Residual Insulin Production and Pancreatic β-Cell Turnover After 50 Years of Diabetes: Joslin Medalist Study

OBJECTIVE-To evaluate the extent of pancreatic beta-cell function in a large number of insulin-dependent diabetic patients with a disease duration of 50 years or longer (Medalists). RESEARCH DESIGN AND METHODS-Characterization of clinical and biochemical parameters and beta-cell function of 411 Medalists with correlation with postmortem morphologic findings of 9 Medalists. RESULTS-The Medalist cohort, with a mean +/- SD disease duration and age of 56.2 +/- 5.8 and 67.2 +/- 7.5 years, respectively, has a clinical phenotype similar to type 1 diabetes (type 1 diabetes): mean +/- SD onset at 11.0 +/- 6.4 years, EMI at 26.0 +/- 5.1 kg/m(2), insulin dose of 0.46 +/- 0.2 u/kg, similar to 94% positive for DR3 and/or DR4, and 29.5% positive for either IA2 or glutamic acid decarboxylase (GAD) autoantibodies. Random serum C-peptide levels showed that more than 67.4% of the participants had levels in the minimal (0.03-0.2 nmol/l) or sustained range (>= 0.2 nmol/l). Parameters associated with higher random C-peptide were lower hemoglobin A1C, older age of onset, higher frequency of HLA DR3 genotype, and responsiveness to a mixed-meal tolerance test (MMTT). Over half of the Medalists with fasting C-peptide >0.17 nmol/l responded in MMTT by a twofold or greater rise over the course of the test compared to fasting. Postmortem examination of pancreases from nine Medalists showed that all had insulin+ beta-cells with some positive for TUNEL staining, indicating apoptosis. CONCLUSIONS-Demonstration of persistence and function of insulin-producing pancreatic cells suggests the possibility of a steady state of turnover in which stimuli to enhance endogenous beta cells could be a viable therapeutic approach in a significant number of patients with type 1 diabetes, even for those with chronic duration. Diabetes 59:2846-2853, 2010