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294 Cardio Diabetes Medicine 2017

CVD in Diabetes -

Is It Only Macrovascular?

Dr. Arulprakash,

MD., MRCP(UK).,FRCP(London)
Endocrinologist, Indra Diabetes Centre, Tuticorin, Tamil Nadu

Introduction: complications progress, despite intensive glycaemic
CVD account for most morbidity and mortality in control, in patients with DM. Hyperglycemia triggers
patients with diabetes mellitus. Diabetic subjects the production of ROS in vascular cells through en-
are known to have a two to four times increased zymatic (protein kinase C and the reduced form of
CAD risk, and CAD has been reported to occur two nicotinamide adenine dinucleotide phosphate [NA-
to three decades earlier in diabetic subjects as op- DPH] oxidases) and nonenzymatic sources of oxi-
posed to their nondiabetic counterparts.Diabetes dant stress (e.g., the formation of advanced glycation
causes microvascular diseases, such as nephropa- end products, AGEs).As oxidative stress increases,
thy, neuropathy, and retinopathy, and macrovascular the eNOS cofactor tetrahydrobiopterin becomes oxi-
disease (e.g., atherosclerosis). Atherosclerosis of the dized and uncouples eNOS, which cause the enzyme
coronary, cerebral, and peripheral arteries accounts to produce superoxide anion instead of NOSuperox-
for approximately 80 percent of mortality and for 75 ide anion quenches NO in a diffusion-limited reac-
percent of hospitalizations in persons with diabetes. tion to produce peroxynitrite. Peroxynitrite inhibits
prostacyclin synthase and endothelium-dependent
As type 2 diabetes shares several risk factors in com- hyperpolarizing factor activity. Similar to the effects
mon with coronary artery disease (CAD), such as age, of hyperglycemia, free fatty acids activate intracel-
hypertension, dyslipidemia, obesity, physical inactiv- lular enzymatic oxidant sources, including protein
ity, and stress, an increase in the prevalence of dia- kinase C, NADPH oxidases, and eNOS, yielding
betes indirectly implicates an escalating risk of CAD. analogous increases in superoxide anion.The excess
adipose tissue that usually accompanies type 2 dia-
Diabetes and Endothelial dysfunction: betes mellitus releases excess fatty acids. Free fatty
Diabetes causes metabolic abnormalities, including acids attenuate prostacyclin bioavailability by inhib-
hyperglycemia, dyslipidemia, and insulin resistance, iting prostacyclin synthase. Moreover, free fatty ac-
that disrupt normal arterial function and render arter- ids interfere with intracellular signaling pathways to
ies susceptible to atherosclerosis. It specifically alters cause not only muscle and visceral insulin resistance
the function of vascular endothelium and smooth but also vascular insulin resistance. In diabetes, hy-
muscle cells, as well as platelets, in ways that pro- perglycemia and increased free fatty acids increase
mote atherogenesis. Diabetes impairs the vasodila- the concentration in the cell of the metabolite dia-
tor function of endothelial cells and decreases the cylglycerol. Diacylglycerol , in turn, activates a family
bioavailability of nitric oxide (NO).Hyperglycemia de- of enzymes known as protein kinase C (PKC), that
creases NO production from endothelial nitric oxide perform key regulatory functions by phosphorylating
synthase (eNOS) and increases its degradation via proteins important in metabolic control. Activation of
generation of reactive oxygen species (ROS). Recent PKC can inhibit the expression of eNOS, augment
evidence suggests that hyperglycaemia-induced ROS cytokine-induced tissue factor gene expression and
generation is involved in the persistence of vascular procoagulant activity in human endothelial cells,
dysfunction despite normalization of glucose levels. and increase the production of proinflammatory cy-
This phenomenon has been called ’metabolic mem- tokines, proliferation of vascular wall cells, and pro-
ory’ and may explain why macro- and microvascular duction of extracellular matrix macromolecules that

GCDC 2017