XBP1 maintains beta cell identity, represses beta-to-alpha cell transdifferentiation and protects against diabetic beta cell failure during metabolic stress in mice

• DOI: 10.1007/s00125-022-05669-7
• Publication Date: 2022-03-22T09:04:04Z
• Authors: Kailun Lee; Jeng Yie Chan; Cassandra Liang; Chi Kin Ip; Yan-Chuan Shi; Herbert Herzog; William E. Hughes; Mohammed Bensellam; Viviane Delghinga...; Mark E. Koina; Christopher J. Nolan; D. Ross Laybutt
• Keywords: Transdifferentiation; BETA (programming language); Alpha (finance); Alpha cell

Abstract Aims/hypothesis Pancreatic beta cell dedifferentiation, transdifferentiation into other islet cells and apoptosis have been implicated in failure type 2 diabetes, although the mechanisms are poorly defined. The endoplasmic reticulum stress response factor X-box binding protein 1 (XBP1) is a major regulator of unfolded response. XBP1 expression reduced islets people with but its role adult differentiated unclear. Here, we assessed effects Xbp1 deletion tested whether XBP1-mediated makes necessary contribution to compensation insulin resistance states. Methods Mice inducible cell-specific were studied under normal (chow diet) or metabolic (high-fat diet obesity) conditions. Glucose tolerance, secretion, gene expression, alpha mass, mass assessed. