IGF-Binding Proteins in Type-1 Diabetes Are More Severely Altered in the Presence of Complications.

Ashok Sharma,Wenbo Zhi,Jin-Xiong She,Sithara Raju Ponny,Diane Hopkins,Sharad Purohit,Bruce Bode,Leigh Steed,Shan Bai,Shruti Sharma,Stephen W Anderson

doi:10.3389/fendo.2016.00002

Ashok Sharma, Wenbo Zhi + Show 9 more

Open Access

https://doi.org/10.3389/fendo.2016.00002

Copy DOI

Abstract

Reduced levels of free and total insulin-like growth factor 1 (IGF-I) have been observed in type-1 diabetes (T1D) patients. The bioavailability of IGF-I from the circulation to the target cells is controlled by multifunctional IGF-binding proteins (IGFBPs). The aim of this study was to profile serum IGFBPs in T1D and its complications. We measured the IGFBP levels in 3662 patient serum samples from our ongoing Phenome and Genome of Diabetes Autoimmunity (PAGODA) study. IGFBP levels of four different groups of T1D patients (with 0, 1, 2, and ≥3 complications) were compared with healthy controls. Three serum IGFBPs (IGFBP-1, -2, and -6) are significantly higher in T1D patients, and these alterations are greater in the presence of diabetic complications. IGFBP-3 is lower in patients with diabetic complications. Analyses using quintiles revealed that risk of T1D complications increases with increasing concentrations of IGFBP-2 (fifth quintile ORs: 18-60, p < 10(-26)), IGFBP-1 (fifth quintile ORs: 8-20, p < 10(-15)), and IGFBP-6 (fifth quintile ORs: 3-148, p < 10(-3)). IGFBP-3 has a negative association with T1D complications (fifth quintile ORs: 0.12-0.25, p < 10(-5)). We found that elevated serum levels of IGFBP-1, -2, and -6 were associated with T1D, and its complications and IGFBP-3 level was found to be decreased in T1D with complications. Given the known role of these IGFBPs, the overall impact of these alterations suggests a negative effect on IGF signaling.

Highlights

Type-1 diabetes (T1D) patients have reduced levels of circulating free and total IGF-I with alterations in the other components of the insulin-like growth factor (IGF)-axis [1,2,3,4,5,6]
Serum levels of five IGFBPs were measured in T1D patients and healthy controls to discover the alterations associated with T1D and/or its complications
Significant changes were observed in the levels of IGFBP-1, -2, -3, and -6, these four proteins were moved forward to the confirmation phase using a larger cohort of samples (1328 antibody negative controls (AbN) controls; 1085 T1D subjects)

Summary

Introduction

Type-1 diabetes (T1D) patients have reduced levels of circulating free and total IGF-I with alterations in the other components of the insulin-like growth factor (IGF)-axis [1,2,3,4,5,6]. A decrease in IGF-I activity has been shown to promote cerebromicrovascular dysfunction [8], accelerate endothelial apoptosis, and reduce the IGF-Binding Proteins in Type-1 Diabetes regenerative capacity of endothelium [9]. The bioavailability of IGF-I from the circulation to the target cells is controlled by multifunctional IGF-binding proteins (IGFBP1–6) [5]. Several IGFBPs have IGF-independent actions, modulating numerous processes in the extracellular environment and inside the cell [10, 12,13,14,15]. IGFBPs have been shown to possess anti-inflammatory function independent of IGF. IGFBPs can inhibit NF-κB activity using their own receptors and subsequently suppress monocyte adhesion to endothelial cells [16]

Methods

Results

Conclusion