This Article Full Text Full Text (PDF) All Versions of this Article: 90/12/6561    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clemmons, D. R. Articles by Busby, W. H. Search for Related Content PubMed PubMed Citation Articles by Clemmons, D. R. Articles by Busby, W. H., Jr. Related Collections Diabetes and Insulin Metabolism

Recombinant, Nonglycosylated Human Insulin-Like Growth Factor-Binding Protein-3 (IGFBP-3) Is Degraded Preferentially after Administration to Type II Diabetics, Resulting in Increased Endogenous Glycosylated IGFBP-3

Department of Medicine, University of North Carolina School of Medicine (D.R.C., W.H.B.), Chapel Hill, North Carolina 27599; and Insmed, Inc. (M.S.), Richmond, Virginia 23060

Address all correspondence and requests for reprints to: Dr. David R. Clemmons, 6111 Thurston-Bowles, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599. E-mail: endo{at}med.unc.edu.

Context: Administration of IGF-binding protein-3 (IGFBP-3) with IGF-I stabilizes IGF-I concentrations 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 after administration of an IGF-I/IGFBP-3 combination to patients with diabetes.

Design: Thirty-two patients received either 1 (n = 8) or 2 (n = 24) mg/kg·d IGF-I/IGFBP-3 by bolus sc injection (n = 16) or continuous sc infusion (n = 16).

Results: When nonglycosylated IGFBP-3 was given, the abundance of both glycosylated and nonglycosylated forms of IGFBP-3 in serum was increased. Incubation of nonglycosylated IGFBP-3 with diabetic serum in vitro resulted in more rapid degradation compared with glycosylated IGFBP-3. When the serum obtained from subjects who had received nonglycosylated 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 IGF-I and nonglycosylated IGFBP-3 for 2 wk to 32 subjects increased glycosylated IGF-I/IGFBP-3 by 20–40%. The increases were the greatest in the groups that received IGFBP-3 by infusion (e.g. 31% and 40%).

Conclusions: After 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.

This article has been cited by other articles:

				D. R. Clemmons, M. Sleevi, G. Allan, and A. Sommer 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 J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2652 - 2658. [Abstract] [Full Text] [PDF]