Data of many investigatorssuggests that the IR in many type 2 diabetic patients results from an increasein visceral adiposity. It has been hypothesized that the direct release of FFA orother products from visceral adipose tissue into the portal circulation may bean important mechanism in causing IR (Banerji et al., 1997). Lipotoxicity and Glucotoxicity in thepathophysiology of T2DM· Lipotoxicity: Chronicelevation of plasma FFA adversely affects insulin secretion and insulin action(lipotoxicity). Chronic exposure of pancreatic ?-cells to FFA recruitsmultiple mechanisms of toxicity, including accelerated ceramide synthesis,increased fatty acid oxidation and esterification and fatty acid-inducedapoptosis (Del Prato, 2009). Also,increased FFA concentrations contribute to IR in peripheral tissues. Initially,Randle et al. were the first to suggest a primary role for elevated FFAavailability and the development of IR.
They showed that there are substratecompetition between glucose and FFA. Moreover, they speculated that increase infat oxidation would cause an increase in the mitochondrial acetyl CoA:CoA andNADH:NAD ratios with subsequent inactivation of pyruvate dehydrogenase (PDH).This in turn would induce an increase in intracellular citrate levels, resultingin inhibition of phosphofructokinase (PFK) and glucose-6-phosphate (G6P) accumulation.As G6P inhibits hexokinase activity, this would result in intracellular accumulationof glucose and decreased glucose uptake (Randle et al.,1963). Another hypothesis account for the effectsof fatty acidsin IR is shown in (Figure 1.2), this model holds that increasing intracellular fatty acid metabolites such as fattyacyl CoA’s, diacylglycerol or ceramides activate a serine/threonine kinase cascade (possibly initiatedby protein kinase Cq (PKCq)), resulting inphosphorylation of serine/threonine sites on insulin receptor substrates (IRS-1and IRS-2) which in turn decreases the ability of the IRSs to activatePI3-kinase.
As a consequence, glucose transport activity and other eventsdownstream of insulin receptor signaling are diminished including muscle glycogen synthesis (Shulman,2000). All are the main reasons that shed a light for the involvement ofother mechanisms in the development of IR. Figure (1.2) Mechanism offatty acid-induced insulin resistance in skeletal muscle (Savage et al.,2007).Abbreviations: DAG: diacylglycerol, GLUT: glucose transporter, G6P: glucose6-phosphate, GSK3: glycogen synthase kinase-3, IRS: insulin receptor substrate,LCCoA: long-chain acyl coenzyme A; nPKCs, novel protein kinase Cs, PI 3-kinase:phosphatidylinositol 3-kinase; PTB: phosphotyrosine binding domain, PH:pleckstrin homology domain, SH2: src homology domain, AKT2: protein kinase B.
· Glucotoxicity: Chronic elevation ofplasma glucose impairs both insulin secretion and insulin action(glucotoxicity) where it may induces IR and decreases pancreatic ?-cellfunction by several different mechanisms. Hyperglycaemia in vivo as well as invitro repeatedly has been shown to exert a cytostatic and proapoptotic effecton ?-cells including cytoplasmic DNA fragmentation, highercaspase 3 (a pro-apoptotic protease) activity and greater expression of thegene encoding the pro-apoptotic protein (Del Prato, 2009). Multiple mechanisms havebeen reported to show the hyperglycemia-induced loss of ?-cell function, but amajor contributor is alteration of intracellular energy metabolism andoxidative stress, as well as mitochondrial dysfunction. Other pathways linkedto hyperglycemia include endoplasmic reticulum (ER) stress and hypoxia-inducedstress (Kim and Yoon, 2011). Therefore, glucotoxicity is one of the mostimportant mechanisms of ?-cell dysfunction and loss in diabetic patients. T2DM and Mitochondrial dysfunction: There is evidence thatmitochondrial dysfunction is related to T2DM and IR (Montgomery and Turner,2015).
A free radical defined asany chemical species that have one or more unpaired electrons and that often makesthe free radical to be very reactive and acts as an electron acceptor that stealselectrons from other molecules (Bhattacharya, 2015). Freeradicals and related molecules are generally classified as reactive oxygenspecies (ROS) due to their ability to create oxidative changes inside the celland can be divided into two types: free radical ROS, like hydroxylradical ion (OH?), superoxide anion (?O2•)and nitric oxide ion (NO?) and highly reactive non-radical ROS,like molecular oxygen (O2) and hydrogen peroxide(H2O2) producing radical forms of ROS (Chen et al., 2012). Most intracellular ROS arebrought from ?O2•, whose formation is oftenthrough NADPH oxidases (NOXs), xanthine oxidase (XO) and the mitochondrial electron-transportchain (mETC) in endogenous biologic systems. ?O2•is short-lived and can be converted to H2O2 either throughspontaneous dismutation or through the catalytic action of superoxide dismutase(SOD), mitochondrial MnSOD and cytosolic CuZnSOD. H2O2 iseventually converted to highly toxic OH? in the existence of reducediron (Fe2+) or copper (Cu+) through the Fenton reaction (Wen et al.
, 2013) (Figure 1.3). The most characterized NOXenzyme is Nox2 NADPH oxidase which can induce electron transfer from cytosolic NADPHto the oxygen molecules in the phagosomal lumen, producing ?O2•. Another enzyme, XO, can also produce ?O2•by transferring electrons from hypoxanthine to oxygen molecules (Perevoshchikovaet al., 2013). Moreover, mETC, composed of four protein complexes(complexes I to IV), cytochrome c (cyto c) and coenzyme Q (CoQ), is the major sourceof ROS in living cells, through which continued aerobic respiration produces ?O2•.Great amounts of ?O2• are generated at the mitochondrial complex I when the NADH/NAD+ratio is high or reverse electron transport happens.
For H2O2,both peroxisomes and ER luminal thiol oxidase I (EroI) are major sourcesfor H2O2 production (Wen et al., 2013).