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

Abstract

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.

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

“…Work reported by Clemmons et al (40) demonstrates an induction of IGFBP-3 proteolysis, which is preferential for the nonglycosylated form, after the administration of IGF-I/IGFBP-3 complex to subjects with type 2 diabetes. The mechanism and relevance of this induction in proteolysis has not yet been clarified.…”

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

“…This suggests that the decrease in ALS limits the degree of increase in IGFBP-3. The degree of increase could also be limited by IGFBP-3 proteolysis, which is known to be increased in diabetic plasma (29). The net result of these changes would be that free IGF-I levels would increase relative to the increase in total IGF-I, thus limiting the ability of IGFBP-3 to control the rate of efflux of IGF-I from the circulation.…”

Posttranslational modifications of the insulin-like growth factor-binding protein 3 in patients with type 2 diabetes mellitus assessed by affinity chromatography

“…According to Cortizo et al, levels of IGF-I and IGFBP-3 were comparable in the type 2 diabetic patients and controls for the population ranging from 35 to 70 years [9]. The amount of intact IGFBP-3 depends on the rate of its synthesis, a degree of proteolysis, which increases in diabetes [14,25], and the severeness of diabetic nephropathy, which slowers the clearance rate of IGFBP-3 [26]. Clemmons et al [14] have demonstrated that the non-glycosylated IGFBP-3 is degraded more rapidly than the glycosylated IGFBP-3.…”

“…The amount of intact IGFBP-3 depends on the rate of its synthesis, a degree of proteolysis, which increases in diabetes [14,25], and the severeness of diabetic nephropathy, which slowers the clearance rate of IGFBP-3 [26]. Clemmons et al [14] have demonstrated that the non-glycosylated IGFBP-3 is degraded more rapidly than the glycosylated IGFBP-3. If methodological differences in IGFBP-3 assays are taken into account (some immunoassays measure only intact IGFBP-3, whereas others measure both intact and fragmented molecules) [27], the search for more accurate data on IGFBP-3 levels in diabetics is still actual.…”

“…In patients with DM a glycated IGFBP-3 was detected [9], and it was postulated to have an increased number of IGF-binding sites [12]. Increased proteolytic activity against IGFBP-3 was measured in these patients [13] and it seems to be related to glycosylation and/or glycation status [14]. Several enzymes may cleave IGFBP-3 causing formation of different fragments [15] and a fragmentation pattern can point to an enzyme principally responsible for IGFBP-3 degradation.…”