RECOMBINANT HUMAN INSULIN-LIKE GROWTH-FACTOR-I INCREASES INSULIN SENSITIVITY AND IMPROVES GLYCEMIC CONTROL IN TYPE-II DIABETES

Insulin resistance is a major factor in the pathophysiology of type II diabetes and a major impediment to successful therapy, The identifica tion of treatments that specifically target insulin resistance could i mprove diabetes management significantly. Since IGFs exert insulin-lik e actions and increase insulin sensitivity when administered at suprap hysiological doses, we determined the effect of 6 weeks of recombinant human IGF-I (rhIGF-I) administration on insulin resistance and glycem ic control in obese insulin-resistant patients with type II diabetes. A total of 12 patients with type II diabetes were recruited for the st udy, Subcutaneous administration of rhIGF-I (100 mu g/kg b.i.d.) signi ficantly lowered blood glucose, Fructosamine declined from 369 to 299 mu mol/l by 3 weeks of administration and then declined further to 271 at the end of 5 weeks. Glycosylated hemoglobin, which was 10.4% pretr eatment, declined to 8.1% at the end of therapy. Mean 24-h blood gluco se during a modal day was 14.71 +/- 4.5 mmol/l pretreatment and declin ed to 9.1 +/- 3.21 mmol/l by the end of treatment, These improvements in glycemia were associated with a decrease in serum insulin levels, M ean insulin concentrations declined from 108.0 to 57.0 pmol/l during t he modal day measurements and from 97.2 to 72.0 pmol/l during the mixe d-meal tolerance test, Changes in glycemia were accompanied by a marke d increase in insulin sensitivity, The insulin sensitivity index (S-I) calculated from a frequently sampled intravenous glucose tolerance te st (FSIVGTT) after the method of Bergman et al, (Bergman RN, Finegold DT, Ader M: Assessment of insulin sensitivity in vivo. Endocr Rev 6:45 -86, 1985) increased 3.4-fold. Furthermore, the improvement in glycemi c control was accompanied by a change in body composition with a 2.1% loss in body fat as calculated by dual energy x-ray absorptiometry wit hout change in total body weight. Significant side effects were presen t in some subjects, although nine subjects were able to complete at le ast 4.5 weeks of the protocol and six subjects completed the entire 6 weeks, Supraphysiological IGF-I concentrations were maintained through out the study, increasing from 206 mu g/l in the control period to 849 mu g/l at the end of 6 weeks of rhIGF-I treatment, The increase in IG F-I levels was accompanied by a significant increase in IGF binding pr otein-a levels, a slight reduction in IGF binding protein-3 levels, an d an increase in levels of IGF binding protein-1. In summary, IGF-I si gnificantly lowered blood glucose as reflected by short-term and long- term indexes of glycemic control and increased insulin sensitivity. It remains to be determined whether a dosage can be administered that av oids significant side effects and still achieves reasonable glycemic c ontrol.