Primordial Prevention A Futuristic Approach to Intervene in Gestational Diabetes and its sequelae

Primordial Prevention: A Futuristic Approach to Intervene in Gestational Diabetes and its sequelae

 Veeraswamy Seshiah 1* Honorary Distinguished Professor, The Tamil Nadu Dr. MGR Medical University, Chennai, India. Diabetes mellitus is a relentlessly evolving pandemic and a significant public health problem in recent decades. Diabetes disturbs millions of people worldwide, with a significant adverse effect on the quality of their lives. Efforts are underway worldwide to detect diabetes in its early stages and prevent complications of diabetes. Although in medical practice, what is accomplished by screening for hyperglycemia and detecting diabetes in the initial stages of its accepted history, recommends that impaired glucose tolerance is akin to the ‘primary prevention of diabetes. Likewise, treating a patient with diabetes and handling those with diabetic problems are parallel to ‘secondary prevention’ and ‘tertiary prevention,’ respectively.

‘Detection’ of diabetes by screening does not mean ‘prevention.’ What is needed is Primordial Prevention of Diabetes; that is, the disease should not develop.

 

Diabetes Prevention Program In September 2001, the Centers for Disease Control and Prevention (CDC) issued a press release stating that “twin epidemics of diabetes and obesity continue to impend the health of Americans,” and the “Diabetes Prevention Program” was announced [1]. In 2001, 6.1% of the US population had been diagnosed with Diabetes; currently, by 2021, about 10.5 % of Americans have diabetes leading to a rethink of the Goals of Diabetes Prevention Programs. If this is not a Successful Program, what could be successful? Is it possible? To Achieve Diabetes-Free Generation Whom to Focus on? Lise Kingo suggested that Female Gender is the Key to Diabetes Prevention. Based on the concept of developmental Origin, the ovum is well supplied with mitochondria, but the sperm contains a few, and even those few do not persist in the offspring. At fertilization, only the spermatozoa’s nucleus enters the ovum; thus, all the cytoplasm, mitochondria, and mitochondrial DNA are exclusively maternally inherited [2].

 

Gestational programming is a process whereby stimuli, maternal fuels, or stresses that occur at critical or sensitive periods of fetal development permanently change structure, physiology, and metabolism, predisposing individuals to disease in adult life [3]. “Fetal origin of adult diseases” detection of GDM is possible with 2hr PG > 140 mg/dl. The concern is about the prediction of GDM. So that it can prevent the development of GDM and its consequences, blood tests may identify gestational diabetes risk in the first trimester. NIH analysis suggests early screening could allow for lifestyle changes before the condition develops at the 10th week [5], which is possible if HBA1C is > 5.3 and the 2hr PPBS > 110 mg/dl.

 

NIH recommends screening at the 10^th week as the Fetal Beta cell starts insulin secretion at the 11^th week of gestation [4,8]. Prandial Glycemic Level can be considered abnormal and may stimulate beta cell secretion. Based on the Pattern of Glycemia in Normal Pregnancy [6].

 

• PPBS at 10th week > 110 mg/dl predicts GDM, hence blood glucose has to be brought to <110 mg/dl as fetal beta cells start secreting insulin around 10-11 week
• With fetal insulin secretion, changes in maternal metabolism start.

 

The obvious implication is that glycemic control needs to be optimized very early in pregnancy to prevent the establishment of fetal hyperinsulinemia [7]. PPBS should be < 110 mg/dl.

 

When maternal PPBS > 110 mg/dl is recorded, immediate action has to be taken to bring PPBS < 110 mg/dl, lest she will develop GDM and its consequences. Contribution to glucose gradient. The priming of the fetal beta cells may account for the tenacity of fetal hyperinsulinemia throughout pregnancy. (The fetal glucose steal) across the placenta to the fetus. Subsequently, the overactive glucose giveaway would increase the removal of maternal glucose into the fetus, thus decreasing the levels of maternal hyperglycemia. Importantly, this effect of dropping maternal glucose driven by the fetus would be highest in pregnancies with the most hyperinsulinemia fetuses. Fetal glucose steal is less highlighted in Gestational diabetic pregnancies [9]. An exaggerated glucose steal by a hyperinsulinemia fetus could also attenuate maternal glucose levels during an oral glucose tolerance test (OGTT), elucidating why some

mothers with affected fetuses have a normal glucose tolerance.

