Effects of Combined Recombinant Insulin-Like Growth Factor (IGF)-I and IGF Binding Protein-3 in Type 2 Diabetic Patients on Glycemic Control and Distribution of IGF-I and IGF-II among Serum Binding Protein Complexes

Abstract

Context: Administration of recombinant human IGF-I (rhIGF-I)/recombinant human IGF binding protein-3 (rhIGFBP-3) to patients with type 2 diabetes improves blood glucose and enhances insulin sensitivity. The changes in various components of the IGF system that occur in response to rhIGF-I/rhIGFBP-3 as well as the minimum effective dose have not been determined. Objectives: The aim was to determine the dose of rhIGF-I/rh-IGFBP-3 necessary to achieve a significant decrease in glucose and to determine the changes that occur in the IGF-II and acid labile subunit in response to treatment. Design: A total of 39 insulin-requiring type 2 diabetics were randomized to placebo or one of six groups that received different dosages of rhIGF-I/rhIGFBP-3. After 3 d in which insulin doses were adjusted to improve glucose control, a variable insulin dosage regimen was continued, and either placebo or one of six dosages (0.125–2.0 mg/kg·d) of rhIGF-I/rhIGFBP-3 was administered for 7 d. All subjects were hospitalized, and dietary intake as well as insulin dosage were controlled with instructions to treat to normal range targets. Results: Fasting glucose was reduced in the groups that received either 1 (32 ± 5% reduction) or 2 mg/kg·d (40 ± 6% reduction) of the complex. Mean daily glucose (four determinations) was reduced by 26 ± 4% in the 1 mg/kg group and by 33 ± 5% in the 2 mg/kg group compared with 18 ± 4% in the placebo group. Total serum IGF-I increased between 2.0 ± 0.3- and 5.7 ± 1.3-fold by d 8. IGFBP-3 concentrations increased significantly only in the 2 mg/kg group. IGF-II concentrations declined to values that were between 27 ± 4% and 64 ± 7% below baseline. Acid labile subunit concentrations declined significantly in the three highest dose groups. The sum of the IGF-I + IGF-II concentrations was significantly increased at the two highest dosages. There were very few drug-associated adverse events reported in this study with the exception of hypoglycemia, which occurred in 15 subjects who had received rhIGF-I/rhIGFBP-3 treatment. Conclusions: Administration of rhIGF-I/rhIGFBP-3 resulted in a redistribution of the amount of IGF-I and IGF-II that bound to IGFBP-3. Fasting and mean daily blood glucose were reduced significantly in the two highest dosage groups. The results suggest that both the total concentration of IGF-I as well as its distribution in blood may determine the extent to which insulin sensitivity is enhanced.

IGF-1 and atherothrombosis: relevance to pathophysiology and therapy

“…Subcutaneous rhIGF-1 administration (100 μg/kg of body weight, twice a day) in insulin-resistant Type 2 diabetic patients improved short-and long-term indexes of glycaemic control and insulin sensitivity, therefore decreasing insulin levels. Co-administration of IGFBP-3 and IGF-1 in Type 2 diabetic patients has been shown to produce a low number of side effects [308], with the same degree of efficacy also being shown in a more recent study [309].…”

Treatment with Recombinant Human Insulin-Like Growth Factor (rhIGF)-I/rhIGF Binding Protein-3 Complex Improves Metabolic Control in Subjects with Severe Insulin Resistance

“…The physiological effects of rhIGF-I/rhIGFBP-3 have been explored in both type 1 and 2 diabetes, with dose-dependent increases in insulin sensitivity (S I 2* ) and few reported side effects (17)(18)(19)(20)(21). Thus rhIGF-I/rhIGFBP-3 may also have therapeutic potential in subjects with SIR, and we provide data to support this hypothesis.…”

Evidence of a Role for Insulin-Like Growth Factor Binding Protein (IGFBP)-3 in Metabolic Regulation

“…Mechanistically, both explanations could be relevant because IGFBP-3 overabundance leads to insulin resistance (9 -12). Initially, IGFBP-3 was used in combination therapy with IGF-I to amplify the half-life of IGF-I and maximize its hypoglycemic effects in treatment of insulin resistance in patients with type 2 diabetes (29). However, IGFBP-3 may have additional IGFindependent effects on metabolism because antibody blockade of the type 1 IGF receptor and use of IGFBP-3 mutants without IGF binding were still able to significantly inhibit insulin-stimulated glucose uptake in 3T3-L1 adipocytes (3).…”