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

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          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/m 2, 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.

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          Most cited references21

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          Pathologic anatomy of the pancreas in juvenile diabetes mellitus.

          W Gepts (1965)
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            Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial.

            In patients with type 1 diabetes, measurement of connecting peptide (C-peptide), cosecreted with insulin from the islets of Langerhans, permits estimation of remaining beta-cell secretion of insulin. In this retrospective analysis to distinguish the incremental benefits of residual beta-cell activity in type 1 diabetes, stimulated (90 min following ingestion of a mixed meal) C-peptide levels at entry in the Diabetes Control and Complications Trial (DCCT) were related to measures of diabetic retinopathy and nephropathy and to incidents of severe hypoglycemia. Based on the analytical sensitivity of the assay (0.03 nmol/l) and study entry criteria, the DCCT subjects were divided into four groups of stimulated C-peptide responses: 40 mg/24 h once and repeated at the next annual visit). There were also differences in severe hypoglycemia across C-peptide levels in both treatment groups. In the intensively treated cohort there were essentially identical prevalences of severe hypoglycemia ( approximately 65% of participants) in the first three groups; however, those subjects with mixed-meal stimulated C-peptide level >0.20 nmol/l for at least baseline and the first annual visit in the DCCT experienced a reduced prevalence of approximately 30%. Therefore, even modest levels of beta-cell activity at entry in the DCCT were associated with reduced incidences of retinopathy and nephropathy. Also, continuing C-peptide (insulin) secretion is important in avoiding hypoglycemia (the major complication of intensive diabetic therapy).
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              Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group.

              To investigate and monitor the patterns in incidence of childhood type 1 diabetes worldwide. The incidence of type 1 diabetes (per 100,000 per year) from 1990 to 1994 was determined in children 350-fold variation in the incidence among the 100 populations worldwide. The global pattern of variation in incidence was evaluated by arbitrarily grouping the populations with a very low ( or =20/100,000 per year) incidence. Of the European populations, 18 of 39 had an intermediate incidence, and the remainder had a high or very high incidence. A very high incidence (> or =20/ 100,000 per year) was found in Sardinia, Finland, Sweden, Norway Portugal, the U.K., Canada, and New Zealand. The lowest incidence (<1/100,000 per year) was found in the populations from China and South America. In most populations, the incidence increased with age and was the highest among children 10-14 years of age. The range of global variation in the incidence of childhood type 1 diabetes is even larger than previously described. The earlier reported polar-equatorial gradient in the incidence does not seem to be as strong as previously assumed, but the variation seems to follow ethnic and racial distribution in the world population.
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                Author and article information

                Journal
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                November 2010
                10 August 2010
                : 59
                : 11
                : 2846-2853
                Affiliations
                [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.
                Author notes
                Corresponding author: George L. King, George.King@ 123456joslin.harvard.edu .
                Article
                0676
                10.2337/db10-0676
                2963543
                20699420
                8d886ac0-7e78-4bdc-99d0-c3fa31975598
                © 2010 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 12 May 2010
                : 30 July 2010
                Funding
                Funded by: National Institutes of Health
                Award ID: K12-16335
                Award ID: T32-DK-007260
                Award ID: R24-DK-083957 01
                Award ID: P30-DK-036836-23
                Categories
                Islet Studies

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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