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

Disclosures

Diabetes. 2010;59(11):2846-2853. 

In This Article

Abstract and Introduction

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.

Introduction

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.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....