      Overview

      When is screening indicated for type 1 diabetes mellitus (DM)?

      What is type 1 diabetes mellitus (DM)?

      What are the classic symptoms of type 1 diabetes mellitus (DM)?

      What are non-classic symptoms of type 1 diabetes mellitus (DM)?

      How might type 1 diabetes mellitus (DM) initially present?

      What are the ADA diagnostic criteria for type 1 diabetes mellitus (DM)?

      Which lab tests are performed in the diagnosis of type 1 diabetes mellitus (DM)?

      How are glycemic goals established for type 1 diabetes mellitus (DM)?

      How are blood glucose levels monitored in type 1 diabetes mellitus (DM)?

      When is insulin therapy indicated for type 1 diabetes mellitus (DM)?

      What are common insulin regimens used for the treatment of type 1 diabetes mellitus (DM)?

      What is the role of diet in the treatment of type 1 diabetes mellitus (DM)?

      What is the role of exercise in the treatment of type 1 diabetes mellitus (DM)?

      What is type 1 diabetes mellitus (DM)?

      Which age groups are at highest risk for type 1 diabetes mellitus (DM)?

      How are type 1 and type 2 diabetes mellitus (DM) differentiated?

      What is the approach to treatment of type 1 diabetes mellitus (DM)?

      What is the medical cost of type 1 diabetes mellitus (DM) in the US?

      What is the pathophysiology of type 1 diabetes mellitus (DM)?

      What is the role of autoimmunity in the pathogenesis of type 1 diabetes mellitus (DM)?

      Which autoimmune diseases are associated with type 1 diabetes mellitus (DM)?

      What is the role of pancreatic volume in the pathogenesis of type 1 diabetes mellitus (DM)?

      What are the genetic determinants of type 1 diabetes mellitus (DM)?

      What is the cause of sensory and autonomic neuropathy in type 1 diabetes mellitus (DM)?

      What is the association between microvascular disease and type 1 diabetes mellitus (DM)?

      What is the source of renal lesions in type 1 diabetes mellitus (DM)?

      What is the significance of vitamin D deficiency in type 1 diabetes mellitus (DM)?

      What is the pathogenesis of nephropathy in type 1 diabetes mellitus (DM)?

      What is double diabetes?

      What is the significance of low estimated glucose disposal rate (eGDR) in type 1 diabetes mellitus (DM)?

      What causes type 1 diabetes mellitus (DM)?

      What is the sibling risk for type 1 diabetes mellitus (DM)?

      What is the parent-to-child risk for type 1 diabetes mellitus (DM)?

      How does the frequency of type 1 diabetes mellitus (DM) vary geographically?

      Which DR-DQ haplotypes increase the risk for type 1 diabetes mellitus (DM)?

      Which DR-DQ haplotypes decrease the risk for type 1 diabetes mellitus (DM)?

      Which DR-DQ haplotypes confers the highest risk for type 1 diabetes mellitus (DM)?

      Which ethnic groups carry high risk DR-DQ haplotypes for type 1 diabetes mellitus (DM)?

      Which genes are associated with susceptibility to type 1 diabetes mellitus (DM)?

      What are the nongenetic risk factors for type 1 diabetes mellitus (DM)?

      What is the relationship between maternal age and the susceptibility to type 1 diabetes mellitus (DM)?

      What is the association between vitamin D and type 1 diabetes mellitus (DM)?

      What is the association between upper respiratory infection and type 1 diabetes mellitus (DM), and is coronavirus disease 2019 (COVID-19) related to new-onset type 1 and type 2 diabetes mellitus?

      What is the prevalence and incidence of type 1 diabetes mellitus (DM) in the US?

      What is the global prevalence of type 1 diabetes mellitus (DM)?

      How does the incidence of type 1 diabetes mellitus (DM) vary by age?

      How does the prevalence of type 1 diabetes mellitus (DM) vary by sex?

      How does the prevalence of type 1 diabetes mellitus (DM) vary by race?

      What are the morbidities of type 1 diabetes mellitus (DM)?

      What factors affect the long-term prognosis of type 1 diabetes mellitus (DM)?

      What are complications of type 1 diabetes mellitus (DM)?

      How does coronary vasodilator dysfunction affect the prognosis of type 1 diabetes mellitus (DM), and how does diabetes affect mortality in coronavirus disease 2019 (COVID-19)?

      What is the association between type 1 diabetes mellitus (DM) and small-fiber neuropathy?

