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      Sex differences underlying pancreatic islet biology and its dysfunction

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          The sex of an individual affects glucose homeostasis and the pathophysiology, incidence, and prevalence of diabetes as well as the response to therapy.

          Scope of the review

          This review focuses on clinical and experimental sex differences in islet cell biology and dysfunction during development and in adulthood in human and animal models. We discuss sex differences in β-cell and α-cell function, heterogeneity, and dysfunction. We cover sex differences in communication between gonads and islets and islet-cell immune interactions. Finally, we discuss sex differences in β-cell programming by nutrition and other environmental factors during pregnancy.

          Major conclusions

          Important sex differences exist in islet cell function and susceptibility to failure. These differences represent sex-related biological factors that can be harnessed for gender-based prevention of and therapy for diabetes.

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          Most cited references 102

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          Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo.

          Development of a cell therapy for diabetes would be greatly aided by a renewable supply of human beta-cells. Here we show that pancreatic endoderm derived from human embryonic stem (hES) cells efficiently generates glucose-responsive endocrine cells after implantation into mice. Upon glucose stimulation of the implanted mice, human insulin and C-peptide are detected in sera at levels similar to those of mice transplanted with approximately 3,000 human islets. Moreover, the insulin-expressing cells generated after engraftment exhibit many properties of functional beta-cells, including expression of critical beta-cell transcription factors, appropriate processing of proinsulin and the presence of mature endocrine secretory granules. Finally, in a test of therapeutic potential, we demonstrate that implantation of hES cell-derived pancreatic endoderm protects against streptozotocin-induced hyperglycemia. Together, these data provide definitive evidence that hES cells are competent to generate glucose-responsive, insulin-secreting cells.
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            Genetics, pathogenesis and clinical interventions in type 1 diabetes.

            Type 1 diabetes is an autoimmune disorder afflicting millions of people worldwide. Once diagnosed, patients require lifelong insulin treatment and can experience numerous disease-associated complications. The last decade has seen tremendous advances in elucidating the causes and treatment of the disease based on extensive research both in rodent models of spontaneous diabetes and in humans. Integrating these advances has led to the recognition that the balance between regulatory and effector T cells determines disease risk, timing of disease activation, and disease tempo. Here we describe current progress, the challenges ahead and the new interventions that are being tested to address the unmet need for preventative or curative therapies.
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              Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer.

              Androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist is associated with increased fat mass and insulin resistance in men with prostate cancer, but the risk of obesity-related disease during treatment has not been well studied. We assessed whether androgen deprivation therapy is associated with an increased incidence of diabetes and cardiovascular disease. Observational study of a population-based cohort of 73,196 fee-for-service Medicare enrollees age 66 years or older who were diagnosed with locoregional prostate cancer during 1992 to 1999 and observed through 2001. We used Cox proportional hazards models to assess whether treatment with GnRH agonists or orchiectomy was associated with diabetes, coronary heart disease, myocardial infarction, and sudden cardiac death. More than one third of men received a GnRH agonist during follow-up. GnRH agonist use was associated with increased risk of incident diabetes (adjusted hazard ratio [HR], 1.44; P .20). GnRH agonist treatment for men with locoregional prostate cancer may be associated with an increased risk of incident diabetes and cardiovascular disease. The benefits of GnRH agonist treatment should be weighed against these potential risks. Additional research is needed to identify populations of men at highest risk of treatment-related complications and to develop strategies to prevent treatment-related diabetes and cardiovascular disease.

                Author and article information

                Mol Metab
                Mol Metab
                Molecular Metabolism
                30 May 2018
                September 2018
                30 May 2018
                : 15
                : 82-91
                [1 ]Department of Medicine, Vanderbilt University Medical Center, Nashville, USA
                [2 ]Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN, USA
                [3 ]Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, USA
                [4 ]Department of Medicine, Harvard Medical School, Boston, USA
                [5 ]Harvard Stem Cell Institute, Boston, MA, USA
                [6 ]Department of Microbiology, Birmingham, USA
                [7 ]Comprehensive Diabetes Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
                [8 ]Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center School of Medicine, New Orleans, USA
                [9 ]Southeast Louisiana Veterans Healthcare System Medical Center, New Orleans, LA, USA
                Author notes
                []Corresponding author. Tulane University Health Science Center, New Orleans, LA, USA. fmauvais@

                This is an open access article under the CC BY-NC-ND license (



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