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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #89: Lipid and Lipoprotein Metabolism, Hypolipidemic Agents, and Therapeutic Goals Part 1

Introduction

Any discussion of lipid and lipoprotein metabolism in diabetes mellitus, especially type 2 diabetes mellitus (T2DM), must consider the role of insulin resistance (IR). IR plays a central role in the abnormal lipid and lipoprotein metabolism of T2DM [1] as evidenced by the characteristic set of lipid and lipoprotein abnormalities accompanying IR, even in the absence of frank hyperglycemia or abnormal glucose tolerance. Individuals with IR have low plasma levels of HDL-C and elevations in plasma triglyceride (TG) levels compared with levels seen in individuals who have normal insulin sensitivity. There is also an increase in the proportion of low-density lipoprotein (LDL) particles that are small, dense, and cholesterol ester-poor. Importantly, total cholesterol levels in insulin-resistant individuals are generally comparable to levels in people who are insulin sensitive, reinforcing the need for more detailed measures of lipoprotein to assess CVD risk [2–4]. Lipid derangements seen with IR progressively worsen across a continuum of declining glucose tolerance, from normal glucose tolerance (NGT) through impaired glucose tolerance (IGT) and T2DM [5].

Importantly, the relationship between IR and dyslipidemia extends across major ethnic groups, including African- and Hispanic Americans. Among women, IR and T2DM seem to exert a greater negative impact on several CVD risk factors, including TG and HDL-C levels and LDL particle size. This may, at least in part, account for the greater relative increase in coronary heart disease (CHD) risk observed in women with T2DM compared with their male counterparts [6]. IR and T2DM are also associated with increases in very low-density lipoprotein (VLDL) particle number and VLDL TG concentration, and a predominance of larger, more buoyant VLDL1 particles. In contrast, HDL particle number and size decrease in the face of increasing IR [2,3,5]. Plasma levels of apolipoprotein B100 (apo B100), the defining protein of the atherogenic lipoprotein series, which includes VLDL, intermediate-density lipoproteins (IDL), and LDL, are increased in the setting of IR [1].This is particularly true when hypertriglyceridemia is also present, as is usually the case in individuals with IR or T2DM. In contrast, plasma levels of apolipoprotein A1 (apo A1), the surface protein unique to HDL particles, are reduced with IR [1].

The derangements in lipid and lipoprotein physiology discussed thus far occur in the context of the fasting state. Importantly, however, IR and T2DM are also associated with disordered postprandial lipid metabolism [7]. Although the severity of postprandial hyperlipidemia is typically closely related to the fasting plasma TG level [7], postprandial dyslipidemia has been demonstrated in people with T2DM even in the setting of normal fasting TG levels and optimal blood glucose control [8]. Although postprandial dyslipidemia has been associated with increased CVD prevalence in individuals without diabetes [7,9,10], this relationship has not been well characterized in people with IR or T2DM [7,11]. Importantly, a study in 150 individual with diabetes with or without coronary artery disease (CAD) demonstrated no differences in several aspects of postprandial lipid and lipoprotein levels [12]. This is probably indicative of the nearly universal abnormalities of postprandial lipid metabolism in T2DM. On the other hand, several recent studies in large cohorts, most without diabetes, have demonstrated that nonfasting TG levels are as predictive or even more predictive of future CVD events than fasting TG concentrations [13,14].

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