Chronic physiologic hyperinsulinemia impairs suppression of plasma free fatty acids and increases de novo lipogenesis but does not cause dyslipidemia in conscious normal rats

Abstract

Type 2 diabetes mellitus and obesity are characterized by fasting hyperinsulinemia, insulin resistance with respect to glucose metabolism, elevated plasma free fatty acid (FFA) levels, hypertriglyceridemia, and decreased high-density lipoprotein (HDL) cholesterol. An association between hyperinsulinemia and dyslipidemia has been suggested, but the causality of the relationship remains uncertain. Therefore, we infused eight 12-week-old male catheterized conscious normal rats with insulin (1 mU/min) for 7 days while maintaining euglycemia using a modification of the glucose clamp technique. Control rats (n = 8) received vehicle infusion. Baseline FFAs were 1.07 ± 0.13 mmol/L, decreased to 0.57 ± 0.10 ( P < .05) upon initiation of the insulin infusion, and gradually increased to 0.95 ± 0.12 by day 7 ( P = NS v baseline). On day 7 after a 6-hour fast, plasma insulin, glucose, and FFA levels in control and chronically hyperinsulinemic rats were 32 ± 5 versus 116 ± 21 mU/L ( P < .005), 122 ± 4 versus 129 ± 8 mg/dL ( P = NS), and 1.13 ± 0.18 versus 0.95 ± 0.12 mmol/L ( P = NS); total plasma triglyceride and cholesterol levels were 78 ± 7 versus 66 ± 9 mg/dL ( P = NS) and 50 ± 3 versus 47 ± 2 mg/dL ( P = NS), respectively. Very—low-density lipoprotein (VLDL) + intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and HDL2 and HDL3 subfractions of plasma triglyceride and cholesterol were similar in control and hyperinsulinemic rats. Plasma FFA correlated positively with total ( r = .61, P < .005) triglycerides. On day 7 after an 8-hour fast, hyperinsulinemic-euglycemic clamps with 3- 3H-glucose infusion were performed in all rats. Chronically hyperinsulinemic rats showed peripheral insulin resistance (glucose uptake, 15.8 ± 0.8 v 19.3 ± 1.4 mg/kg · min, P < .02) but normal suppression of hepatic glucose production (HGP) compared with control rats (4.3 ± 1.0 v 5.6 ± 1.4 mg/kg · min, P = NS). De novo tissue lipogenesis (3- 3H-glucose incorporation into lipids) was increased in chronically hyperinsulinemic versus control rats (0.90 ± 0.10 v 0.44 ± 0.08 mg/kg · min, P < .005). In conclusion, chronic physiologic hyperinsulinemia (1) causes insulin resistance with regard to the suppression of plasma FFA levels and increases lipogenesis; (2) induces peripheral but not hepatic insulin resistance with respect to glucose metabolism; and (3) does not cause an elevation in VLDL-triglyceride or a reduction in HDL-cholesterol.