Dysfunctional Proinsulin Processing in Longstanding Type 1 Diabetes

Presentation Number: SUN 601
Date of Presentation: April 2nd, 2017

Emily Kristen Sims*1, Julius Nyalwidhe2, Fangqian Ouyang3, Susan Perkins3, Linda A DiMeglio4, Janice Blum5, Margaret Morris2, Raghavendra G Mirmira6, Jerry L Nadler7, Teresa Mastracci3 and Carmella Evans-Molina5
1Indiana University Scool of Medicine, Indianapolis, IN, 2Eastern Virginia Medical School, 3Indiana University School of Medicine, 4Indiana Univ Sch of Med, Indianapolis, IN, 5Indiana University School of Medicine, Indianapolis, IN, 6Indiana Univ Sch of Medicine, Indianapolis, IN, 7Eastern Virginia Medical School, Norfolk, VA

Abstract

Impaired proinsulin processing, a manifestation of β-cell stress, has been linked to type 1 diabetes (T1D) development. We predicted that abnormal proinsulin processing may persist in longstanding T1D, even in the absence of residual C-peptide production. To this end, proinsulin and insulin immunostaining were performed on pancreatic sections from the Network for Pancreatic Organ Donors with Diabetes (nPOD). In parallel, fasting proinsulin and C-peptide were assayed in sera from 90 adult subjects in the T1D Exchange clinic registry (median T1D duration: 9 years), determined to be C-peptide negative or positive based on stimulated levels from mixed-meal tolerance tests (n=45/group). Islet proinsulin staining was detectable in 1/9 T1D donors lacking immunoreactive insulin staining. Furthermore, 58.1% of C-peptide negative T1D Exchange subjects had detectable fasting serum proinsulin. In C-peptide positive subjects, fasting proinsulin:c-peptide (PI:C) ratios were associated with antibody positivity and inversely correlated with measures of β-cell function. Finally, targeted proteomic analysis of T1D donor islets revealed reduced proinsulin processing enzymes compared to controls. These results confirm continued alterations in proinsulin processing and β-cell dysfunction in C-peptide positive, as well as a subset of C-peptide negative subjects with longstanding T1D and support the use of therapeutics targeting β-cell dysfunction in this population.

 

Nothing to Disclose: EKS, JN, FO, SP, LAD, JB, MM, RGM, JLN, TM, CE