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Small intracellular membrane-permeant oligomers, the most toxic form of IAPP, are more frequent in \u03b2 cells of patients with T2D and rodents expressing human IAPP. \u03b2 Cells in T2D, and affected cells in neurodegenerative diseases, share a comparable pattern of molecular pathology, including endoplasmic reticulum stress, mitochondrial dysfunction, attenuation of autophagy, and calpain hyperactivation. While this adverse functional cascade in response to toxic oligomers is well described, the sequence of events and how best to intervene is unknown. We hypothesized that calpain hyperactivation is a proximal event and tested this in vivo by \u03b2 cell\u2013specific suppression of calpain hyperactivation with calpastatin overexpression in human IAPP transgenic mice. \u03b2 Cell\u2013specific calpastatin overexpression was remarkably protective against \u03b2 cell dysfunction and loss and diabetes onset. The critical autophagy\/lysosomal pathway for \u03b2 cell viability was protected with calpain suppression, consistent with findings in models of neurodegenerative diseases. We conclude that suppression of calpain hyperactivation is a potentially beneficial disease-modifying strategy for protein misfolding diseases, including T2D.<\/jats:p>","DOI":"10.1172\/jci.insight.89590","type":"journal-article","created":{"date-parts":[[2016,11,2]],"date-time":"2016-11-02T11:00:44Z","timestamp":1478084444000},"source":"Crossref","is-referenced-by-count":20,"title":["\u03b2 Cell\u2013specific increased expression of calpastatin prevents diabetes induced by islet amyloid polypeptide toxicity"],"prefix":"10.1172","volume":"1","author":[{"given":"Tatyana","family":"Gurlo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safia","family":"Costes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D.","family":"Hoang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline F.","family":"Rivera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra E.","family":"Butler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"Butler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2016,11,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.1.102"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2007-0037"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00042.2009"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.47.5.743"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.6.1509"},{"issue":"1","key":"B6","first-page":"36","article-title":"Diabetes mellitus and islet amyloidosis in cynomolgus monkeys","volume":"46","author":"Wagner","year":"1996","journal-title":"Lab Anim Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/ilar.47.3.234"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.48.3.491"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.659797"},{"issue":"12","key":"B10","doi-asserted-by":"crossref","first-page":"4842","DOI":"10.1523\/JNEUROSCI.22-12-04842.2002","article-title":"Calpain activation in Huntington\u2019s disease","volume":"22","author":"Gafni","year":"2002","journal-title":"J Neurosci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.2002.0542"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2826-07.2007"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2174\/187152708784936680"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.024190"},{"key":"B15","doi-asserted-by":"crossref","DOI":"10.5402\/2012\/728571","article-title":"Calpain dysregulation in Alzheimer\u2019s disease","volume":"2012","author":"Ferreira","year":"2012","journal-title":"ISRN Biochem"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2345-11.2012"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1421055111"},{"issue":"Pt 3","key":"B18","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1042\/bj3280721","article-title":"Structure and physiological function of calpains","volume":"328","author":"Sorimachi","year":"1997","journal-title":"Biochem J"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.79"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.151"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1172\/JCI71981"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1172\/JCI69866"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1172\/JCI69625"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-009-1347-2"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2014.04.003"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3390\/ijms161125990"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090532"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/science.1079469"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2013.02.004"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4119-08.2008"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.14.7283"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2009.04.010"},{"issue":"3","key":"B33","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.tins.2016.01.008","article-title":"There\u2019s Something Wrong with my MAM; 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