Residual Insulin Production and Pancreatic β Cell Turnover after 50 Years of Diabetes: Joslin Medalist Study.
- Hillary A. Keenan1,2,
- Jennifer K. Sun1,3,4,
- Jared Levine1,2,
- Alessandro Doria1,2,
- Lloyd P. Aiello1,3,4,
- George Eisenbarth5,
- Susan Bonner-Weir1,2 and
- George L. King ()1,2
Objective: To evaluate the extent of pancreatic β cell function in a large number of insulin-dependent diabetic patients with disease duration of 50 years or longer (Medalists).
Research Design and Methods: Characterization of clinical and biochemical parameters, and β cell function of 411 Medalists with correlation with post-mortem morphological findings of nine Medalists.
Results: The Medalist cohort, with mean 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 (T1DM): mean onset at 11.0 ± 6.4 years, body mass index (BMI) at 26.0 ± 5.1 kg/m2, insulin dose of 0.46 ± 0.2 u/kg, approximately 94% positive for DR3 and/or DR4, and 29.5% positive for either IA2 or GAD autoantibodies. Random serum C-peptide levels showed that greater than 67.4% 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 HbA1c, older age of onset, higher frequency of HLA DR3 genotype, and responsiveness to mix meal tolerance test (MMTT). Over half of Medalists with fasting C-peptide >0.17 nmol/L responded in MMTT by two-fold or greater rise over fasting. Post-mortem examination of pancreases from nine Medalists showed that all had insulin+ β cells with some positive for apoptosis (TUNEL), proliferation (Ki67) and insulitis (CD3).
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 β cells could be a viable therapeutic approach in a significant number of patients with T1DM, even with chronic duration.
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