The combination of insulin-like growth factor I and insulin-like growth factor-binding protein-3 reduces insulin requirements in insulin-dependent type 1 diabetes: Evidence for in vivo biological activity

Insulin-Like growth factor-I (TGF-I) enhances insulin action in normal subj ects and in patients with both type 1 and 2 diabetes; however, its administ ration is associated with significant side effects in a high percentage of patients. The coadministration of IGF binding protein-3 (IGFBP-3, the predo minant IGF binding protein in serum) with IGF-I limits IGF-I inducible side effects, but it does not attenuate the ability of IGF-I to enhance protein synthesis and bone accretion; therefore, we determined whether IGF-I/IGFBP -3 would retain biological activity in type I DM and limit side effects ass ociated with free IGF-I administration. Twelve patients received recombinant human IGF-I plus IGFBP-3 (2 mg/kg day) by continuous sc infusion for 2 weeks. Each subject served as his own cont rol; and, during a paired 2-week period, each received a placebo infusion. The order of the treatments was randomized. Subjects were placed on a const ant caloric intake but mere allowed to adjust insulin doses to maintain app ropriate levels of glycemic control. Subjects measured blood glucose four t imes per day at home and kept a log of their insulin use. Frequent sampling for glucose, insulin, and GH was conducted during four inpatient study per iods, one at the beginning and one at the end of each a-week study interval . During IGF-I/IGFBP-3, insulin doses were reduced by 49%, and mean serum glu cose was reduced by 23%. Free insulin levels obtained during frequent sampl ing in hospital fell 47% on IGF-I/IGFBP-3, compared with control, but showe d no change with placebo. Concomitant glucose measurements did not differ i n the two treatment groups. There was no change in body weight. Fructosamin e levels decreased by 12%, but this was not significant (P < 0.1). Fasting triglyceride was unchanged, but cholesterol declined from 110 +/- 24 to 149 +/- 31 mg/dL (P < 0.05). IGFBP-2 (an IGF-I-dependent responsive variable) rose from 141 +/- 56 to 251 +/- 98 ng/mL (P < 0.01) on IGF-I/IGFBP-3. To an alyze the mechanism by which IGF-I/IGFBP-3 might reduce insulin requirement s, the change in serum GH was quantified. Mean GH levels were reduced by 72 %, from 2.48 to 0.55 ng/mL (P < 0.001). An equal number (40%) of drug- and placebo treated subjects had minor hypoglycemic episodes at home that requi red adjustment of insulin doses. No episode was classified as severe. In co ntrast to previous studies with free IGF-I, there were no cases of edema, h eadache, jaw pain, retinal edema, or Bell's palsy. No subject withdrew beca use of drug complications. These findings indicate that IGF-I/IGFBP-5 is bi ologically active on carbohydrate metabolism, as measured by a decrease in insulin requirements in patients with type 1 diabetes. Further studies will be required to determine the long-term safety and efficacy of this combina tion in patients with insulin resistance and diabetes.