IN VIVO METABOLIC ACTIONS OF IGF I

Abstract

The availability of IGF I produced by recombinant gene technology has opened the possibility to explore the therapeutic potential of this hormone by studying its metabolic effects in normal subjects and in various diseases in which a pathogenetic role of IGF I may be suspected. The first in vivo studies in healthy men carried out by Guler et al. in 1986 had shown that IGF I did not only act like insulin, but also in an analogous as well as opposite way to growth hormone (GH), the main stimulator of endogenous IGF I production, and that it affected glucose, fat and protein metabolism. Iv bolus injections of recombinant human (rh) IGF I (100 μg/kg) induced sustained hypoglycemia. The hypoglycemic effect was blunted during long-term sc administration by specific IGF serum binding proteins (BPs) which cause sequestration of IGF I into a meta-bolically inactive large mol. mass (150 kd) complex. Effects of IGF I on fat and protein metabolism were reflected by a decrease of serum triglycerides (TG) and cholesterol and of serum urea. In addition, it stimulated glomerular filtration in the kidney and it suppressed insulin and GH secretion.

Recent studies in normal subjects showed that sc IGF I (7-14 μg/kgxh) as compared to saline treatment 1) lowered fasting blood glucose levels despite suppression of basal insulin secretion; 2) suppressed glucose-stimulated insulin levels without impairing glucose tolerance; 3) increased oxidative and non-oxidative glucose disposal and inhibited hepatic glucose production during a euglycemic, hyperinsulinemic clamp suggesting increased insulin sensitivity; 4) enhanced lipolysis, lipid oxidation and basal metabolic rate (BMR), but reduced protein oxidation (as measured by indirect calorimetry).

In GH-deficient adults, sc infusion of rhIGF I (10 μg/kgxh) for 7 d 1) had no significant influence on fasting glucose levels or basal glucose oxidation, but suppressed serum insulin levels, whereas GH treatment (2 IU/m²×d) raised fasting blood sugar despite concomitantly elevated serum insulin levels; 2) like GH raised BMR and lipid oxidation and reduced protein oxidation; 3) did not enhance insulin sensitivity during euglycemic, hyperinsulinemic clamping. Thus, IGF I like GH acts as an anabolic agent. However, in the absence of GH, when insulin sensitivity is already increased, IGF I does not further enhance insulin sensitivity. It therefore appears that suppression of GH observed during IGF I treatment of normal subjects is mainly responsible for enhanced insulin sensitivity. In type 2 diabetics, rhIGF I treatment reduced elevated serum insulin levels, lowered serum TG and improved glucose tolerance. In patients with type A insulin resistance, iv bolus injections of rhIGF I lowered serum insulin and normalized blood sugar levels.

All of these findings suggest that IGF I may become therapeutically interesting for the treatment of catabolic (heavy injuries, burns) and insulin resistant states (type 2 diabetes, syndrome X).

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