      What are the mortality differences between early-onset and late-onset type 1 diabetes mellitus (DM)?

      Which factors are indicators of poorer prognosis in type 1 diabetes mellitus (DM)?

      What is the role of patient education in the management of type 1 diabetes mellitus (DM)?

      What education about type 1 diabetes mellitus (DM) should patients be given at every clinical visit?

      What are the ADA recommendations for patient education of older adolescents with type 1 diabetes mellitus (DM)?

      What is key information to include in patient education about type 1 diabetes mellitus (DM)?

      What education should dietitians give patients with type 1 diabetes mellitus (DM)?

      Presentation

      What are the most common symptoms of type 1 diabetes mellitus (DM)?

      What causes polyuria in type 1 diabetes mellitus (DM)?

      What causes symptoms of type 1 diabetes mellitus (DM)?

      How soon after beta-cell destruction do patients with type 1 diabetes mellitus (DM) become symptomatic?

      How is the onset of symptomatic type 1 diabetes mellitus (DM) characterized?

      What are the signs and symptoms of type 1 diabetes mellitus (DM)?

      What are the GI symptoms of type 1 diabetes mellitus (DM)?

      What is frequency of neuropathy in type 1 diabetes mellitus (DM)?

      What is the focus of medical history of a patient with type 1 diabetes mellitus (DM)?

      What history is needed in patients with type 1 diabetes mellitus (DM) who use a pump or a multiple-injection regimen?

      What information should be included in a type 1 diabetes mellitus (DM) history?

      How is glycemic exposure in established type 1 diabetes mellitus (DM) assessed?

      Which questions regarding hypoglycemia and hyperglycemia symptoms should be asked of patients with type 1 diabetes mellitus (DM)?

      Which questions regarding microvascular complications should be asked of patients with type 1 diabetes mellitus (DM)?

      Which questions regarding macrovascular complications should be asked of patients with type 1 diabetes mellitus (DM)?

      Which questions regarding neuropathy should be asked of patients with type 1 diabetes mellitus (DM)?

      Which questions regarding foot disease should be asked of patients with type 1 diabetes mellitus (DM)?

      What are the physical findings characteristic of new-onset type 1 diabetes mellitus (DM)?

      How often should patients with type 1 diabetes mellitus (DM) be examined?

      What is included in a diabetes-focused physical exam?

      How are the vital signs assessed in type 1 diabetes mellitus (DM)?

      What is included in the funduscopic exam for type 1 diabetes mellitus (DM)?

      What is included in the foot exam for type 1 diabetes mellitus (DM)?

      Which factors increase the risk of infection in type 1 diabetes mellitus (DM)?

      What are the most common sites of infection in type 1 diabetes mellitus (DM)?

      Which infections occur almost exclusively in type 1 diabetes mellitus (DM), and what is the relationship of coronavirus disease 2019 (COVID-19) to diabetes?

      What are ophthalmologic complications of type 1 diabetes mellitus (DM)?

      What is diabetic retinopathy?

      What are the stages in the progression of diabetic retinopathy?

      How does diabetic retinopathy progress in stage 1 and 2?

      How does diabetic retinopathy progress in stages 3, 4 and 5?

      What are renal complications of type 1 diabetes mellitus (DM)?

      What are the types of diabetic neuropathy?

      What is the most common type of diabetic neuropathy?

      What are acute-onset mononeuropathies of type 1 diabetes mellitus (DM)?

      What are cranial nerve complications of type 1 diabetes mellitus (DM)?

      What are macrovascular complications of type 1 diabetes mellitus (DM)?

      What are the risk factors for macrovascular disease in type 1 diabetes mellitus (DM)?

      DDX

      Which conditions and factors should be considered in the differential diagnosis of type 1 diabetes mellitus (DM)?

      How are type 1 and type 2 diabetes mellitus (DM) differentiated?

      How is monogenic diabetes differentiated from type 1 diabetes mellitus (DM)?

      What are the differential diagnoses for Type 1 Diabetes Mellitus?

      Workup

      What is the role of HbA1c measurement in the diagnosis of type 1 diabetes mellitus (DM)?

      What is the role of plasma glucose concentration in the diagnosis of type 1 diabetes mellitus (DM)?

      What is the role of fingerstick glucose test in the diagnosis of type 1 diabetes mellitus (DM)?

      How are glucose levels determined in the diagnosis of type 1 diabetes mellitus (DM)?

