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72 Cardio Diabetes Medicine 2017

particularly atherogenic and underlinethe need to compared with thosefrom healthy subjects.Moreover,
consider the whole lipid profile ratherthan just to- platelet reactivity and excretionof thromboxane me-
tal or LDL-cholesterol in the dyslipidaemiaof type tabolites are increased in obese patients withinsu-
2 diabetes . lin resistance and this phenomenon is reversed by
(4)
weight loss or 3-week treatment with pioglitazone .
(9)
Mechanism that links cardiovascular Body weight as well asimpaired insulin sensitivity
disease and insulin resistance -The may also account for the faster recoveryof cycloox-
metabolic syndrome: ygenase activity despite aspirin treatment. Hypergly-
A constellation of metabolic derangements often cemia and insulin resistance alone may not explain
seen in patients with insulin resistance and T2DM the persistent cardiovascular risk burden associated
with an increased risk of cardiovascular disease have with type 2 diabetes. In this regard, adipose tissue
been designated as syndrome X. The profile includes dysfunction, inflammation, and release of aberrant
mainly dyslipidaemia comprising of hypertriglyceri- adipokines like leptin, adipocyte fatty acid-binding
(10)
demia, low plasma HDL, and small, dense LDL parti- protein, interleukins, may be particularly relevant .
cle concentrations. The normal vasodilative response These molecules may drive vascular dysfunction via
of insulin is disrupted in obese, insulin-resistant, and increased proliferation/migration of smooth muscle
diabetic persons and also through insulin’s inability cells, eNOS inhibition, and activation of NFkB signal-
to increase the production of the potent vasodilator ling with subsequent expression of adhesion mole-
(11)
nitric oxide by endothelial cells .An intrinsic defect cules and atherosclerosis .
(7)
invasodilation in Hypertensive patients might con-
tribute to insulin resistance by decreasingthe surface Hyperglcemia per se causing diabetic tissue
area of the vasculature perfusing skeletalmuscle, damage:
decreasing the efficiency of glucose uptake.Several Postulated mechanisms are:
factors involved in clotting and fibrinolysis, including-
fibrinogen, factor VII, and PAI-1, have been shownto 1. Increased activation of the polyol pathway,where
be increased in persons with insulin resistance . aldosereductase involved in the reduction of tox-
(5)
ic aldehydes to their respective alcohols, is divert-
Atherogenesis in Insulin resistance: ed to reducing excess glucose to sorbitol, which
is later oxidized to fructose under conditions of
The atherogenic effects of insulin resistance are intracellular hyperglycaemia. T his process con-
also due to changes in lipid profile such as high tri- sumes the cofactor NADPH, which is then not
glycerides, low HDL cholesterol, increased remnant available for the regeneration of reduced glutathi-
lipoproteins, elevated apolipoproteins B (ApoB) as one, thus rendering cells vulnerable to the effects
well as small and dense LDL. Atherogenic dyslip- of oxidative stress .
(12)
idemia is a reliable predictor of cardiovascular risk
and its pharmacological modulation reduces vascular 2. Slow accumulation over time of advanced gly-
events in subjects with type 2 diabetes and metabolic cation endproducts (AGEs), Glucose and amino
syndrome . acids combine with matrix, cellular and plasma
(8)
proteins to form unstable Schiffbase adducts,
Coronary events are triggered because of a pro- which undergo chemical rearrangement overtime
thrombotic state in patients with insulin resistance. to form Amadori products and, eventually, AGEs
Under physiological conditions,insulin inhibits plate- by nonenzymatic glycation. Advanced glycation
let aggregation and thrombosis via tissue factor (TF) endproducts are thought to cause tissue damage
inhibition and enhanced fibrinolytic action due to by alterationsin the structure and function of the
modulationof plasminogen activator inhibitor-1 (PAI- extracellular matrix and these changes maycon-
1) levels. In contrast, insulin resistance facilitates ath- tribute to the endothelial dysfunction, basement
erothrombosis through increased cellular synthesis membranethickening and increased vascular
of PAI-1 and fibrinogen and reduced production of permeability .
(7)
tissue plasminogen activator.
3. Intracellular hyperglycaemia, by causing in-
In platelets, lack of insulinleads to a down-regulation creased diacylglycerol (DAG) concentration, may
of the IRS-1/Akt pathway resulting incalcium accu- cause further activation of theNFκB pathway via
mulation upon basal conditions. This lattermecha- activation of protein kinase C (PKC).The end re-
nism explains why platelets from diabetic patients sult is vasoconstriction and hypercoagulabilityvia
show faster response and increased aggregation increased endothelin-1, TGF-β and plasminogen-

GCDC 2017