Differential Effects of IGF-I and Insulin on Glucoregulation and Fat Metabolism in Depancreatized Dogs

  1. Mladen Vranic
  1. Departments of Physiology, Medicine, and Surgery, University of Toronto Toronto, Canada Department of Endocrinology, Karolinska Hospital, and KabiVitrum AB Stockholm, Sweden
  1. Address correspondence and reprint requests to Mladen Vranic, MD, DSc, FRCP(C), Department of Physiology, University of Toronto, Medical Sciences Building, Room 3358, Toronto, Ontario M5S 1A8, Canada.

Abstract

The effects of equipotent glucose-lowering doses of insulinlike growth factor I (IGF-I) and insulin on tracer-determined glucose kinetics and several metabolites were compared in 14 experiments (7 in each group) in fasted, totally depancreatized dogs. This model prevented variations in insulin secretion induced by IGF-I and permitted evaluation of the effects of IGF-I on extrapancreatic glucagon. Steady-state moderate hyperglycemia (9.9 ± 0.2 mM) was maintained by a subbasal intraportal infusion of insulin (1.29 ± 0.17 pmol · kg−1 · min−1). This was continued throughout the experiment, allowing evaluation of IGF-I effects on insulin clearance. Human recombinant IGF-I or insulin was given intravenously as a primed infusion for 90 min, followed by a 50-min recovery period. The dose of IGF-I was a 2.6-nmol/kg bolus plus 57.4 pmol · kg−1 · min−1. The insulin dose required to induce the same plasma glucose decline as IGF-I (44 ± 6 vs. 43 ± 5%, NS) was 9–12 times lower (0.06-nmol/kg bolus + 6.4 ± 0.6 pmol · kg−1 · min−1). However, the mechanism of this decline differed with IGF-I and insulin; glucose production was much less suppressed (25 ± 9 vs. 42 ± 11%, P < 0.001) and glucose utilization was more stimulated (68 ± 18 vs. 38 ± 19%, P < 0.05) with IGF-I. Lactate and pyruvate increased significantly with IGF-I (by 85 ± 28 and 123 ± 83%, respectively) but not with insulin. Glycerol and free-fatty acid levels decreased much less with IGF-I than insulin (29 ± 16 vs. 52 ± 5%, P < 0.05, and 36 ± 10 vs. 56 ± 8%, P < 0.01). β-Hydroxybutyrate, alanine, and glucagon decreased similarly with IGF-I or insulin by 60, 20, and 20%, respectively. Plasma insulin was not affected by IGF-I administration (92.6 ± 8.5 vs. 92.6 ± 10.1 pM). In conclusion, in insulin-infused depancreatized dogs, 1) IGF-I is 8–11% as potent as insulin as a glucose-lowering agent on a molar basis, 2) IGF-I does not affect insulin clearance at doses effective in lowering plasma glucose, and 3) equipotent glucose-lowering doses of IGF-I and insulin have very different effects on both glucose kinetics and lipolysis. This suggests that the IGF-I-insulin potency ratio in vivo is higher in muscle than liver or adipose tissue. Therefore, insulinlike effects of supraphysiological doses of IGF-I can be mediated not only through the insulin but also the IGF-I receptor.

  • Received July 21, 1989.
  • Revision received November 1, 1989.
  • Accepted November 1, 1989.
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