      What are the ADA recommendations for the measurement of HbA1c in type 1 diabetes mellitus (DM)?

      What are limitations of HbA1c levels in the diagnosis of type 1 diabetes mellitus (DM)?

      What is an HbA1c assay indicated in the diagnosis of type 1 diabetes mellitus (DM)?

      What are the advantages of HbA1c testing over glucose measurement for the diagnosis of type 1 diabetes mellitus (DM)?

      What is the HbA1c criterion for diagnosis of type 1 diabetes mellitus (DM)?

      What effect does seasonal variability have on HbA1c levels used for diagnosis of type 1 diabetes mellitus (DM)?

      What is the role of HbF in the diagnosis of type 1 diabetes mellitus (DM), and what are the concerns regarding the accuracy of HbA1c testing?

      What are the ADS guidelines for use of HbA1c in the management of type 1 diabetes mellitus (DM)?

      What is the role of fructosamine assay in the diagnosis of type 1 diabetes mellitus (DM)?

      What is the role of WBC count and blood and urine cultures in the diagnosis of type 1 diabetes mellitus (DM)?

      How is diabetic ketoacidosis (DKA) diagnosed?

      Who should be screened for type 1 diabetes mellitus (DM)?

      What are the AACE recommendations for distinguishing between type 1 and type 2 diabetes mellitus (DM)?

      What are some classical symptoms of type 1 diabetes mellitus (DM)?

      What is the role of islet-cell (IA2) levels in the diagnosis of type 1 diabetes mellitus (DM), and what is the ADA/EASD algorithm for the diagnosis of type 1 DM?

      Treatment

      What is included in insulin therapy for type 1 diabetes mellitus (DM)?

      When is little or no insulin therapy needed for type 1 diabetes mellitus (DM)?

      What is the approach for treatment of new-onset type 1 diabetes mellitus (DM)?

      What are the American Disease Association (ADA) treatment guidelines for type 1 diabetes mellitus (DM)?

      What is the role of exogenous glucagonlike peptide 1 (GLP-1) in the treatment of type 1 diabetes mellitus (DM)?

      When is pancreatic transplantation indicated for the treatment of type 1 diabetes mellitus (DM)?

      What health risks are decreased with tight glycemic control in type 1 diabetes mellitus (DM)?

      What are the benefits to tight glycemic control in type 1 diabetes mellitus (DM)?

      How are HbA1c target levels determined in the treatment of type 1 diabetes mellitus (DM)?

      Which health risks increase with tight glycemic control of type 1 diabetes mellitus (DM)?

      What is the role of self-monitoring in the management of type 1 diabetes mellitus (DM)?

      How frequently should plasma glucose be monitored in type 1 diabetes mellitus (DM)?

      When is urine ketone testing indicated in type 1 diabetes mellitus (DM)?

      What is the role of continuous glucose monitors (CGMs) in the treatment of type 1 diabetes mellitus (DM)?

      What are the limitations of continuous glucose monitors (CGMs) for the treatment of type 1 diabetes mellitus (DM)?

      What is the benefit of continuous glucose monitors (CGMs) for the treatment of type 1 diabetes mellitus (DM)?

      When is the intermittent use of a continuous glucose monitor (CGM) indicated in the treatment of type 1 diabetes mellitus (DM)?

      Which continuous glucose monitor (CGM) is the most accurate for type 1 diabetes mellitus (DM)?

      What is the sensor-augmented insulin pump system for type 1 diabetes mellitus (DM)?

      Which continuous glucose monitors (CGMs) have been FDA approved for the management of type 1 diabetes mellitus (DM), and what is a flash glucose monitoring system?

      What is the role of artificial pancreases in the treatment of type 1 diabetes mellitus (DM)?

      What types of insulin preparations are used in the treatment of type 1 diabetes mellitus (DM)?

      What is the role of rapid-acting insulins in the treatment of type 1 diabetes mellitus (DM)?

      What is the efficacy of rapid-acting inhaled insulin powder (Afrezza) in the treatment of type 1 diabetes mellitus (DM)?

      What is the role of short-acting insulins in the treatment of type 1 diabetes mellitus (DM)?

      Which type of insulin is the most effective for lowering postprandial hyperglycemia in type 1 diabetes mellitus (DM)?

      What is the role of aspart (Fiasp) in the treatment of type 1 diabetes mellitus (DM)?

      What is the role of Semilente insulin in the treatment of type 1 diabetes mellitus (DM)?

