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 NID DM, however, its pathophysiologic mechanisms are not well understood. Many clues about the mechanisms of insulin action have come from patie nts 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 res istance. To date, we have studied six subjects with varying phenotypes of severe insulin resistance but without mutations in the insulin rec eptor itself. All subjects underwent baseline physiologic monitoring t o quantitate carbohydrate tolerance, insulin secretion, and insulin ac tion 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 sensitivit y. None of the six subjects noted significant side effects from the rh IGF-I. Four of the six subjects had overt diabetes during control test ing; three of these subjects demonstrated normalization of fasting and postprandial blood glucose concentrations during rhIGF-I administrati on on no other therapy. In the fourth patient, insulin requirements an d fasting hypertriglyceridemia decreased without improvement in glycem ic control. The two subjects with normal glucose tolerance (two sister s with congenital lipodystrophy) maintained normal glucose tolerance a t dramatically lower insulin levels and had a dramatic reduction in tr iglyceride levels. The efficacy of IGF-I continued to increase over th e duration of the study. Steady state plasma glucose decreased in five /six subjects from 280 +/- 68 in the control period to 207 +/- 43 duri ng rhIGF treatment (14 h after last dose of rhIGF-I). Steady-state pla sma insulin decreased from 127 +/- 120 in the control period to 59 +/- 55 during rhIGF-I. Thus, blood glucose was reduced at lower ambient i nsulin concentrations, demonstrating improved insulin sensitivity. The se data demonstrate that rhIGF-I effectively can treat some patients w ith severe insulin resistance and suggest the potential utility of rhI GF-I in Type II diabetes mellitus.