Mitochondrial feature and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet
Domenico Sergi1,2*, Nenad Naumovski3,4, Leonie Kaye Heilbronn2, Mahinda Abeywardena1, Nathan O’Callaghan1, Lillà Lionetti5, and Natalie Luscombe-Marsh1,2
1Nutrition and Health Substantiation Group, Nutrition and Health Program, Health and Biosecurity, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Adelaide, SA, Australia
The mitochondrial disorder has been implicated withinside the pathogenesis of insulin resistance, the hallmark of kind two diabetes mellitus (T2DM). However, the cause-impact courting stays to be completely elucidated. Compelling proof shows that boosting mitochondrial features may also constitute a precious healing device to enhance insulin sensitivity.
Mitochondria are tremendously dynamic organelles, which adapt to short- and long-time period metabolic perturbations through present process fusion and fission cycles, spatial rearrangement of the electron shipping chain complexes into supercomplexes, and biogenesis ruled through peroxisome proliferator-activated receptor γ co-activator 1α (PGC 1α).
Introduction
Obesity has reached epidemic proportions internationally, and its occurrence is at the upward thrust affecting each adult and children1. Obesity is strongly related to kind two diabetes mellitus (T2DM), non-alcoholic fatty liver disease, certain forms of cancers and, poorer intellectual fitness (Hotamisligil, 2006; Brown et al., 2009; Luchsinger and Gustafson, 2009).
The affiliation among weight problems and metabolic dysfunctions is predominantly dictated through fats distribution with improved visceral or intra-belly fats being greater unfavorable to metabolic fitness in comparison to peripheral adiposity depots, which seem to confer a higher metabolic profile (Vazquez et al., 2007; Hayashi et al., 2008; Castro et al., 2014).
Of note, weight problems and visceral fats accumulation specifically are underlain through a persistent low-grade inflammation (Hotamisligil, 2006) and improved ectopic fats garage in metabolically energetic tissues such as skeletal muscle and liver, a phenomenon termed lipotoxicity (Unger, 2002). Those pathophysiological functions of weight problems constitute the primary mechanisms bridging the distance among improved fatty acid availability, sustained through stronger adipose tissue lipolysis and impaired fatty acid beta-oxidation, and insulin resistance, the hallmark of T2DM.
Mitochondrial disorder and the following impairment in metabolic gas oxidation appear like the metabolic offender underlying the buildup of lipotoxic lipid metabolites. In guide of this notion, a lower in fatty acid oxidation induces the accumulation of ceramide and diacylglycerol, which have been proven to impair the insulin sign transduction pathway (Samuel et al., 2010).
Insulin Signalling Pathway
Insulin is a peptide hormone secreted through the pancreatic β cells positioned withinside the islet of Langerhans. Insulin exerts its position within the law of complete frame metabolism through binding to a molecular floor receptor, which belongs to a subfamily of receptor tyrosine kinases and is characterized by extracellular ligand-binding α subunits intracellular tyrosine-kinase β subunits (Lee et al., 2014). Upon binding to its cognate receptor, insulin induces conformational modifications by bringing the α subunits nearer and inducing the autophosphorylation of tyrosine residues mediated through the β subunits (Ryder et al., 2001).
The β subunits of the insulin receptor are answerable for the phosphorylation of insulin receptor substrate (IRS) at tyrosine residues (Sun and Rothenberg, 1991), which in flip sell the interplay among IRS and proteins containing SRC homology 2 (SH2) domains (Koch et al., 1991) such as phosphoinositide 3-kinase (PI3K; Myers et al., 1992).
PI3K is a heterodimeric protein, which includes subunits, the p85 regulatory subunit, which consists of the SH2 area and is worried in IRS-PI3K interplay (Skolnik et al., 1991), and the p110, which consists of the catalytic subunit of the enzyme (Hiles et al., 1992).