 

The idea is to test for glucose tolerance in the 8th week (2 months); the reason is Prediction of GDM is 2hr PPBS > 110 mg/dl in the 10th week. Hence in the 8th week itself, PPBS has to be estimated. because…If PPBS is > 110 mg/dl in the 8th week, a grace period of 2 weeks is available to attain PPBS < 110 mg/dl in the 10th week. If > 110 mg/dl, MNT and metformin 250 mg/bd must be started and continued [10]. The target glycemia to be obtained is PPBS 99 ± 10 mg/dl. Metformin is Safe as the Embryonic stage is over by the 8th week. To use metformin as an adjunct or alternative to insulin in the preconception period and during pregnancy, when the likely benefit from improved blood glucose control outweighs the potential for harm [11]. The study in The Lancet Diabetes & Endocrinology also showed no difference in weight, height, head circumference, and waist circumference between children of metformin-treated and placebo-treated mothers [12].

Preventive measures against NCD should start during the INTRAUTERINE PERIOD and continue throughout life from early childhood [13,14]. Prevention of type 2 diabetes must begin in the uterus and continue throughout the life course.

 

The aim is to maintain maternal 2hr Plasma Glucose 99 ± 10 mg/dl throughout pregnancy from conception to confinement. This prevents the Transgenerational Transmission of Diabetes.

CARRY HOME MESSAGE  

• Pre-pregnancy planning is ideal for a better fetal outcome.
• It is necessary to optimize metabolic control early in pregnancy.
• Prediction of GDM – PPBS >110 mg/dl at 10th week.
• Preventive action must be taken at the 8^th week so maternal PPBS remains < 110 mg/dl throughout pregnancy.
• MNT throughout pregnancy.
• MNT + Metformin to be continued till Confinement.

The priming of the fetal beta cells around the 11th week may account for the persistence of fetal hyperinsulinemia throughout pregnancy.

• This “Make in India” concept for Primordial Prevention of Diabetes is Evidence-Based, Feasible, and Doable.
• Hope to achieve Diabetes Free Generation.

 

 

 

 

REFERENCE: 

 

1. Mezuk B, Allen JO: Rethinking the goals of diabetes prevention programs. Diabetes Care. 2021, 44(11):2457-9. DOI:10.2337/dci21-0038

1. Nausheen Khan et al. Early Age at Onset and High Frequency of Associated Complications in Maternally Transmitted Type 2 Diabetes Mellitus. Int. J. Diab. Dev. Countries. 2004, 24: 36 – 39.

1. Lucas A (1991) Programming by early nutrition in man. In: Bock GR, Whelan J (eds) The childhood environment and adult disease. John Wiley and Sons, Chichester (UK), pp 38 – 55 Fetal origin of adult diseases – David Barker

1. Piper K, Brickwood S, Turnpenny LW, et al. Beta cell differentiation during early human pancreas development. J Endocrinol. 2004; 181:11–23
2.  Hinkle SN, Tsai MY, Rawal S, Albert PS, Zhang C: HbA1c measured in the first trimester of pregnancy and the association with gestational diabetes. Sci Rep. 2018, 8:12249. 10.1038/s41598-018-30833-8

6. Hernandez TL, Friedman JE, Van Pelt RE, Barbour LA. Patterns of Glycemia in Normal Pregnancy: Should the current therapeutic targets be challenged? Diabetes Care. 2011 Jul;34(7):1660-8
7. Nahum GG, Stephen B Wilson, Stanislaw H. Early-pregnancy glucose screening for gestational diabetes mellitus. J Reprod Med 2002 Aug;47(8):656-
8. Wood S, Turnpenny LW, et al. Beta cell differentiation during early human pancreas development.  J 62
9. Desoye G, Nolan CJ. The fetal glucose steal: an underappreciated phenomenon in diabetic pregnancy. Diabetologia 2016; 59:1089-94. doi: 10.1007/s00125-016- 3931-6.

