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

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.