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

  1. George L. King (George.King{at}joslin.harvard.edu)1,2
  1. 1Research Division, Joslin Diabetes Center, Boston, MA
  2. 2Department of Medicine, Harvard Medical School, Boston, MA
  3. 3Beetham Eye Institute, Joslin Diabetes Center, Boston, MA
  4. 4Department of Ophthalmology, Harvard Medical School, Boston, MA
  5. 5 Barbara Davis Center for Childhood Diabetes, Denver, CO

Abstract

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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