The effects of hyperinsulinemia on arterial wall and peripheral muscle metabolism in dogs

Abstract

Peripheral hyperinsulinemia may be associated with metabolic consequences that could contribute to the high incidence of macrovascular disease in patients with diabetes mellitus. Arterial wall and striated muscle cells were studied in dogs to examine the effect of hyperinsulinemia on the lipid content and on lipogenic and glycolytic enzyme activity. Eight pancreatectomized dogs received segmental pancreatic autografts with venous drainage into the iliac vein. Glucose disappearance rates (K values) were normal four years after transplantation, but both fasting serum insulin levels (48.9 ± 4.8 v 11.8 ± 1.9 μU/mL) and the total area under the glucose-insulin response curve (1797 ± 196 v 1110 ± 158 μU · min/mL) were significantly greater than in control animals ( P < 0.05). The hyperinsulinemic dogs had a marked triglyceride elevation in arterial smooth muscle (20.6 ± 8.0 v 0.5 ± 0.4 μmol/g) and striated muscle (171.4 ± 46.6 v 41.2 ± 7.7 μmol/g) ( P < 0.001). Moreover, key enzymes in lipid synthesis (glucose-6-phosphate dehydrogenase, malic enzyme, and 3-hydroxyacyl-CoA DH) were significantly increased ( P < 0.01) in the hyperinsulinemic animals, while the glycolytic enzymes, (phosphofructokinase, hexokinase, pyruvate kinase, and α-glycerophosphate DH) were not significantly different. These data demonstrate substantial enhancement of lipid synthesis in arterial wall and striated muscle in hyperinsulinemic dogs. Altered substrate metabolism in arterial walls, in association with hyperinsulinemia, may have important implications with regard to macrovascular disease in diabetes, particularly in insulin-treated patients. In addition, these studies may serve to stimulate longer term assessments of macroangiopathy in the increasing number of patients with functioning pancreatic allografts draining into the systemic circulation.