PI3K catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and its conversion to phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], which in flip, through activating 3-phosphoinositide-based protein kinase (PDK) 1, results in the activation of AKT (Walker et al., 1998).
The activation of AKT calls for a twin serine/threonine phosphorylation mediated through PDK1 (threonine 308) and mammalian goal of rapamycin complicated 2 (mTORC2) (serine 473), respectively (Figure 1; Kumar et al., 2008). Once activated, AKT phosphorylates downstream objectives such as forkhead field O1 (FOXO1), glycogen synthase kinase 3 (GSK3), AKT substrate of one hundred sixty kDa (AS160), and mammalian goal of rapamycin (mTOR; Taniguchi et al., 2006), which can be pivotal in mediating the metabolic consequences of insulin (Figure 1).
Although the law of metabolic gas homeostasis consequences from the combination of insulin signaling at distinctive organs and tissues encompassing the liver (Petersen et al., 1998; Leavens and Birnbaum, 2011; Perry et al., 2015; Samuel and Shulman, 2016), skeletal muscle, adipose tissue (Anthonsen et al., 1998; Virtanen et al., 2002) and the brain (Tups et al., 2017), the primary consciousness of this assessment may be on skeletal muscle.
Lipotoxicity and Insulin Resistance
Insulin resistance is the hallmark of T2DM etiology. It is called a blunted reaction of metabolically energetic tissues to insulin due to dysregulation of nutrient fluxes, metabolism, and homeostasis. At the molecular level, the ectopic accumulation of lipids and lipid secondary metabolites in metabolically energetic tissues, especially skeletal muscle, represents a primary determinant of insulin resistance.
In guide of this notion, intramyocellular lipids constitute a higher predictor of muscle insulin resistance than adiposity in young, sedentary, lean subjects (Krssak et al., 1999). However, the buildup of intramyocellular lipids isn’t always enough to explain the affiliation between ectopic lipid accumulation and insulin resistance.
Indeed, athletes are surprisingly insulin-touchy no matter accelerated intramyocellular lipid especially saved withinside the shape of triglycerides (Goodpaster et al., 2001), which brought about the system of the so-known as athlete paradox. The athlete paradox gives insights into the connection between intramyocellular lipid and insulin resistance, highlighting that the damaging impact of lipids on insulin sensitivity depends on the buildup of reactive lipid species, including diacylglycerols and ceramides in place of accumulation of lipids withinside the shape of triglycerides in line with se (Dresner et al., 1999; Yu et al., 2002; Samuel and Shulman, 2012; Kitessa and Abeywardena, 2016). Diacylglycerols are lipid intermediates that sign through protein kinase C (PKC).
Notably, the lipotoxic buildup of diacylglycerol in skeletal muscle consequences in sustained activation of PKCθ (Yu et al., 2002), which in flip phosphorylates IRS on serine residues hampering insulin-mediated tyrosine-phosphorylation and consequently selling insulin resistance (Figure 1; Li et al., 2004). Importantly, this mechanism has also been shown in human beings to assist the pathophysiological relevance of diacylglycerol-brought on insulin resistance past rodent models (Itani et al., 2002).
As correctly as diacylglycerol, ceramide additionally contributes to insulin resistance. The deleterious impact of ceramide on insulin signaling consequences from its cap potential to dam the activation of AKT through impartial mechanisms (Chavez and Summers, 2012). The first mechanism entails the phosphorylation of AKT on the pleckstrin homology area using PKCζ, which in flip is activated with the aid assistance of using ceramide. This lowers the affinity of AKT for phosphoinositide (Powell et al., 2003) and blocks AKT translocation to the plasma membrane (Stratford et al., 2001). By contrast, dephosphorylation of AKT with the aid of using protein phosphatase 2A (PP2A) underlies the second mechanism linking intracellular ceramide accumulation to insulin resistance (Figure 1; Chavez et al., 2003).
