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

Abstract

OBJECTIVETo 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 METHODSCharacterization of clinical and biochemical parameters and β-cell function of 411 Medalists with correlation with postmortem morphologic findings of 9 Medalists.RESULTSThe 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.CONCLUSIONSDemonstration 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.

Organ-specific autoimmunity in relation to clinical characteristics in children with long-lasting type 1 diabetes

“…In 43 patients with diabetes duration between 5 and 10 years, 90% had at least one diabetes associated Ab detected, with GAD Ab, ZnT8 Ab and IA-2 Ab positivity at 62%, 58% and 41%, respectively. This is in agreement with previous observations that 65% to 85% of diabetic patients tested 4-10 years after the diagnosis had detectable levels of islet-cell Ab [5][6][7]. However, only five out of 10 (50%) patients with disease duration longer than 10 years were positive for at least one diabetes associated Ab.…”

“…Measurement of these specific Ab has an important role in clinical practice including classification of diabetes, identification of individuals at risk of developing T1DM and as endpoints in observation studies [4]. The prevalence of islet cell Ab in T1DM varies in relation to patient's age and ethnic origin, as well as to disease duration [5][6][7][8]. In our study, we have assessed the prevalence of diabetes associated Ab in Polish children with T1DM.…”

Why were we wrong for so long? The pancreas of type 1 diabetic patients commonly functions for decades

“…The first to detect islets was the pathologist M. B. Schmidt, who in 1902 observed the rare presence of islet-like structures in an autopsy sample, albeit from a child with recent-onset disease [1]. Further histological confirmation of islet existence in all stages of diabetes came in 1959 through to 1985 [2][3][4][5][6], as well as more recently [7][8][9][10]. Despite this evidence, the accepted opinion persisted that the pancreas functionally dies a couple of years after diagnosis for the majority of patients.…”

Can we make a better beta cell?

“…It has long been recognised that beta cell destruction underpins type 1 diabetes, but it has become apparent only relatively recently that individuals with long-term type 1 diabetes still show residual beta cell turnover [2]. Reductions in beta cell mass are also involved in the aetiology of type 2 diabetes [3], so devising strategies for preserving a functional mass of beta cells to maintain normoglycaemia in people with both type 1 and type 2 diabetes is a fast moving area of research.…”