Excessive production of very lowdensity lipoproteins vldls the primary lipid abnormality in the insulinresistant state

The primary metabolic abnormality associated with insulin-resistant states is overproduction of VLDLs. Because newly secreted VLDL particles are TG rich, the result is mild-to-moderate hypertriglyceridemia. If the overproduction of VLDLs is accompanied by other defects, such as Apo C-II deficiency (which reduces lipoprotein lipase activation), or a defect in the hepatic clearance of TG-rich Apo B-containing lipopro-teins, the result can be more severe hypertriglyceridemia (Fredrickson Types IV and V) and/or mixed dyslipidemia, involving elevations in TG and LDL-C (Types IIB and III).

Two features of the insulin-resistant state are centrally involved in the pathogenesis of VLDL overproduction: elevated circulating levels of FFAs and hyperinsulinemia. It appears that both must be present to generate overproduction of VLDLs. For example, in subjects with normal insulin sensitivity, a glucose infusion will not only increase the plasma insulin concentration but also lower levels of FFAs and reduce hepatic VLDL secretion (1). In contrast, patients with poorly controlled type 1 diabetes have low insulin levels and high concentrations of FFA but do not have elevated VLDL secretion (1). However, among insulin-resistant subjects with abdominal obesity, fasting and postprandial levels of circulating insulin are elevated, but this hyperinsulinemia does not normally suppress FFA release into the circulation; thus, both insulin and FFA levels are elevated, resulting in VLDL overproduction.

Increased hepatic exposure to FFAs inhibits Apo B degradation and leads to increased VLDL synthesis (9). Insulin promotes lipogenesis, which contributes to the TG pool available for incorporation into VLDL particles. In addition, insulin's ability to enhance Apo B degradation may be impaired in the insulin-resistant patient (9).

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