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Islet β cell mass in diabetes and how it relates to function, birth, and death

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      Abstract

      In type 1 diabetes (T1D) β cell mass is markedly reduced by autoimmunity. Type 2 diabetes (T2D) results from inadequate β cell mass and function that can no longer compensate for insulin resistance. The reduction of β cell mass in T2D may result from increased cell death and/or inadequate birth through replication and neogenesis. Reduction in mass allows glucose levels to rise, which places β cells in an unfamiliar hyperglycemic environment, leading to marked changes in their phenotype and a dramatic loss of glucose-stimulated insulin secretion (GSIS), which worsens as glucose levels climb. Toxic effects of glucose on β cells (glucotoxicity) appear to be the culprit. This dysfunctional insulin secretion can be reversed when glucose levels are lowered by treatment, a finding with therapeutic significance. Restoration of β cell mass in both types of diabetes could be accomplished by either β cell regeneration or transplantation. Learning more about the relationships between β cell mass, turnover, and function and finding ways to restore β cell mass are among the most urgent priorities for diabetes research.

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      Most cited references 123

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      Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.

      Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors--elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle--are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups. The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.
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        Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes.

        Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in beta-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m(2); 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m(2); 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative beta-cell volume, frequency of beta-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative beta-cell volume was increased in obese versus lean nondiabetic cases (P = 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative beta-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of beta-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of beta-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that beta-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased beta-cell apoptosis. Since the major defect leading to a decrease in beta-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and beta-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.
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          Biology of incretins: GLP-1 and GIP.

          This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes.
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            Author and article information

            Affiliations
            Section on Islet Cell Biology and Regenerative Medicine, Research Division, Joslin Diabetes Center, Department of Medicine, Harvard Medical School Boston, Massachusetts
            Author notes
            Address for correspondence: Gordon C. Weir, M.D., Section on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. gordon.weir@ 123456joslin.harvard.edu
            Journal
            Ann N Y Acad Sci
            Ann. N. Y. Acad. Sci
            nyas
            Annals of the New York Academy of Sciences
            Blackwell Publishing Ltd
            0077-8923
            1749-6632
            April 2013
            30 January 2013
            : 1281
            : 1
            : 92-105
            23363033 3618572 10.1111/nyas.12031
            © 2013 The New York Academy of Sciences

            Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

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            beta cell, insulin secretion, neogenesis, diabetes, islets

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