Recombinant human insulin-like growth factor-I (rhIGF-I) therapy in adultswith type 1 diabetes mellitus: effects on IGFs, IGF-binding proteins, glucose levels and insulin treatment

OBJECTIVE Insulin-like growth factor-I (IGF-I) has both insulin-like and an abolic actions but unlike insulin, IGF-I circulates bound to a number of sp ecific binding proteins that regulate its availability and activity. Patien ts with type 1 diabetes mellitus have low levels of circulating IGF-I despi te increased growth hormone (GH) secretion, and are a group that may benefi t from rhIGF-I therapy. Understanding the relationship between IGF-I and it s binding proteins is necessary to appreciate the actions of exogenously ad ministered rhIGF-I. Therefore, we examined the effects of 19 days' subcutan eous administration of rhlGF-I (50 mu g/kg BID) on the levels of IGF-I, IGF -II and the IGF-binding proteins (IGFBPs), as well as the daily dose of ins ulin necessary to maintain glycaemic control in patients with type 1 diabet es mellitus. DESIGN AND PATIENTS This was an open study, and the patients were studied i nitially while resident (days 1-5) in the hospital and thereafter (days 6-2 4) as outpatients. Serum was collected at baseline and at intervals through out the study for the measurement of total IGF-I, IGF-II, IGFBP-1, -2, -3, free insulin and growth hormone (GH). Daily insulin doses and glucometer re adings were recorded throughout the study. The changes in each of these var iables were examined. The subjects were six adults (35.3 +/- 4.0 years, mea n +/- SE), with type I diabetes, and all had reasonable glycaemic control ( HbA1c 7.2 +/- 0.5%). RESULTS rhIGF-I administration increased circulating total IGF-I over two-f old (15.3 +/- 1.9 vs. 33.7 +/- 5.4 nmol/l, mean +/- SEM, P < 0.01, day 1 vs . day 20) and decreased plasma IGF-II concentration (85.0 +/- 4.7 vs. 50.6 +/- 4.7 nmol/l, P < 0.01, day 1 vs. day 20). The dose of insulin required f or adequate glycaemic control decreased significantly during rhIGF-I therap y (46 +/- 7 vs. 31 +/- 8 U/day, P < 0.05, day -1 vs, day 19), as did the fa sting free insulin concentration (8.4 +/- 1.5 vs. 5.0 +/- 0.8 mU/l, P < 0.0 5, baseline vs, day 5). IGFBP-2 concentration increased (388 +/- 115 vs. 75 8 +/- 219 mu g/I, P < 0.05, day 1 vs. day 20), but IGFBP-1 and IGFBP-3 were unchanged during rhIGF-I treatment. Mean nocturnal GH concentration decrea sed (12.7 +/- 3.3 vs. 3.8 +/- 0.9 mU/l, P = 0.05) after 4 days' rhIGF-I the rapy. CONCLUSION Twice daily rhIGF-I therapy in adults with type 1 diabetes resul ted in an increase in circulating IGF-I with a reciprocal decrease in IGF-I I, and a marked elevation of IGFBP-2 concentration. The levels of IGFBP-1 a nd -3 were not dramatically changed despite a reduction in the concentratio n of serum free insulin, and a large decrease in the requirement for insuli n. The mechanisms behind these changes remains unclear but alterations in c irculating levels of IGFBPs may alter IGF-I bioactivity. If rhIGF-I is to h ave an application in the management of adults with type 1 diabetes, furthe r work is necessary to determine the metabolic consequences of the alterati ons seen in the IGFs and their binding proteins following rhIGF-I administr ation.