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Increased Insulin Translation from an Insulin Splice-Variant Overexpressed in Diabetes, Obesity, and Insulin Resistance

Department of Medicine, University of Wisconsin (A.H.M., A.S.), Madison, Wisconsin 53792; Department of Biochemistry, University of Wisconsin (H.L., M.E.R., A.D.A.), Madison, Wisconsin 53706; and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services (D.M.H., B.A.P.), Bethesda, Maryland 20892

Address requests for reprints to: Dr. Anath Shalev, University of Wisconsin-Madison, H4/526 Clinical Science Center, 600 Highland Avenue, Madison, Wisconsin 53792. E-mail: as7{at}medicine.wisc.edu.

Type 2 diabetes occurs when pancreatic ß-cells become unable to compensate for the underlying insulin resistance. Insulin secretion requires ß-cell insulin stores to be replenished by insulin biosynthesis, which is mainly regulated at the translational level. Such translational regulation often involves the 5'-untranslated region. Recently, we identified a human insulin splice-variant (SPV) altering only the 5'-untranslated region and conferring increased translation efficiency. We now describe a mouse SPV (mSPV) that is found in the cytoplasm and exhibits increased translation efficiency resulting in more normal (prepro)insulin protein per RNA. The RNA stability of mSPV is not increased, but the predicted secondary RNA structure is altered, which may facilitate translation. To determine the role of mSPV in insulin resistance and diabetes, mSPV expression was measured by quantitative real-time RT-PCR in islets from three diabetic and/or insulin-resistant, obese and nonobese, mouse models (BTBRob/ob, C57BL/6ob/ob, and C57BL/6azip). Interestingly, mSPV expression was significantly higher in all diabetic/insulin-resistant mice compared with wild-type littermates and was dramatically induced in primary mouse islets incubated at high glucose. This raises the possibility that the mSPV may represent a compensatory ß-cell mechanism to enhance insulin biosynthesis when insulin requirements are elevated by hyperglycemia/insulin resistance.

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