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

Type 2 diabetes mellitus and obesity are characterized by fasting hyperinsu linemia, insulin resistance with respect to glucose metabolism, elevated pl asma free fatty acid (FFA) levels, hypertriglyceridemia. and decreased high -density lipoprotein (HDL) cholesterol. An association between hyperinsulin emia and dyslipidemia has been suggested, but the causality of the relation ship remains uncertain. Therefore, we infused eight 12-week-old male cathet erized conscious normal rats with insulin (1 mU/min) for 7 days while maint aining euglycemia using a modification of the glucose clamp technique. Cont rol rats (n = 8) received vehicle infusion. Baseline FFAs were 1.07 +/- 0.1 3 mmol/L, decreased to 0.57 +/- 0.10 (P < .05) upon initiation of the insul in infusion, and gradually increased to 0.95 +/- 0.12 by day 7 (P = NS v ba seline). On day 7 after a g-hour fast, plasma insulin, glucose, and FFA lev els in control and chronically hyperinsulinemic rats were 32 +/- 5 versus 1 16 +/- 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 triglycerid e and cholesterol levels were 78 +/- 7 versus 66 +/- 9 mg/dL (P = NS) and 5 0 +/- 3 versus 47 +/- 2 mg/dL (P = NS), respectively Very-low-density lipop rotein (VLDL) + intermediate-density lipoprotein (LDL), low density lipopro tein (LDL), and HDL2 and HDL3 subfractions of plasma triglyceride and chole sterol were similar in control and hyperinsulinemic rats. Plasma FFA correl ated positively with total (r = .61, P < .005) triglycerides, On day 7 afte r an LI-hour fast, hyperinsulinemic-euglycemic clamps with 3-H-3-glucose in fusion 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 physiolo gic hyperinsulinemia (1) causes insulin resistance with regard to the suppr ession of plasma FFA levels and increases lipogenesis; (2) induces peripher al but not hepatic insulin resistance with respect to glucose metabolism; a nd (3) does not cause an elevation in VLDL-triglyceride or a reduction in H DL-cholesterol. Copyright (C) 1999 by W.B. Saunders Company.