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Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes

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Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes 258 Diabetes Care Volume 42, February 2019 Proinsulin Secretion Is a Emily K. Sims,1,2 Henry T. Bahnson,3 Julius Nyalwidhe,4 Leena Haataja,5 Persistent Feature of Type 1 Asa K. Davis,3 Cate Speake,3 Linda A. DiMeglio,1,2 Janice Blum,6 Diabetes Margaret A. Morris,7 Raghavendra G. Mirmira,1,2,8,9,10 7 10,11 Diabetes Care 2019;42:258–264 | https://doi.org/10.2337/dc17-2625 Jerry Nadler, Teresa L. Mastracci, Santica Marcovina,12 Wei-Jun Qian,13 Lian Yi,13 Adam C. Swensen,13 Michele Yip-Schneider,14 C. Max Schmidt,14 Robert V. Considine,9 Peter Arvan,5 Carla J. Greenbaum,3 Carmella Evans-Molina,2,8,9,10,15 and the T1D Exchange Residual C-peptide Study Group* OBJECTIVE Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin. RESEARCH DESIGN AND METHODS C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (‡3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) 1Department of Pediatrics, Indiana University ‡ 2 School of Medicine, Indianapolis, IN C-peptide positive, with high stimulated values 0.2 nmol/L; ) C-peptide posi- 2 tive, with low stimulated values ‡0.017 but <0.2 nmol/L; and 3)C-peptide Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indian- <0.017 nmol/L. Longitudinal samples were analyzed from C-peptide–positive apolis, IN subjects with diabetes after 1, 2, and 4 years. 3Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA RESULTS 4Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum Norfolk, VA proinsulin (>3.1 pmol/L), while 89.9% of participants with stimulated C-peptide 5Division of Metabolism, Endocrinology & Di- values below the limit of detection (<0.017 nmol/L; n = 99) had measurable abetes, University of Michigan Medical Center, proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while Ann Arbor, MI 6Department of Microbiology and Immunology, C-peptide decreased slowly during longitudinal analysis. Correlations between Indiana University School of Medicine, Indian- proinsulin with C-peptide andmixed-meal stimulationof proinsulin were foundonly apolis, IN ‡ fi 7Department of Internal Medicine, Eastern Vir- PATHOPHYSIOLOGY/COMPLICATIONS in subjects with high stimulated C-peptide values ( 0.2 nmol/L). Speci cally, increases in proinsulin with mixed-meal stimulation were present only in the ginia Medical School, Norfolk, VA 8Department of Cellular and Integrative Physi- group with high stimulated C-peptide values, with no increases observed among ology, Indiana University School of Medicine, subjects with low or undetectable (<0.017 nmol/L) residual C-peptide. Indianapolis, IN 9Department of Medicine, Indiana University CONCLUSIONS School of Medicine, Indianapolis, IN 10 In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, persists, even in those with undetectable serum C-peptide. Indianapolis, IN 11Indiana Biosciences Research Institute, Indian- apolis, IN Type 1 diabetes results from autoimmune-mediated destruction of the pancreatic 12 Northwest Lipid Metabolism and Diabetes Re- b-cell, resulting in the need for exogenous insulin treatment (1). The classic paradigm search Laboratories, University of Washington, that type 1 diabetes leads to a complete loss of b-cell mass and absolute insulin Seattle, WA deficiency has been challenged by recent data (1). Analysis of pancreatic sections from 13Biological Sciences Division, Pacific Northwest organ donors with diabetes indicates the presence of residual insulin-containing National Laboratory, Richland, WA 14Department of Surgery, Indiana University islets many years after disease onset (2). In addition, multiple groups have reported School of Medicine, Indianapolis, IN detectable levels of serum C-peptide in cohorts of individuals with long-duration T1D 15Richard L. Roudebush VA Medical Center, In- (3–9). These studies have included highly selected populations, such as the Joslin dianapolis, IN care.diabetesjournals.org Sims and Associates 259 Medalists, who were identified on the relative to insulin and C-peptide have received a pancreas or islet transplant) basis of long-term survival, as well as also been reported in whole pancreata (3). From this group, 319 subjects in groups more reflective of general diabe- from donors with long-standing type 1 whom mixed-meal tolerance tests tes populations, with estimates that up diabetes (18). However, whether de- (MMTTs) were performed were included to 80% of individuals with type 1 diabe- tectable proinsulin secretion is present in in the current analysis (3). In brief, this tes retain the ability to secrete small individuals with extended-duration type 1 included subjects with detectable random amounts of stimulated C-peptide (3–7). diabetes has not been adequately tested. nonfasting C-peptide and 