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

Hillary A. Keenan; Jennifer K. Sun; Jared Levine; Alessandro Doria; Lloyd P. Aiello; George Eisenbarth; Susan Bonner-Weir; George L. King


Diabetes. 2010;59(11):2846-2853. 

In This Article

Abstract and Introduction


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.


The incidence of type 1 diabetes is increasing around the world and age at onset is becoming younger.[1–4] More than 90% of diabetic patients will develop significant vascular complications resulting in loss of visual acuity, kidney failure, and increased risk of cardiovascular diseases.[5–7] Enhancing endogenous insulin production in diabetic patients can substantially improve glycemic control and decrease complications. However, the comparative analysis of residual pancreatic function and morphology in long-term diabetic patients has not been studied. The Joslin 50-Year Medalist Study has been characterizing as a large cohort of patients who have been insulin dependent for 50 years or longer.[8,9] Surprisingly, preliminary screening by random serum C-peptide levels suggests that a majority of Medalists may still be producing insulin.

Studies on individuals with extreme duration of type 1 diabetes are rare, but they can be uniquely useful in identifying protective factors against the development of complications and for the preservation of endogenous insulin-producing β-cells.[10] Bain et al.[8] characterized the golden years cohort, a population of people with 50 or more years of type 1 diabetes from the U.K., for complication status and other clinical parameters, but not for residual insulin production. Lohr and Kloppel[9] reported residual β-cells in 46% of their 16 autopsied cases of individuals with more than 21 years duration of diabetes. Pipeleers and Ling[10] reported residual β-cells in 40% of 43 patients with 10–30 years duration of diabetes and onset after 7 years of age. More recently, Meier et al.[11] reported the presence of insulin-containing β-cells in 88% of the pancreases from 42 type 1 diabetic patients with duration of diabetes ranging from 4–67 years of whom 14 had diabetes for 32 or more years. Gianani et al.[12] reported that 3 of 13 pancreases of people with childhood-onset diabetes for 10 years or longer were positive for insulin, but only 1 of these had either DR3 or DR4 allele. However, no clinical premortem studies on β-cell function were reported in any of these studies.

In the present study, we are reporting the clinical and physiologic characterization of 411 patients with insulin-dependent diabetes of 50 years or longer duration, particularly with regard to their pancreatic β-cell function. In addition, uniquely, multiple samples of pancreases from 9 Medalists were analyzed morphologically and correlated with premortem data to determine whether the clinical evidence of residual insulin production correlates with the pancreatic histologic findings.


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