Lipid And Lipoprotein Metabolism In Insulin Resistant States

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Insulin resistance is central to the dyslipidemia of type 2 diabetes (21). A simplified overview of the mechanisms of the dyslipidemia of diabetes is shown in Fig. 1. In the presence of insulin resistance there is an increased flux of free fatty acids from adipose tissue to the liver, as a result of decreased inhibition of the hormone-sensitive lipase. Fatty acids stimulate increased hepatic production and secretion of very low-density lipoprotein (VLDL), which is also increased by insulin resistance and hyperinsulinemia. Increased hepatic output of VLDL continues in the postprandial state and competes with exogenously-derived triglyceride carried in chylomicrons for the enzyme lipoprotein lipase. As a result, there is accumulation of triglyceride-rich lipoproteins and prolonged postprandial lipemia. The lipemia stimulates increased lipid transfer via cholesterol ester transfer protein (CETP) exchanging triglyceride for cholesterol ester between triglyceride-rich lipoproteins and lipoproteins of higher density. As a result, LDL and HDL are enriched in triglycerides and become substrates for hepatic lipase (HL), which hydrolyses triglyceride, producing small dense LDL and small dense HDL. The importance of small dense LDL has been discussed above in relation to atherogenesis. Small dense HDL is more rapidly catabolized than other HDL species, leading to lower plasma HDL concentrations (22). Low HDL cholesterol concentrations are a strong predictor of vascular risk in diabetes, as in the general population (9). Furthermore, small dense HDL cannot pick up cholesterol from tissues and deliver it to the liver as efficiently as larger HDL (23).

FIGURE 1 Essential steps in the development of diabetic dyslipidemia. Cholesteryl ester transfer protein (CETP) is synthesized in the liver and circulates primarily bound to HDL. It transfers triglycerides from VLDL to HDL and LDL for the exchange of cholesterol, thereby generating triglyceride-rich HDL and LDL particles. These particles are substrate for hepatic lipase (HL), which cleaves triglycerides and leaves small dense HDL and LDL.

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