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The Applied Biochemical and 71
Metabolic Aspects of Diabetes and Heart

Figure 1 : Insulin suppresses hepatic glucose production ofHDL particles by the liver and loss of apolipoprotein (Apo)
by direct and indirect mechanisms. In insulin resistance, A, resulting in low HDLconcentrations. The triglyceride-rich
the ability of insulin to suppress lipolysis in adipose tissue LDL particle is stripped of its triglycerides, resultingin the
and glucagon secretion by alpha cells in the islet results in accumulation of atherogenic small, dense LDL particles. (5)
increased gluconeogenesis. In addition, insulin inhibition
of glycogenolysis is impaired. Therefore, both hepatic and The probable mechanisms are:
peripheral insulin resistance result in abnormal glucose pro- 1. Non-enzymatic glycation of apolipoproteins im-
duction by the liver . pairs lipoprotein clearance.
(5)
Highcirculating concentrations of alternative fuels 2. Insulin inhibits lipolysis through inhibition of hor-
such as triglycerides, NEFA, lactate and ketone mone-sensitive lipase, which breaks down adi-
bodies compete with glucose for uptake and in their pose tissue triglyceride and consequently mobi-
presence, glucose clearance is reduced. Insulin re- lizes fat stores for subsequent utilization. In dia-
sistance is a consequence of ‘cellularsatiety’, seen betes, insulinmediated inhibition is attenuated or
whenever intracellular sensors such as uridinedi- lost, so breakdown of fat stores carries on even if
phosphate (UDP)-glucosamine detect excess energy- food is available. The uncontrolledrelease of free
supply .To maintain metabolic homeostasis, nutrient fatty acids is followed by their uptake by the liv-
(4)
intake exceeding expenditure whether carbohydrate, er in a simple concentration-dependent manner.
protein, or lipid, are ultimately stored as triglyceride Free fatty acids are metabolized by β-oxidation,
in adipose tissue . If this storage capacity of adipose but once their concentration exceeds capacity
tissue is exceeded, lipids and other for oxidationthey are re-esterified with glycerol
Nutrients enter nonstorage tissues, such as myo- to formtriacylglycerol (triglyceride) which leads to
cytes, hepatocytes, vascular cells, and beta cells, increasedrate of synthesis (and thereby release)
and trigger a variety of cellular responses that lead of triglyceriderichvery low density lipoprotein
to insulin resistance and cellular dysfunction. (VLDL).
Dyslipidaemia: Dyslipidaemia is said to be charac- 3. PeripheralVLDL-triglyceride clearance may be
terised by elevated triglycerides, reduced high-den- impaired becauselipoproteinlipase, the principal
sity lipoprotein (HDL), and increased small dense enzyme responsible for clearingVLDL-triglycer-
low-density lipoprotein (LDL) particles. Diabetes is ide, is synthesis and secretion is induced by In-
(6)
(4)
strongly associated with abnormalities of lipid me- sulin .
tabolism (fig.2). 4. High density lipoprotein(HDL) acts as an anti-
oxidant and thereby limitsthe lipid peroxidation,
which is responsiblefor atheroma formation. The
overproduction of VLDL triglyceride in Diabetes
mellitus results in increased transfer of VLDL
triglyceride to HDL particles in exchange for
HDL-cholesterol esters mediated by the choles-
terol ester transfer protein. The triglyceride-rich
HDL is hydrolyzed by hepatic lipase leading to
the generation of small HDL, which is degrad-
ed more readily by the kidneys, resulting in low
serum HDL levels contributing to the increased
cardiovascular risk in diabetes . Total plasma
(9)
cholesterolconcentration is often normal in type
2 diabetes, but theHDL: LDL and HDL:total cho-
lesterol ratios are usually low .
(4)
Figure 2 Insulin resistance and dyslipidemia. The suppres-
sion of lipoprotein lipase and very low density lipoprotein 5. The composition of VLDL changes such thatit
(VLDL) production by insulin is defective in insulin resis- contains more triglyceride and cholesteroyl es-
tance, leading to increased flux of free fatty acids (FFAs) ters relativeto the apoprotein content. Cholester-
to the liver and increased VLDL production, which results ol ester transfer protein–mediated exchange of
in increased circulating triglyceride concentrations. The tri- VLDL triglyceride for LDL-cholesterol esters and
glycerides are transferred to low-density lipoprotein (LDL)
and highdensitylipoprotein (HDL), and the VLDL particles subsequent triglyceride hydrolysis by hepatic li-
gain cholesterol esters by the actionof the cholesterol ester pase probably result in generation of the small,
transfer protein (CETP). This leads to increased catabolism dense LDLparticles (6) . Theseabnormalities are

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