      Which intermediate-acting insulins are used for the treatment of type 1 diabetes mellitus (DM)?

      What is the role of lente insulin in the treatment of type 1 diabetes mellitus (DM)?

      Which long-acting insulins are used for the treatment of type 1 diabetes mellitus (DM)?

      What is the role of degludec (Tresiba) in the treatment of type 1 diabetes mellitus (DM)?

      How are insulins mixed in the treatment of type 1 diabetes mellitus (DM)?

      What is the role of ultrafast-acting insulin in the treatment of type 1 diabetes mellitus (DM)?

      What is the evidence of increased cancer risk from insulin glargine (Lantus) treatment of type 1 diabetes mellitus (DM)?

      How is insulin administered for the treatment of type 1 diabetes mellitus (DM)?

      What are some common insulin regimens for the treatment of type 1 diabetes mellitus (DM)?

      How quickly does insulin used for the treatment of type 1 diabetes mellitus (DM) expire?

      How is the initial daily insulin dose calculated for type 1 diabetes mellitus (DM)?

      How is the initial daily insulin dose calculated for children with type 1 diabetes mellitus (DM)?

      What are the risks and benefits of administering multiple subcutaneous insulin injections for type 1 diabetes mellitus (DM)?

      Which types of insulin are administered for the treatment of type 1 diabetes mellitus (DM)?

      How should daily doses of insulin be adjusted in the treatment of type 1 diabetes mellitus (DM)?

      How are small battery-operated infusion pumps used in the treatment of type 1 diabetes mellitus (DM)?

      What is the role of continuous subcutaneous insulin infusion (CSII) in the treatment of type 1 diabetes mellitus (DM)?

      What are the benefits of pump therapy for the treatment of type 1 diabetes mellitus (DM)?

      How can early morning hyperglycemia be prevented in type 1 diabetes mellitus (DM)?

      How do altitude changes affect insulin pump delivery in the treatment of type 1 diabetes mellitus (DM)?

      What are the AACE/ACE guidelines for insulin pump management in type 1 diabetes mellitus (DM)?

      Which are the signs and symptoms of insulin allergy?

      What are the causes of hypoglycemia in type 1 diabetes mellitus (DM)?

      What are symptoms of hypoglycemia in type 1 diabetes mellitus (DM)?

      What are the health risks of repeated hypoglycemia in type 1 diabetes mellitus (DM)?

      What is the evidence of cognitive impairment as a result of hypoglycemia in type 1 diabetes mellitus (DM)?

      What are the risks of hyperglycemia in type 1 diabetes mellitus (DM)?

      What is the treatment for hyperglycemia in type 1 diabetes mellitus (DM)?

      What is the importance of follow-up following treatment of hyperglycemia in type 1 diabetes mellitus (DM)?

      Which type 1 diabetes mellitus (DM) comorbidities may aggravate hyperglycemia?

      What is diabetic ketoacidosis (DKA)?

      What is the dawn phenomenon in type 1 diabetes mellitus (DM)?

      What is the Somogyi phenomenon in type 1 diabetes mellitus (DM)?

      How are the dawn and Somogyi phenomena in type 1 diabetes mellitus (DM) managed?

      What is the role of insulin in the treatment of hyperglycemia in type 1 diabetes mellitus (DM)?

      What is the ADA recommendation for dietary treatment of type 1 diabetes mellitus (DM)?

      What is included in the diet management plan for type 1 diabetes mellitus (DM)?

      What is the recommended caloric distribution for management of type 1 diabetes mellitus (DM)?

      What are the recommended food group intakes for patients with type 1 diabetes mellitus (DM)?

      What are the activity recommendations for management of type 1 diabetes mellitus (DM)?

      Which infectious diseases are at higher risk in patients with type 1 diabetes mellitus (DM)?

      What are the ophthalmologic complications of type 1 diabetes mellitus (DM)?

      What are the dangers of nephrotoxic agents in patients with type 1 diabetes mellitus (DM)?

      What the alternative to contrast-enhanced imaging for patients with type 1 diabetes mellitus (DM)?

      What are the ADA recommendations for nephropathy screening in type 1 diabetes mellitus (DM)?

      What are complications of micro- and macroalbuminuria in type 1 diabetes mellitus (DM)?

      How is blood pressure controlled in type 1 diabetes mellitus (DM)?

      What are complications of diabetic neuropathy?

