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      Human Islet Amyloid Polypeptide Transgenic Mice: In Vivo and Ex Vivo Models for the Role of hIAPP in Type 2 Diabetes Mellitus

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          Abstract

          Human islet amyloid polypeptide (hIAPP), a pancreatic islet protein of 37 amino acids, is the main component of islet amyloid, seen at autopsy in patients with type 2 diabetes mellitus (DM2). To investigate the roles of hIAPP and islet amyloid in DM2, we generated transgenic mice expressing hIAPP in their islet beta cells. In this study, we found that after a long-term, high-fat diet challenge islet amyloid was observed in only 4 of 19 hIAPP transgenic mice. hIAPP transgenic females exhibited severe glucose intolerance, which was associated with a downregulation of GLUT-2 mRNA expression. In isolated islets from hIAPP males cultured for 3 weeks on high-glucose medium, the percentage of amyloid containing islets increased from 5.5% to 70%. This ex vivo system will allow a more rapid, convenient, and specific study of factors influencing islet amyloidosis as well as of therapeutic strategies to interfere with this pathological process.

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          Most cited references42

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          Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.

          Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.
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            Diet-induced type II diabetes in C57BL/6J mice.

            We investigated the effects of diet-induced obesity on glucose metabolism in two strains of mice, C57BL/6J and A/J. Twenty animals from each strain received ad libitum exposure to a high-fat high-simple-carbohydrate diet or standard Purina Rodent Chow for 6 mo. Exposure to the high-fat, high-simple-carbohydrate, low-fiber diet produced obesity in both A/J and C57BL/6J mice. Whereas obesity was associated with only moderate glucose intolerance and insulin resistance in A/J mice, obese C57BL/6J mice showed clear-cut diabetes with fasting blood glucose levels of greater than 240 mg/dl and blood insulin levels of greater than 150 microU/ml. C57BL/6J mice showed larger glycemic responses to stress and epinephrine in the lean state than AJ mice, and these responses were exaggerated by obesity. These data suggest that the C57BL/6J mouse carries a genetic predisposition to develop non-insulin-dependent (type II) diabetes. Furthermore, altered glycemic response to adrenergic stimulation may be a biologic marker for this genetic predisposition to develop type II diabetes.
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              Type 2 diabetes-a matter of beta-cell life and death?

              In type 2 diabetes, the beta cells of the pancreas fail to produce enough insulin to meet the body's demand, in part because of an acquired decrease in beta-cell mass. In adults, pancreatic beta-cell mass is controlled by several mechanisms, including beta-cell replication, neogenesis, hypertrophy, and survival. Here, I discuss evidence supporting the notion that increased beta-cell apoptosis is an important factor contributing to beta-cell loss and the onset of type 2 diabetes. Interestingly, a key signaling molecule that promotes beta-cell growth and survival, insulin receptor substrate 2 (IRS-2), is a member of a family of proteins whose inhibition contributes to the development of insulin resistance in the liver and other insulin-responsive tissues. Thus, the IRS-2 pathway appears to be a crucial participant in the tenuous balance between effective pancreatic beta-cell mass and insulin resistance.
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                Author and article information

                Journal
                Exp Diabetes Res
                EDR
                Experimental Diabetes Research
                Hindawi Publishing Corporation
                1687-5214
                1687-5303
                2008
                12 May 2008
                : 2008
                : 697035
                Affiliations
                1Division of Biomedical Genetics, Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands
                2Netherlands Metabolomics Centre, location Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands
                3Division Laboratories and Pharmacy, Department of Endocrinology, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands
                4Department of Experimental Medical Sciences, Lund University, BMC, C 12, S-221 84 Lund, Sweden
                5Division of Medical Biology, Department of Pathology and Laboratory Medicine, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
                6Department of Clinical Sciences, Lund University, BMC, C 12, S-221 84 Lund, Sweden
                Author notes

                Recommended by Hiroshi Okamoto

                Article
                10.1155/2008/697035
                2386890
                18497871
                a60c4ec8-e1c1-48f2-8fa9-90cd6f3c9c27
                Copyright © 2008 J. W. M. Höppener et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 October 2007
                : 30 January 2008
                : 14 February 2008
                Categories
                Research Article

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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