{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T12:31:09Z","timestamp":1778589069114,"version":"3.51.4"},"reference-count":42,"publisher":"American Diabetes Association","issue":"11","license":[{"start":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T00:00:00Z","timestamp":1630281600000},"content-version":"vor","delay-in-days":3605,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,11,1]]},"abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>Insulin receptor substrate-2 (IRS-2) plays an essential role in pancreatic islet \u03b2-cells by promoting growth and survival. IRS-2 turnover is rapid in primary \u03b2-cells, but its expression is highly regulated at the transcriptional level, especially by glucose. The aim was to investigate the molecular mechanism on how glucose regulates IRS-2 gene expression in \u03b2-cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                  <jats:p>Rat islets were exposed to inhibitors or subjected to adenoviral vector\u2013mediated gene manipulations and then to glucose-induced IRS-2 expression analyzed by real-time PCR and immunoblotting. Transcription factor nuclear factor of activated T cells (NFAT) interaction with IRS-2 promoter was analyzed by chromatin immunoprecipitation assay and glucose-induced NFAT translocation by immunohistochemistry.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>Glucose-induced IRS-2 expression occurred in pancreatic islet \u03b2-cells in vivo but not in liver. Modulating rat islet \u03b2-cell Ca2+ influx with nifedipine or depolarization demonstrated that glucose-induced IRS-2 gene expression was dependent on a rise in intracellular calcium concentration derived from extracellular sources. Calcineurin inhibitors (FK506, cyclosporin A, and a peptide calcineurin inhibitor [CAIN]) abolished glucose-induced IRS-2 mRNA and protein levels, whereas expression of a constitutively active calcineurin increased them. Specific inhibition of NFAT with the peptide inhibitor VIVIT prevented a glucose-induced IRS-2 transcription. NFATc1 translocation to the nucleus in response to glucose and association of NFATc1 to conserved NFAT binding sites in the IRS-2 promoter were demonstrated.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>The mechanism behind glucose-induced transcriptional control of IRS-2 gene expression specific to the islet \u03b2-cell is mediated by the Ca2+\/calcineurin\/NFAT pathway. This insight into the IRS-2 regulation could provide novel therapeutic means in type 2 diabetes to maintain an adequate functional mass.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db11-0341","type":"journal-article","created":{"date-parts":[[2011,9,23]],"date-time":"2011-09-23T01:01:52Z","timestamp":1316739712000},"page":"2892-2902","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":61,"title":["Specific Glucose-Induced Control of Insulin Receptor Substrate-2 Expression Is Mediated via Ca2+-Dependent Calcineurin\/NFAT Signaling in Primary Pancreatic Islet \u03b2-Cells"],"prefix":"10.2337","volume":"60","author":[{"given":"Damien","family":"Demozay","sequence":"first","affiliation":[{"name":"Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, Illinois"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin","family":"Tsunekawa","sequence":"additional","affiliation":[{"name":"Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, Illinois"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabelle","family":"Briaud","sequence":"additional","affiliation":[{"name":"Theriac Pharmaceutical Corporation, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramila","family":"Shah","sequence":"additional","affiliation":[{"name":"Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, Illinois"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher J.","family":"Rhodes","sequence":"additional","affiliation":[{"name":"Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and 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