10. Seshiah V, Bronson SC, Balaji V, Jain R, Anjalakshi C. Prediction and Prevention of Gestational Diabetes Mellitus and Its Sequelae by Administering Metformin in the Early Weeks of Pregnancy. Cureus. 2022;15;14(11): e31532. doi: 10.7759/cureus.31532.

11.Brand KMG, Saarelainen L, Sonajalg J, et al. Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study. BMJ Open Diab Res Care 2022;10: e002363

12.Feig DS, Donovan LE, Zinman B, Sanchez JJ, Asztalos E, Ryan EA, et al. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomized, placebo-controlled trial. Lancet Diabetes Endocrinol [Internet]. 2020 ;8(10):834–44.

13.Seshiah V, Balaji V. Primordial Prevention: maternal health and diabetes. 2013. Future medicine, Diabetes Manage. 2013; 3(4): 1-9

14. Tuomilehto J. A paradigm shift is needed in the primary prevention of Type 2 DM, Prevention of DM, John Wiley & Sons Limited, 153-165; 2005

article can be accessed at

Seshiah, V. Primordial prevention: a futuristic approach to intervene in gestational diabetes and its sequelae. Int J Diabetes Dev Ctries 43, 483–484 (2023). https://doi.org/10.1007/s13410-023-01216-1

https://diabetesjournals.org/care/article/44/11/2457/138508/Rethinking-the-Goals-of-Diabetes-Prevention

https://link.springer.com/article/10.1007/s13410-023-01216-1

 

INTRODUCTION

Globally prevalence of DIABETES is increasing Exponentially; Diabetes EPIDEMIC has become PANDEMIC as per IDF President Prof Andrew Boulton.¹

Worldwide, the prevalence of diabetes is expected to increase from 537 million in 2021 to 783 million in 2045, a 46% increase.¹ There is an increase in the prevalence of diabetes worldwide and in India. Diabetes in India was 2.4% and 3.3% in the rural and urban areas in 1972, increasing to 15% and 19%, respectively.² This is a matter of concern; by 2021, there will be 74.1 million diabetics in India.¹       The increase in prevalence can be because of the structure of the aging population, physical inactivity, urbanization, and the obesity epidemic. These factors result in the diabetes epidemic; however, early life exposure is a   potential risk factor. As David Baker proposed the “fetal origin of adult diseases” hypothesis, gestational programming may critically influence adult health and disease. Gestational programming can be defined as a process where stresses or stimuli occurring during the sensitive or critical periods of fetus development permanently alter the structure, physiology, and metabolism that predispose the person to disease in adulthood.⁴ The lifestyle and drug intervention modifications are reported to delay or post­ pone the overt diabetes development among individuals with impaired glucose tolerance (IGT). This is a post-primary prevention strategy. Instead of only preventing the development of type 2 diabetes mellitus (T2DM), keeping genetically or otherwise susceptible persons normoglycemic would be the best to prevent T2DM. The epidemic of diabetes can be reversed or halted by primary prevention. For the primary prevention of diabetes, women with gestational diabetes mellitus (GDM) are considered an ideal group because there is an increased risk of developing diabetes, mainly T2DM, as are their children. Gestational diabetes mellitus may be a significant factor in the rise in the prevalence of diabetes and obesity.⁵ The worldwide prevalence of hyperglycemia in pregnancy (HIP) in 2021 was 21.1 million, or 16.7% of births in 20–49 years.¹ Some forms of hyperglycemia may be present in such individuals during pregnancy; 80.3% were because of GDM.¹ Therefore, it is essential to perform screening in all women for GDM, even when asymptomatic.⁶

Five things are decided in the womb; It has been told in Chanakya Niti that when the child is in the mother’s womb, then these five things are decided- how long he will live, what he will do, how much wealth and knowledge he will earn and when he will die.⁷

 

In Utero Fertilization: The ovum is well supplied with mitochondria, but the sperm contains a few, and even those few do not persist in the offspring.

