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 micrograms/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.(ABSTRACT TRUNCATED AT 250 WORDS)