Context: Administration of insulin-like binding protein-3 (IGFBP-3) with IGF-I stabilizes IGF-I and prolongs its half life. One determinant of IGFBP-3 stability is proteolysis. Normal subjects have minimal IGFBP-3 protease activity, however with pregnancy, acute catabolic illness, or diabetes, IGFBP-3 protease activity is increased.

Objective: This study was conducted to determine the degree of proteolysis that occurs in glycosylated, endogenous serum IGFBP-3 and nonglycosylated IGFBP-3 following administration of IGF-I/IGFBP-3 combination to patients with diabetes.

Design: 32 patients received either 1 (n=8) or 2 mg/kg/day (n=24) IGF-I/IGFBP-3 by bolus subcutaneous injection (n=16) or continuous subcutaneous infusion (n=16).

Results: When nonglycosylated IGFBP-3 was given the abundance of both glycosylated and nonglycosylated forms of IGFBP-3 was increased. Incubation of nonglycosylated IGFBP-3 with diabetic serum in vitro resulted in more rapid degradation compared to glycosylated IGFBP-3. When the serum obtained from subjects who had received nonglycoslated IGFBP-3 was analyzed, significant differences in the stability of glycosylated and nonglycosylated IGFBP-3 were present. The addition of increasing concentrations of nonglycosylated IGFBP-3 to diabetic serum resulted in a dose dependent increase in the abundance of endogenous, glycosylated IGFBP-3. Administration of nonglycosylated IGFBP-3 for 2 weeks to 32 subjects increased glycosylated IGF-I/IGFBP-3 by 20-40%. The increases were greatest in the groups that received IGFBP-3 by infusion (eg. 31 and 40%).

Conclusions: Following administration to diabetics, nonglycosylated IGFBP-3 is degraded more rapidly than glycosylated IGFBP-3. By acting as a preferential substrate for the IGFBP-3 protease, nonglycosylated IGFBP-3 protects endogenous, glycosylated IGFBP-3 from degradation allowing total IGFBP-3 concentrations to increase.