At fertilization, only the nucleus of the spermatozoon that enters the ovum, and thus all the cytoplasm, mitochondria, and mitochondrial DNA, are maternally inherited. ⁸

Intrauterine programming

Gestational programming is a process whereby stimuli(hyperglycemia) or stresses that occur at critical or sensitive periods of fetal development permanently change the structure, physiology, and metabolism, predisposing individuals to disease in adult life. ⁹

 

 

IMPACT OF MATERNAL HYPERGLYCEMIA

It has been recognized that GDM may play an essential role in increasing the prevalence of diabetes. It is also causing insulin resistance, obesity, dyslipidemia, increased inflammatory markers, endothelial dysfunction, and hypertension, leading to an increased risk of cardiovascular diseases (CVDs).  The maternal HIP is an independent risk factor for putting the offspring at increased risk of IGT, obesity, and hypertension at seven years of age, while cardiometabolic disorder (CMD) risk increases from adolescence to adulthood. There is also an effect on childhood adiposity. Maternal hyperglycemia has been associated with offspring’s adiposity and insulin resistance. Intrauterine exposure to hyperglycemia has harmful effects in addition to those related to genetic predisposition.¹⁴ Also, in utero direction, hyperinsulinemia is an independent predictor of abnormal glucose tolerance in later childhood. Maternal HIP predisposes both mother and child to future risk of developing Cardio-metabolic disorder (CMD).²

Maternal Glycemia and Insulin Response Pregnancy induce a progressive change in maternal carbohydrate metabolism. As the pregnancy advances, insulin resistance, and diabetogenic stress due to placental hormones necessitate a compensatory increase in insulin secretion.

GDMTable: Glycemic Level and Insulin in GDM and NGT Women

 

Progressively increasing insulin elaboration enables maintaining Plasma Glucose levels following Glucose load throughout pregnancy. Where this compensation is inadequate, Gestational diabetes occurs.¹⁰

GDM women in our population are hyperinsulinemia, a manifestation of insulin resistance. ¹¹

Increased IR during pregnancy in Asian Indian Women and escalates further in GDM ¹²

and insulin resistance is higher compared to Caucasians.¹³

 

Glucose is typically fuel for a developing fetus but harms the growing fetus in a hyperglycemic state. This gave rise to a hypothesis called “fuel-mediated teratogenesis.” This proposed the explanation for the association of excessive growth of the fetus. Maternal insulin does not cross the placenta freely while maternal glucose does, and in response, the fetal pancreas tries to balance by secreting more insulin (Fig. 1). This, in turn, acts as a fetal growth hormone and becomes responsible for promoting growth and adiposity.¹⁴

 

 

It can be safely concluded that exposure to a hyper­ glycemic environment in intrauterine life is associated with increased IGT and a defective insulin secretory response. GDM allows for the development and CVD in young women, which can be prevented by appropriate management. Women with previous gestational diabetes (PGDM) are at increased risk of developing T2DM. GDM may represent an early stage in the natural history of T2DM in women with prior GDM

FIG. 1: Schematic representation of maternal-fetal nutrient transport in humans.

And have a two­fold higher risk of CVD emerging within the first decade after pregnancy and is not dependent on the intercurrent development of T2DM.¹⁵ in subsequent years after the index pregnancy; these women with PGDM show a deranged cardiovascular profile with an increased incidence of CVD.

Glycemic Level and Insulin in GDM and NGT Women, GDM women in our population are hyperinsulinemia, a manifestation of insulin resistance.^16.

