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

  1. George L. King1,2
  1. 1Research Division, Joslin Diabetes Center, Boston, Massachusetts;
  2. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts;
  3. 3Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts;
  4. 4Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts;
  5. 5Barbara Davis Center for Childhood Diabetes, Denver, Colorado.
  1. Corresponding author: George L. King, George.King{at}joslin.harvard.edu.

Abstract

OBJECTIVE To evaluate the extent of pancreatic β-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 β-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, BMI at 26.0 ± 5.1 kg/m2, insulin dose of 0.46 ± 0.2 u/kg, ∼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+ β-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 β cells could be a viable therapeutic approach in a significant number of patients with type 1 diabetes, even for those with chronic duration.

Footnotes

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  • Received May 12, 2010.
  • Accepted July 30, 2010.

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  1. Diabetes vol. 59 no. 11 2846-2853
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