      What are complications of diabetic foot disease?

      When is referral to a podiatrist indicated in the treatment of type 1 diabetes mellitus (DM)?

      What is Charcot joint in type 1 diabetes mellitus (DM)?

      What are macrovascular disease complications in type 1 diabetes mellitus (DM)?

      What is the ADA recommended blood pressure goal for comorbid hypertension and type 1 diabetes mellitus (DM)?

      How is atherosclerosis prevented in type 1 diabetes mellitus (DM)?

      What is the risk of cardiovascular disease in patients with type 1 diabetes mellitus (DM)?

      What is the association between silent ischemia and type 1 diabetes mellitus (DM)?

      How are lipid abnormalities resolved in patients with type 1 diabetes mellitus (DM)?

      What are the ADA guidelines on the use of statins in patients with type 1 diabetes mellitus (DM)?

      How is type 1 diabetes mellitus (DM) managed during surgical procedures?

      What are complication of serious medical illness or surgical procedures in patients with type 1 diabetes mellitus (DM)?

      Why should near-normal blood glucose levels be maintained in medical and surgical patients with type 1 diabetes mellitus (DM)?

      How is ketosis prevented in hospitalized patients with type 1 diabetes mellitus (DM)?

      What insulin regimen should be used for patients with type 1 diabetes mellitus (DM) undergoing minor surgery?

      When are the different types of insulin indicated for the treatment of type 1 diabetes mellitus (DM) in patients with restricted food intake prior to medical procedures?

      Which types of insulin should be administered for prevention of hypoglycemia in hospitalized patients with type 1 diabetes mellitus (DM)?

      What effect does cardiovascular disease or renal dysfunction have on the morbidity and mortality of patients with type 1 diabetes mellitus (DM)?

      What are the insulin therapy requirements in critically ill patients with type 1 diabetes mellitus (DM)?

      What are the ADA recommended blood glucose goals for non-critically ill patients with type 1 diabetes mellitus (DM)?

      What are the ACP guidelines for glycemic control in hospitalized patients with type 1 diabetes mellitus (DM)?

      How are plasma glucose and ketones monitored in patients with type 1 diabetes mellitus (DM) undergoing surgical procedures?

      When is insulin administered for type 1 diabetes mellitus (DM) in patients undergoing surgical procedures?

      What is the postoperative standard of care for type 1 diabetes mellitus (DM)?

      What are the treatment options for type 1 diabetes mellitus (DM) during pregnancy?

      Which trials have been conducted on the prevention of type 1 diabetes mellitus (DM)?

      What were the results of the Diabetes Prevention Trial-Type 1 (DPT-1)?

      What is the role of nicotinamide in the prevention of type 1 diabetes mellitus (DM)?

      What is the role of antigen-based immunotherapy in the prevention of type 1 diabetes mellitus (DM)?

      What is the role of teplizumab in the prevention of type 1 diabetes mellitus (DM)?

      What is the role of abatacept in the prevention of type 1 diabetes mellitus (DM)?

      What are the recommended referrals for patients with type 1 diabetes mellitus (DM)?

      Guidelines

      What are the A-grade recommendations from the American Diabetes Association’s Standards of Medical Care in Diabetes 2018?

      What is contained in the American Diabetes Association (ADA) position statement on type 1 diabetes in children and adolescents?

      What are the ADA guidelines on managing hypertension in type 1 diabetes mellitus (DM)?

      What are the ISPAD guidelines on diabetic vascular complications in children and adolescents with type 1 diabetes mellitus (DM)?

      What are the ISPAD clinical practice consensus guidelines on glycemic control targets and glucose monitoring in type 1 diabetes mellitus (DM)?

      What are the Endocrine Society guidelines on the management of diabetes mellitus (DM) in older adults?

      What expert panel recommendations have been put forward on the management of diabetes mellitus (DM) in patients with coronavirus disease 2019 (COVID-19)?

      What are the AACE guidelines for the use of advanced technology in the management of diabetes mellitus (DM)?

      Medications

      What is the first-line treatment for type 1 diabetes mellitus (DM)?

      Which medications in the drug class Hypoglycemia Antidotes are used in the treatment of Type 1 Diabetes Mellitus?

      Which medications in the drug class Antidiabetics, Amylinomimetics are used in the treatment of Type 1 Diabetes Mellitus?

      Which medications in the drug class Antidiabetics, Insulins are used in the treatment of Type 1 Diabetes Mellitus?

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