Impaired Insulin-Stimulated Glucose Oxidation and Free Fatty Acid Suppression in Patients with Familial Combined Hyperlipidemia

Abstract

Abstract-FamilialKey Words: familial combined hyperlipidemia Ⅲ insulin resistance Ⅲ insulin Ⅲ glucose oxidation Ⅲ nonoxidative glucose disposal F amilial combined hyperlipidemia (FCHL) is characterized by hypercholesterolemia and/or hypertriglyceridemia in affected family members. The prevalence of this disorder is approximately 1% in western populations in which it has been estimated to cause 10% of premature coronary artery disease. 1,2 Hepatic overproduction of triglyceride-rich very low density lipoproteins (VLDL) and apolipoprotein B (apoB) may be the causes for FCHL. [3][4][5] Because most of the characteristic metabolic disorders in FCHL (high triglyceride levels, combined hyperlipidemia, high apoB levels, hepatic overproduction of lipoproteins, and small low density lipoprotein [LDL] size) also have been associated with insulin resistance, studies on insulin action in these patients are of great interest. 6 In previous studies hyperinsulinemia 7,8 and impaired insulin action on glucose metabolism and free fatty acid suppression have been associated with combined hyperlipidemia 9 and FCHL, 10,11 indicating that insulin resistance is an essential part of this disorder. Genetic defects that could explain a large part of either insulin resistance or FCHL itself have not yet been found. Therefore, studies aiming to elucidate mechanisms simultaneously leading to dyslipidemia and insulin resistance in FCHL are of great importance.Two recent studies have demonstrated the presence of insulin resistance in patients with FCHL compared with their first-degree relatives or controls. 10,11 However, these studies included a limited number of subjects and more importantly did not apply the indirect calorimetry technique. Therefore, the intracellular defect in insulin action was not evaluated in previous studies. 10,11 To clarify this issue, we performed the hyperinsulinemic euglycemic clamp with indirect calorimetry in 58 FCHL family members and 72 healthy controls. Methods SubjectsProbands with FCHL were selected from the myocardial infarction survivor family study done at our department. 12 In this study 75

Relationship of Insulin Sensitivity and ApoB Levels to Intra-abdominal Fat in Subjects With Familial Combined Hyperlipidemia

“…29,30 Subsequent studies using the clamp technique confirmed that whole-body glucose uptake is reduced in FCHL subjects compared with control subjects. 28,31,32 When the FCHL subjects in these studies were subdivided by lipid phenotype (high cholesterol, high triglycerides, or combined hyperlipidemia), Si was found to be reduced only in those …”

“…30,32,33 In FCHL family members, also reported were significant correlations of free fatty acid levels during the clamp with triglyceride levels but not with apoB levels. 31,32 Visceral adiposity has been associated with a number of metabolic abnormalities, including insulin resistance, increased triglyceride levels, lower HDL 2 cholesterol, more cholesterol in small dense LDL particles, 24,25 increased apoB production rates, 44 and increased apoB levels. 45,46 To determine whether accumulation of IAF is similarly associated with insulin resistance and dyslipidemia in FCHL, subjects in the present study underwent measurement of IAF and SQF by CT scan.…”

“…26 -32 Given these similarities in metabolic phenotype, it has been hypothesized that insulin resistance is a major determinant of the hyperlipidemia phenotype in FCHL, including elevated apoB levels. 27,31,33 However, whether the increased apoB levels in FCHL can be entirely accounted for by the finding of insulin resistance in this population remains to be determined. In a study of FCHL families, Jarvik et al 34 suggested that mechanisms resulting in the dense LDL phenotype (such as insulin resistance) may contribute to the lipid phenotype of FCHL, but they do not fully explain the elevated apoB levels in this disorder.…”

Familial Combined Hyperlipidemia and Insulin Resistance

“…6 Presently, it remains unclear whether FCHL is accompanied by increases in IAF; however, patients with FCHL are insulin resistant. 7,8 Thus, it is important to discern the relative interdependence of insulin resistance and apoB, both potential explanations for the increase in CHD risk in FCHL patients.…”

“…6 Presently, it remains unclear whether FCHL is accompanied by increases in IAF; however, patients with FCHL are insulin resistant. 7,8 Thus, it is important to discern the relative interdependence of insulin resistance and apoB, both potential explanations for the increase in CHD risk in FCHL patients.The study reported by Purnell et al 9 in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology addresses this relationship in a small number (nϭ11, 6 men and 5 women) of well-characterized and zealously studied subjects with FCHL and age-and/or age-and weight-matched controls. Unfortunately, only 1 of the 22 age-and weightmatched controls was female.…”