Insulin Resistance and Lipid Disorders

Roberto Miccoli; Cristina Bianchi; Giuseppe Penno; Stefano Del Prato

Disclosures

Future Lipidology. 2008;3(6):651-664. 

In This Article

Insulin Resistance and Atherogenic Dyslipidemia

In insulin-resistant individuals, such as those with T2DM and MS, it is common to find characteristic changes from the normal lipid and lipoprotein pattern. These changes include elevation of triglycerides (TG), reduction of HDL-cholesterol (hdl-c), a concomitant increase of ApoB and increased small dense LDL in the face of normal or slightly elevated LDL-cholesterol (LDL-C). This combination of lipid and lipoprotein alterations is associated with significant risk of cardiovascular disease so that it is referred to as 'atherogenic dyslipidemia'.[4] In spite of articulate changes in the lipid profile, as highlighted by Ginsberg et al., it is the effect of insulin resistance on the assembly and secretion of VLDL, ApoB and TG - which plays a central role in the development of atherogenic dyslipidemia.[5]

These lipid disorders have often been associated with impaired insulin action. In population-based studies, measures of insulin action have been found to correlate in a positive manner with plasma total or VLDL-TG, and in a negative fashion with HDL-C and small dense LDL particles.[6] In the population studied by the European Group for the Study of Insulin Resistance (EGIR), a strong association between insulin action, as measured by the euglycemic clamp technique, and TGs has been documented.[7] These associations remain significant upon adjustment for obesity, age, smoking and physical activity. Even using sophisticated techniques, such as nuclear magnetic resonance (NMR), mean particle sizes for VLDL (larger), LDL (smaller) and HDL (smaller) of insulin-resistant individuals have been found to be significantly different than those observed in insulin-sensitive subjects.[8]

Abnormalities of postprandial lipoprotein metabolism have been reported in insulin-resistant individuals. Postprandial hyperlipidemia is highly prevalent in diabetic patients with both normal[9] and elevated[10,11,12] fasting TG concentrations. Rivellese et al. also reported that in T2DM patients with normal fasting TG and optimal blood glucose control (HbA1c < 6.5%), a marked alteration of postprandial lipid response may occur with significantly higher VLDL, ApoB-48, ApoB-100, cholesterol and TG levels as compared with control subjects.[13] These findings highlight the role of long residence time of TG-rich lipoprotein remnants as a feature of diabetic dyslipidemia. A direct relationship between insulin resistance and postprandial lipemia has been assessed by Annuzzi et al. by performing hyperinsulinemic clamp studies in T2DM and control individuals.[14] As expected, the former had lower insulin sensitivity but higher postprandial TG, cholesterol and ApoB levels. Excessive postprandial lipemia is associated with multiple abnormalities in LDL and HDL particles, which may contribute to the risk of coronary artery disease in T2DM.[15]

Dyslipidemia is one of the major components of MS. In subjects with MS, the prevalence of isolated hypertriglyceridemia and low HDL-C levels has been determined to occur at rates of 30 and 37%, respectively.[16] In the adult Italian population of the Lucca Cuore project,[17] hypertriglyceridemia occurred at rates of 27% and 13% for male and female subjects meeting the ATPIII criteria for MS, respectively, while the prevalence of low HDL-C in both genders was quite similar (29% and 30%, respectively). Furthermore, more than 80% of patients with both lipid abnormalities met the ATP-III definition for MS.[18] In subjects with MS, abnormalities of lipoprotein subclass profile determined by NMR are independent of age, BMI, systolic blood pressure, smoking and lipid concentrations. In these individuals, impairment in insulin sensitivity represents the main determinant of these abnormalities.[19] More recently, we have demonstrated that the typical atherogenic dyslipidemia is also present in hypertensive subjects with MS.[20]

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