Insulin resistance and
type 2 diabetes mellitus are generally accompanied by low
HDL cholesterol and high plasma
triglycerides, which are major cardiovascular risk factors. This review describes abnormalities in HDL metabolism and reverse
cholesterol transport, i.e. the transport of
cholesterol from peripheral cells back to the liver for metabolism and biliary excretion, in
insulin resistance and
type 2 diabetes mellitus. Several
enzymes including
lipoprotein lipase (LPL), hepatic
lipase (HL) and
lecithin: cholesterol acyltransferase (LCAT), as well as
cholesteryl ester transfer protein (CETP) and
phospholipid transfer protein (PLTP), participate in HDL metabolism and remodelling.
Lipoprotein lipase hydrolyses
lipoprotein triglycerides, thus providing
lipids for HDL formation. Hepatic
lipase reduces HDL particle size by hydrolysing its
triglycerides and
phospholipids. A decreased postheparin plasma LPL/HL ratio is a determinant of low
HDL2 cholesterol in
insulin resistance. The esterification of free
cholesterol by LCAT increases HDL particle size. Plasma
cholesterol esterification is unaltered or increased in
type 2 diabetes mellitus, probably depending on the extent of
triglyceride elevation. Subsequent CETP action results in transfer of
cholesteryl esters from HDL towards
triglyceride-rich
lipoproteins, and is involved in decreasing HDL size. An increased plasma
cholesteryl ester transfer is frequently observed in
insulin-resistant conditions, and is considered to be a determinant of low
HDL cholesterol.
Phospholipid transfer protein generates small
pre beta-HDL particles that are initial acceptors of cell-derived
cholesterol. Its activity in plasma is elevated in
insulin resistance and
type 2 diabetes mellitus in association with high plasma
triglycerides and
obesity. In
insulin resistance, the ability of plasma to promote cellular
cholesterol efflux may be maintained consequent to increases in PLTP activity and
pre beta-HDL. However, cellular
cholesterol efflux to diabetic plasma is probably impaired. Besides, cellular abnormalities that are in part related to impaired actions of
ATP binding cassette transporter 1 and
scavenger receptor class B type I are likely to result in diminished cellular
cholesterol efflux in the diabetic state. Whether hepatic metabolism of HDL-derived
cholesterol and subsequent hepatobiliary transport is altered in
insulin resistance and
type 2 diabetes mellitus is unknown. Specific CETP inhibitors have been developed that exert major
HDL cholesterol-raising effects in humans and retard
atherosclerosis in animals. As an increased CETP-mediated
cholesteryl ester transfer represents a plausible metabolic intermediate between high
triglycerides and low
HDL cholesterol, studies are warranted to evaluate the effects of these agents in
insulin resistance- and diabetes-associated dyslipidaemia.