Mitochondrial Dysfunction and Insulin Resistance
Lower metabolic substrate oxidation seems to be a number one disorder. Using triggering a cascade of occasions culminating with the intracellular accumulation of the diacylglycerol and ceramide hampers insulin signaling and promotes insulin resistance. In mild in their pivotal position in oxidative metabolism, Mitochondria were diagnosed because of the cell organelles on the interphase among impaired fuels, especially fatty acids oxidation, lipotoxicity, and insulin resistance. This intuitive affiliation among inadequate mitochondrial oxidative potential and insulin resistance has been shown in landmark research, which defined an impairment in mitochondrial characteristics in people with T2DM.
The initial proof linking the mitochondrial disorder to insulin resistance comes from research achieved in overweight and insulin-resistant people who exhibited a lower in skeletal muscle mitochondria oxidative potential and faulty lipid metabolism as compared to healthy, lean controls (Kelley et al., 1999; Simoneau et al., 1999; Kim et al., 2000a). Furthermore, people with T2DM have decreased NADH2-O2 oxidoreductase activity (Kelley et al., 2002), which similarly helps the affiliation among T2DM and mitochondrial disorder featuring the latter as an underlying disorder withinside the pathogenesis of insulin resistance.
Microarray research has successively reinforced this affiliation with the aid of using supplying proof that genes concerned in oxidative metabolism and beneathneathbeneath neath the manage of PGC 1α are downregulated withinside the skeletal muscle of people with an own circle of relatives records of T2DM and sufferers laid low with T2DM as compared to healthy controls (Mootha et al., 2003; Patti et al., 2003). Furthermore, evaluation of mitochondria characteristic in vivo the use of non-invasive dimension of the phosphocreatine resynthesis charge after workout corroborated those brilliant mitochondrial defects on the protein in addition to on the transcriptional degrees supplying similarly proof that muscle mitochondria oxidative potential is impaired in sufferers with overt T2DM (Schrauwen-Hinderling et al., 2007).
Regulation of Mitochondrial Biogenesis
An essential peculiarity of mitochondria is that they’ve their very own round DNA, known as mtDNA (Schatz et al., 1964), which encodes 22 switch RNAs and thirteen proteins required for mitochondrial respiratory. Nonetheless, the bulk of genes worried in mitochondrial metabolism and biogenesis are nuclear-encoded genes whose transcription, translation, and delivery into the mitochondria arise in concomitance and are coordinated with mtDNA replication, transcription, and translation. Key in orchestrating this manner is the nuclear-encoded mitochondrial transcription element A (TFAM), that’s pivotal in regulating mtDNA transcription via way of means of at once interacting with the mitochondrial genome at the side of mitochondrial transcription specificity elements TFB1M and TFB2M (Figure 3; Gleyzer et al., 2005; Ljubicic et al., 2010).
In guide of this notion, the insulin-sensitizing impact of exercise (Meex et al., 2010) is paralleled via a concomitant exercise-triggered upregulation of PGC 1α (Uguccioni et al., 2010). Furthermore, the insulin-sensitizing drug, rosiglitazone, restores PGC 1α expression in kind two diabetic people. This drug’s impact on insulin sensitivity is coupled with improved muscular oxidative potential and recovery of oxidative metabolism transcriptome toward the values traditional of wholesome metabolic people (Mensink et al., 2007). Thus, now no longer simplest PGC 1α upregulation is paralleled via way of development in insulin sensitivity. However, PGC 1α-established defects in mitochondrial oxidative metabolism reversibly confirm this transcription cofactor as a precious goal to repair insulin sensitivity and the aberrant transcriptional management of mitochondrial biogenesis (Mootha et al., 2003; Patti et al., 2003).