10% of subjects For detection of residual b-cell mass To gain insight into the relationships with C-peptide ,0.017 nmol/L on a ran- and function, these studies have relied between C-peptide and proinsulin secretion dom nonfasting test (n = 99). For subjects nearly exclusively on the measurement in long-standing type 1 diabetes, we with serum C-peptide $0.017 nmol/L of C-peptide, which is generated from the analyzed longitudinal samples from a (n = 220), repeat MMTTs were performed processing of immature preproinsulin diverse cohort of subjects with estab- 1, 2, and 4 years after the initial MMTT. In molecules into insulin and C-peptide. lished disease ($3 years) who were addition, MMTT was performed in a small Preproinsulin processing begins with categorized based on the presence or group of healthy adult control subjects cleavage of the N-terminal signal peptide absence of residual stimulated C-peptide locally at Indiana University School of to form proinsulin within the lumen of secretion. We sought to define patterns Medicine (n = 12). Subject characteristics the b-cell endoplasmic reticulum (ER) of change in C-peptide and proinsu- are described in Table 1. (10). Disulfide bond formation and ter- lin secretion over 4 years of follow-up minal protein folding occurs in the ER and to explore relationships between Measurements and Assays and Golgi, and proinsulin is eventu- meal-stimulated C-peptide and proinsulin Standard MMTTs were performed as ally cleaved into mature insulin and secretion. previously described with blood sam- C-peptide by the enzymes prohormone ples drawn at 210,0,30,60,90,and convertase 1/3, prohormone convertase RESEARCH DESIGN AND METHODS 120 min (3,19). Control samples drawn 2, and carboxypeptidase E within secre- Study Approval at Indiana University were immediately 2 tory granules (10). b-Cell dysfunction, Sample collections were performed processed and stored at 80 without such as that caused by inflammatory after institutional review board ap- freeze/thaw prior to testing. Serum or ER stress, results in the accumulation proval was obtained from T1D Ex- fromsubjects withdiabetes was shipped and release of incompletely processed change Network sites and Indiana to Northwest Lipid Metabolism and Di- proinsulin (11–13). Thus, measurement University. Written informed consent abetes Research Laboratories (NWRL, of C-peptide secretion alone could un- was obtained from participants prior University of Washington) on cold derestimate the ability of the b-cell to to study inclusion. packs the day of sample collections. initiate hormone production, while in- Samples were immediately analyzed for creased proinsulin secretion may provide Subjects C-peptide. Otherwise, serum was stored insight into specific disease pathology. We previously reported nonfasting se- at 280°C without freeze/thaw until Studies in human cohorts have sug- rum C-peptide levels in 919 individuals proinsulin measurement. HLA-DRB1 gested that abnormalities in b-cell pro- with varying durations of disease (all $3 typing, HbA1c, fasting glucose, and insulin processing have clinical relevance years from disease onset) identified autoantibodies against GAD, islet an- to type 1 diabetes. Levels of circulating through the T1D Exchange clinic regis- tigen 2 (IA-2), and zinc transporter proinsulin relative to C-peptide (PI:C try who participated in the Residual 8 (ZnT8) were measured as previously ratios) are elevated at the time of C-peptide in Type 1 Diabetes Study described (19). type 1 diabetes onset and have been evaluating residual insulin secretion in C-peptide values were measured shown to be predictive of type 1 diabetes those with long-standing type 1 diabetes from each MMTT time point in a blinded development in autoantibody-positive (3). To be enrolled in this study, an fashion by NWRL using the Tosoh two- individuals (14–16). Similarly, the ratio individual must have had a clinical di- site immunoenzymometric assay (Tosoh of proinsulin–to–insulin-positive b-cell agnosis of type 1 diabetes made by an Bioscience), which had a sensitivity of area is increased in pancreatic sections endocrinologist on the basis of either 0.017 nmol/L at study start (3,19). from donors with recent-onset type 1 positive islet cell antibodies or insulin Though the TOSOH assay sensitivity diabetes and in autoantibody-positive therapy started around the time of changed to 0.007 nmol/L over the donors without diabetes (17). Persistent diagnosis and used continually thereafter course of the study, for consistency in elevations in islet proinsulin content (with the exception of individuals who our longitudinal analyses, the threshold Corresponding author: Carmella Evans-Molina, This article contains Supplementary Data online © 2018 by the American Diabetes Association. [email protected], or Emily K. Sims, eksims@iu.
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