Calcium-activated Calpain-2 Is a Mediator of Beta Cell Dysfunction and Apoptosis in Type 2 Diabetes |
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| Authors: | Chang-jiang Huang Tatyana Gurlo Leena Haataja Safia Costes Marie Daval Sergey Ryazantsev Xiuji Wu Alexandra E. Butler Peter C. Butler |
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| Affiliation: | From the ‡Larry Hillblom Islet Research Center, David Geffen School of Medicine, and ;§Electron Imaging Center for Nanomachines, California Nano Systems Institute, UCLA, Los Angeles, California 90024-2852 |
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| Abstract: | The islet in type 2 diabetes (T2DM) and the brain in neurodegenerative diseases share progressive cell dysfunction, increased apoptosis, and accumulation of locally expressed amyloidogenic proteins (islet amyloid polypeptide (IAPP) in T2DM). Excessive activation of the Ca2+-sensitive protease calpain-2 has been implicated as a mediator of oligomer-induced cell death and dysfunction in neurodegenerative diseases. To establish if human IAPP toxicity is mediated by a comparable mechanism, we overexpressed human IAPP in rat insulinoma cells and freshly isolated human islets. Pancreas was also obtained at autopsy from humans with T2DM and nondiabetic controls. We report that overexpression of human IAPP leads to the formation of toxic oligomers and increases beta cell apoptosis mediated by increased cytosolic Ca2+ and hyperactivation of calpain-2. Cleavage of α-spectrin, a marker of calpain hyperactivation, is increased in beta cells in T2DM. We conclude that overactivation of Ca2+-calpain pathways contributes to beta cell dysfunction and apoptosis in T2DM. |
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