INSULIN-LIKE GROWTH-FACTOR I(RHIGF-I) AS A THERAPEUTIC AGENT FOR HYPERINSULINEMIC INSULIN-RESISTANT DIABETES-MELLITUS

Insulin resistance is one of the major underlying abnormalities in NIDDM, however, its pathophysiologic mechanisms are not well understood. Many clues about the mechanisms of insulin action have come from patients with the most severe forms of insulin resistance, including those with genetic abnormalities in the insulin signal transduction cascade. We used rhIGF-I as a probe to differentiate insulin and IGF-I action and to study the therapeutic potential of IGF in states of insulin resistance. To date, we have studied six subjects with varying phenotypes of severe insulin resistance but without mutations in the insulin receptor itself. All subjects underwent baseline physiologic monitoring to quantitate carbohydrate tolerance, insulin secretion, and insulin action prior to receiving rhIGF-I at 100 mu g/kg body wt s.c. bid for 1 month with interval testing of glycemic control and insulin sensitivity. None of the six subjects noted significant side effects from the rhIGF-I. Four of the six subjects had overt diabetes during control testing; three of these subjects demonstrated normalization of fasting and postprandial blood glucose concentrations during rhIGF-I administration on no other therapy. In the fourth patient, insulin requirements and fasting hypertriglyceridemia decreased without improvement in glycemic control. The two subjects with normal glucose tolerance (two sisters with congenital lipodystrophy) maintained normal glucose tolerance at dramatically lower insulin levels and had a dramatic reduction in triglyceride levels. The efficacy of IGF-I continued to increase over the duration of the study. Steady state plasma glucose decreased in five/six subjects from 280 +/- 68 in the control period to 207 +/- 43 during rhIGF treatment (14 h after last dose of rhIGF-I). Steady-state plasma insulin decreased from 127 +/- 120 in the control period to 59 +/- 55 during rhIGF-I. Thus, blood glucose was reduced at lower ambient insulin concentrations, demonstrating improved insulin sensitivity. These data demonstrate that rhIGF-I effectively can treat some patients with severe insulin resistance and suggest the potential utility of rhIGF-I in Type II diabetes mellitus.