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

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 g-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 (LDL), 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 LI-hour fast, hyperinsulinemic-euglycemic clamps with 3-H-3-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-H-3-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. Copyright (C) 1999 by W.B. Saunders Company.