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     Data of many investigators
suggests that the IR in many type 2 diabetic patients results from an increase
in visceral adiposity. It has been hypothesized that the direct release of FFA or
other products from visceral adipose tissue into the portal circulation may be
an important mechanism in causing IR (Banerji et al., 1997). 


Lipotoxicity and Glucotoxicity in the
pathophysiology of T2DM

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elevation of plasma FFA adversely affects insulin secretion and insulin action
(lipotoxicity). Chronic exposure of pancreatic ?-cells to FFA recruits
multiple mechanisms of toxicity, including accelerated ceramide synthesis,
increased fatty acid oxidation and esterification and fatty acid-induced
apoptosis (Del Prato, 2009).

increased FFA concentrations contribute to IR in peripheral tissues. Initially,
Randle et al. were the first to suggest a primary role for elevated FFA
availability and the development of IR. They showed that there are substrate
competition between glucose and FFA. Moreover, they speculated that increase in
fat oxidation would cause an increase in the mitochondrial acetyl CoA:CoA and
NADH:NAD ratios with subsequent inactivation of pyruvate dehydrogenase (PDH).
This in turn would induce an increase in intracellular citrate levels, resulting
in inhibition of phosphofructokinase (PFK) and glucose-6-phosphate (G6P) accumulation.
As G6P inhibits hexokinase activity, this would result in intracellular accumulation
of glucose and decreased glucose uptake (Randle et al.,


     Another hypothesis account for the effects
of fatty acids
in IR is shown in (Figure 1.2), this model holds that increasing  intracellular fatty acid metabolites such as fatty
acyl CoA’s, diacylglycerol or ceramides activate a serine/threonine kinase cascade (possibly initiated
by protein kinase Cq (PKCq)), resulting in
phosphorylation of serine/threonine sites on insulin receptor substrates (IRS-1
and IRS-2) which in turn decreases the ability of the IRSs to activate
PI3-kinase. As a consequence, glucose transport activity and other events
downstream of insulin receptor signaling are diminished including muscle glycogen synthesis (Shulman,
2000). All are the main reasons that shed a light for the involvement of
other mechanisms in the development of IR.  



Figure (1.2) Mechanism of
fatty acid-induced insulin resistance in skeletal muscle (Savage et al.,

Abbreviations: DAG: diacylglycerol, GLUT: glucose transporter, G6P: glucose
6-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 of
plasma glucose impairs both insulin secretion and insulin action
(glucotoxicity) where it may induces IR and decreases pancreatic ?-cell
function by several different mechanisms. Hyperglycaemia in vivo as well as in
vitro repeatedly has been shown to exert a cytostatic and proapoptotic effect
on ?-cells including cytoplasmic DNA fragmentation, higher
caspase 3 (a pro-apoptotic protease) activity and greater expression of the
gene encoding the pro-apoptotic protein (Del Prato, 2009).

     Multiple mechanisms have
been reported to show the hyper­glycemia-induced loss of ?-cell function, but a
major contributor is alteration of intracellular energy metabolism and
oxidative stress, as well as mitochondrial dysfunction. Other pathways linked
to hyperglyce­mia include endoplasmic reticulum (ER) stress and hypoxia-induced
stress (Kim and Yoon, 2011). Therefore, glucotoxicity is one of the most
important mechanisms of ?-cell dysfunction and loss in diabetic patients.     


T2DM and Mitochondrial dysfunction:

     There is evidence that
mitochondrial dysfunction is related to T2DM and IR (Montgomery and Turner,


     A free radical defined as
any chemical species that have one or more unpaired electrons and that often makes
the free radical to be very reactive and acts as an electron acceptor that steals
electrons from other molecules (Bhattacharya, 2015). Free
radicals and related molecules are generally classified as reactive oxygen
species (ROS) due to their ability to create oxidative changes inside the cell
and can be divided into two types: free radical ROS, like hydroxyl
radical 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 are
brought from ?O2•, whose formation is often
through NADPH oxidases (NOXs), xanthine oxidase (XO) and the mitochondrial electron-transport
chain (mETC) in endogenous biologic systems. ?O2•
is short-lived and can be converted to H2O2 either through
spontaneous dismutation or through the catalytic action of superoxide dismutase
(SOD), mitochondrial MnSOD and cytosolic CuZnSOD. H2O2 is
eventually converted to highly toxic OH? in the existence of reduced
iron (Fe2+) or copper (Cu+) through the Fenton reaction (Wen et al., 2013) (Figure 1.3).


     The most characterized NOX
enzyme is Nox2 NADPH oxidase which can induce electron transfer from cytosolic NADPH
to the oxygen molecules in the phagosomal lumen, producing ?O2•.
 Another enzyme, XO, can also produce ?O2•
by transferring electrons from hypoxanthine to oxygen molecules (Perevoshchikova
et al., 2013).


     Moreover, mETC, composed of four protein complexes
(complexes I to IV), cytochrome c (cyto c) and coenzyme Q (CoQ), is the major source
of 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 sources
for H2O2 production (Wen et al., 2013).


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