Increased IR during pregnancy in Asian Indian Women and escalates further in GDM. ¹⁷ In Asian Indian women, insulin resistance is higher compared to Caucasians ¹⁸

 

Procedure

A pregnant woman should be screened during the 8^th week for Postprandial 2 hours after breakfast or meal through Plasma calibrated Glucometer if the PPBS Blood Glucose value is 110 or >110 mg/dl at the 8^th week. Further, 75 g oral glucose load OGCT was done at 16^th, 24^th, and 32 weeks as per DIPSI Single test Procedure Criteria at the antenatal clinic following the preliminary clinical examination, regardless of whether she is in the fasting or non-fasting state and irrespective of the time of the last meal[ref]. When 2 hours post glucose (PG) is 140 mg/dL or more (7.8 mmol/L), the diagnosis of GDM is confirmed.

 

PRIMORDIAL PREVENTION OF DIABETES.

AIM:

A Step towards Primordial Prevention of Diabetes.

Project:  Prevention of Diabetes Mellitus.

Background:

So far, no attempt has been made the Prevention of Diabetes. There is a concept that GDM is the mother of Non-Communicable Diseases. Hence, the aim is to decide the glycemia level which predicts the development of GDM. The suggestion is that HbA1C of more than 5.3 (110mg/dl) during the 10th week of pregnancy indicates GDM. [28-29] HBA1C 5.7 during pregnancy establishes GDM in Asian ethnicity, and HbA_1c measured in the first trimester is helpful for early prediction of GDM. [30-32]

Patterns of glycemia in normal pregnancy (gestational week 33.8 ± 2.3) across 11 studies published between 1975 and 2008. Methodologies used diurnal pattern characterization during inpatient admission (five studies), SMBG via reflectance photometry (one study), and CGMS (six studies) (n = 168–255; BMI range 22–28 at the time of the survey).[33]

 

 

Figure 5—A: Patterns of glycemia in normal pregnancy (gestational week 33.8 6 2.3) across 11 studies published between 1975 and 2008.

The mean pattern of glycemia across 12 studies (n = 168–255) during 33.8 6 2.3 weeks gestation (weighted average ±SD, values rounded to whole numbers for clinical use). Suggested 1- and 2-h PP targets are 22 and 110 mg/dL, respectively.[33]

A blood test performed at the 8^th week of pregnancy and if PPBS >110 mg% may help identify a pregnant woman at risk of GDM. Hence in the 8th week itself, PPBS has to be estimated. If the PPBS is >110 mg%, a grace period of two weeks is available to maintain PPBS<110mg% at the 10th week.

Another essential physiology is that at the 11^th week, Fetal beta cell insulin secretion starts. If PPBS remains, more than 110 mg% fetal hyperinsulinemia occurs, which is undesirable.

Fig. 6 Guidelines to screen Glucose Intolerance at appropriate Gestational weeks.

Fetal hyperinsulinemia will favor a persistently high glucose flux even when maternal blood glucose is average. The obvious implication is that glycemia control needs to be optimized early in pregnancy to prevent the establishment of fetal hyperinsulinemia.³⁴ The aim should be not to allow PPBS > 110mg/dl in the early weeks of pregnancy.  Therefore, hyperglycemia and hyperinsulinemia promote fetal adiposity, resulting in adult IGT and type 2 diabetes.

 

Methodology:  

Testing for PPBS at the 8th week (2 months amenorrhea) with 110mg/dl so that there is enough time available before fetal insulin secretion starts in the 11th week. If PPBS more than 110mg/dl in the 8th week, the PPBS should be controlled with MNT and Exercise and, if necessary, with Metformin so that PPBS should be maintained at less than 110mg/dl (99 +/- 10) till the 12th week. At the 16th week, 75gm OGCT (DIPSI Test) should be done to know whether she developed GDM and, if negative, be repeated at the 24th and 32nd weeks (Fig 6).

 

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