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 vbaseline). 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 x 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 x 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 x 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.
Koopmans
S J
SJ
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7886, USA.
Kushwaha
R S
RS
DeFronzo
R A
RA
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002908:Chronic Disease; D004734:Energy Metabolism / Q000502:physiology; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D015309:Glucose Clamp Technique; D006003:Glycogen / Q000096:biosynthesis; D006019:Glycolysis / Q000187:drug effects; D006946:Hyperinsulinism / Q000097:blood* / Q000150:complications; D006949:Hyperlipidemias / Q000097:blood* / Q000209:etiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D008055:Lipids / Q000096:biosynthesis*; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D008074:Lipoproteins; D014280:Triglycerides; D006003:Glycogen