Ac. Moses et al., INSULIN-LIKE GROWTH-FACTOR I(RHIGF-I) AS A THERAPEUTIC AGENT FOR HYPERINSULINEMIC INSULIN-RESISTANT DIABETES-MELLITUS, Diabetes research and clinical practice, 28, 1995, pp. 185-194
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.