Mitochondria Function and Supercomplex Formation
The mitochondrial feature is likewise regulated through the formation of mitochondrial supercomplexes. The mitochondrial electron shipping chain is a composite multiprotein machine embedded within the mitochondrial internal membrane. It is answerable to harvest electricity from metabolic fuels and rework it into ATP. It encompasses four complexes (complexes I–IV), which ship the electrons derived from the oxidation of NADH and FADH2, which in flip are generated all through glycolysis, beta-oxidation, and the Krebs cycle. Dietary Long-Chain Saturated Fatty Acids as Key Drivers of Mitochondrial Dysfunction
The terrible effect of fats oversupply to a skeletal muscle has been showing through acute elevation of circulating fatty acid levels, which additionally reduced the expression of PGC 1α and β along different genes concerned in mitochondrial metabolism (Richardson et al., 2005; Hoeks et al., 2006) in addition assisting the damaging outcomes of accelerated fatty acid availability on mitochondria fitness. This proof showed in Wistar rats wherein an excessive-fats weight-reduction plan prompted a lower mitochondrial breathing and ATP manufacturing within the soleus muscle. This impact became additionally initiated through an excessive-fructose weight-reduction plan (Chanseaume et al., 2006).
Omega-three Polyunsaturated Fatty Acids (PUFAs) and Mitochondrial Function
Diverse nutritional fats fat assets can also add in another way affect mitochondrial characteristics and insulin resistance improvement in skeletal muscle thru distinct mechanisms (Putti et al., 2015a,b). As defined earlier, lengthy-chain saturated fatty acids play a crucial role in selling insulin resistance by impairing mitochondrial bioenergetics and dynamic behavior.
On the contrary, omega-three PUFAs enhanced skeletal muscle insulin sensitivity by modulating mitochondrial characteristics. Omega-three PUFAs are extraordinarily bendy molecules because of the lengthy tail of double bonds traditional in their carbon chain and encompass the essential α-linoleic acid (ALA) and longer-chain fatty acids eicosapentaenoic (EPA) and docosahexaenoic (DHA).
In latest years, research in rodents and people have indicated that omega-three PUFAs elicit applicable practical consequences on metabolic fitness through decreasing weight problems and enhancing insulin resistance with a mechanism, which relies, at the least in part, on their cap potential to grow fats oxidation and strength expenditure and decreases fats deposition (Xu, 2015; Lalia and Lanza, 2016).
Caloric Restriction, Intermittent Fasting, and Mitochondrial Function
Caloric restriction (CR) improves insulin sensitivity and delays the onset of metabolic and age-associated illnesses in an extensive form of organisms, along with non-human primates. One idea thru which CR is theorized to enhance fitness and sturdiness is through a discounted “price of living” and oxidative harm. However, the effects of CR on mitochondrial characteristics and bioenergetics are controversial.
A quantity of research has proven that CR will increase mitochondrial biogenesis (Nisoli et al., 2005; Lopez-Lluch et al., 2006) and mitochondrial performance (Nisoli et al., 2005) and decreases mitochondrial manufacturing of ROS (Bevilacqua et al., 2005). However, this isn’t always constant throughout research or tissues (Hancock et al., 2011; Lanza et al., 2012; Walsh et al., 2014). Hancock et al. couldn’t come across any modifications in mRNA or protein stages of markers of mitochondrial biogenesis or citrate synthase pastime in muscle from rats that underwent 30% CR for 14 weeks (Hancock et al., 2011). Similarly, lengthy-time period CR no longer regulated any markers of mitochondrial biogenesis, even though CR averted age-associated lack of mitochondrial oxidative potential and performance in remoted mitochondria and muscle fibers and decreased oxidative harm (Hancock et al., 2011).
The Effect of Amino Acids and High-Protein Diet on Mitochondrial Function
Numerous research has fed animal and people various forms of protein-wealthy dietary supplements and validated modest institutions among improved postprandial plasma amino acid concentrations, especially the branched-chain AAs (i.e., leucine, isoleucine, and valine), with physiological effects along with an improved muscle protein synthesis, the launch of a few intestine hormones (especially, GLP-1 and GIP), insulin and a discounted strength intake (Floyd et al., 1966; Nilsson et al., 2007; Veldhorst et al., 2009). More recently, essential and branched-chain amino acids were proven to assist cardiac and skeletal muscle through improved mitochondrial biogenesis and characteristic in each mouse and person (D’Antona et al., 2010; Tatpati et al.,,, 2010; Valerio et al., 2011).
