Defects of Insulin Action on Fatty Acid and Carbohydrate Metabolism in Familial Combined Hyperlipidemia

Abstract

Familial combined hyperlipidemia (FCHL) is a common cause of premature myocardial infarction, but its metabolic basis is unknown. Insulin resistance has been suggested in some patients by the presence of fasting hyperinsulinemia. We studied insulin action on carbohydrate and fatty acid metabolism in FCHL patients and healthy control subjects by a two-step euglycemic, hyperinsulinemic clamp. During low-dose insulin infusion, steady-state nonesterified fatty acids (NEFAs) were higher in patients than in control subjects (0.36 mmol/L [95% confidence limits, 0.19, 0.53] versus 0.19 mmol/L [0.10, 0.28]; P = .05). The ratio of steady-state to basal NEFAs was increased by 88% in patients compared with control subjects (P = .005). During high-dose insulin infusion, insulin sensitivity for peripheral glucose disposal was reduced by 60% in FCHL patients compared with control subjects (P = .03). Hepatic glucose production at baseline and during the clamp was similar in the two groups. In multiple regression analysis, increased upper-body fat in the patient group accounted for the impairment of insulin-mediated glucose disposal but did not influence the defect in insulin-mediated NEFA suppression in the FCHL patients. This defect in fatty acid metabolism may be a primary defect in FCHL that contributes to abnormalities in the secretion and composition of lipoproteins in this disorder. Direct study of this defect may facilitate genetic analysis of this disorder.

Lack of association between central adiposity and lipaemia in UK Sikh men

“…This would increase gluconeogenesis, 51 reduce hepatic insulin extraction 52 and stimulate VLDL apolipoprotein B and TAG production. 53,54 Reduced insulin-mediated glucose uptake through the glucose-fatty acid cycle is also linked with elevated NEFA, 55 which would lead to glucose intolerance and hyperinsulinaemia. The data from the present study showed positive correlations between waist, subcutaneous fat mass, suprailiac skinfold thickness and NEFA concentrations in the Sikh men, and a positive association between suprailiac skinfold thickness and NEFA in the Caucasian men, thereby supporting the above hypothesis.…”

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

“…Insulin resistance has been associated with most of the characteristic metabolic disorders in FCHL 6 (high triglyceride levels, combined hyperlipidemia, high apoB levels, hepatic overproduction of lipoproteins, and small LDL size), as well as with the disorder itself. 10,11 In addition to dyslipidemia, insulin resistance in these patients may also contribute to increased risk of atherosclerosis. 24,25 Therefore, studies on the mechanisms that could potentially cause both insulin resistance and dyslipidemia in these patients are of great importance.…”

“…[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.…”

“…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.…”

“…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. …”