RECOMBINANT HUMAN INSULIN-LIKE GROWTH-FACTOR-I THERAPY IMPROVES GLYCEMIC CONTROL AND INSULIN ACTION IN THE TYPE-A SYNDROME OF SEVERE INSULIN-RESISTANCE

Recombinant human (rh) insulin-like growth factor-I (IGF-I) is a poten tial therapy for individuals with severe insulin resistance, but its e fficacy, mechanism of action, or duration of effect for these patients have not been explored fully. Two subjects with the type A phenotype of severe insulin resistance without insulin receptor mutations were i nvestigated to assess insulin secretion, insulin action, and carbohydr ate tolerance before and after 3-4 weeks of rhIGF-I treatment (100 mu g/kg, sc, twice daily). Tests included 24-h glucose and insulin profil e (modal day), standardized liquid meal with Sustacal, insulin toleran ce test, insulin suppression test, and iv glucose tolerance test. In s ubject 1, the 24-h mean blood glucose level was 8.1 +/- 2.7 mmol/L bef ore rhIGF-I treatment and fell to 4.2 +/- 0.9 mmol/L during rhIGF-I tr eatment. The pretreatment 24-h mean serum insulin level was 10,251 +/- 8,849 pmol/L and fell to 1533 +/- 1198 pmol/L. Fasting blood glucose fell from 4.4 to 3.4 mmol/L, and 2-h blood glucose after Sustacal admi nistration fell from 10.3 to 5.3 mmol/L. Fasting serum insulin decline d from 808 to 246 pmol/L, and the 2-h serum insulin level fell from 5, 491 to 3,443 pmol/L. After bolus iv insulin injection (0.15 U/kg), glu cose fell by 20% before rhIGF-I treatment and by 67% during rhIGF-I tr eatment. The steady state plasma glucose level was 18.2 +/- 0.7 before rhIGF-I and 10.8 +/- 0.1 mmol/L during rhIGF-I. In subject 2, fasting blood glucose fell from 12.0 to 7.4 mmol/L and 24-h mean blood glucos e fell from 12.7 +/- 1.9 to 6.6 +/- 1.3 mmol/L. Twenty-four-hour mean serum insulin fell from 892 +/- 635 to 521 +/- 293 pmol/L, and first p hase insulin secretion was restored during the iv glucose tolerance te st. We conclude that sc rhIGF-I can reduce blood glucose effectively i n selected patients with the type A phenotype of severe insulin resist ance who have diabetes mellitus. rhIGF-I also can enhance insulin sens itivity, as assessed by a decrease in endogenous insulin levels, norma lization of response to iv insulin, and a reduced steady state plasma glucose. The cellular mechanisms for these effects remain undefined.