Food Bioactive Derivatives and Mitochondrial (DYS)Function
Bioactive compounds are typically known as non-nutritive compounds found in tiny portions of ingredients. However, they have a great capacity to supply significant upgrades in human fitness (Naumovski, 2014; Christenson et al., 2016). Furthermore, using meals bioactive derivatives, predominately from plant-primarily based totally products, has long been defined as especially beneficial because it presents a relatively clean and low-cost approach to contain nutraceuticals within the food plan.
The fitness selling impact of those bioactive molecules additionally extends to mitochondria and can constitute a treasured dietary device to save you or mitigate the metabolic aberrations underpinning mitochondrial disorder. In this regard, the bioactive, which have been maximum broadly defined for their impact on mitochondria (days)characteristic, encompass, however, aren’t restricted to, Coenzyme Q10, resveratrol, and quercetin.
The Coenzyme Q10
The Coenzyme Q10 (CoQ10) is a crucial thing of the electron-delivery chain (ETC) and is typically known as ubiquinone. Contrarily to the alternative bioactive defined in this section, CoQ10 is incredibly considerable in animal meals products. Besides its function as an electron transporter from complicated I and II to complex III, CoQ10 is likewise a fantastic antioxidant, protecting cells from oxidative harm.
Thus, ubiquinone supplementation can modulate mitochondria characteristics through helping electron delivery withinside the ETC on the one hand and save you mitochondrial oxidative damage on the alternative (Shen and Pierce, 2015).
Quercetin
Quercetin is a polyphenol, which belongs to the magnificence of flavonoids and is incredibly considerable in apples, onions, peppers, berries, and inexperienced leafy vegetables. Quercetin has broadly been said for its beneficial impact on skeletal muscle and mitochondria biogenesis and characteristics thru the activation of the SIRT1-AMPK-PGC 1α axis (Davis et al., 2009). Indeed, this polyphenol has been said to prompt the AMPK and SIRT1 (Howitz et al., 2003; Hawley et al., 2010), which, as defined above, are pivotal regulators of mitochondrial oxidative metabolism. Furthermore, quercetin can stimulate mitochondria oxidative metabolism without delay lowering the ATP: AMP ratio, which in flip consequences withinside the activation of AMPK and its downstream catabolic pathways (Dorta et al., 2005).
Resveratrol
Resveratrol (trans-three,4′,5-trihydroxy stilbene) is a stilbenoid polyphenol, which has been discovered predominately in grapes, nuts, and berries. Despite the preliminary hobby toward this bioactive molecule in general targeted on its putative function in growing sturdiness, resveratrol has emerged withinside the latest years for its practical consequences on metabolic fitness because of its cap potential to modulate mitochondria characteristic and biogenesis and oxidative metabolism (Christenson et al., 2016).
About its effects on mitochondria biology, resveratrol has been said to sell mitochondria biogenesis through activating SIRT1, which in flip, through deacetylating PGC 1α, induces its transcriptional pastime ensuing in growth in mitochondria quantity in mice (Lagouge et al., 2006). Furthermore, resveratrol has been proven to counteract the harmful impact of a high-fat food plan on metabolic and mitochondria fitness in rats.
Conclusions
The mitochondrial disorder has been broadly defined as a metabolic illness related to insulin resistance and T2DM. Mitochondrial characteristic is regulated at distinct stages, encompassing mitochondrial biogenesis, post-translational amendment of mitochondrial protein, mitochondrial dynamics, and supercomplexes formation; these procedures are dysregulated in type two diabetic people. However, whether or not those mitochondrial defects constitute a purpose or a result of insulin resistance in skeletal muscle remains elucidated.
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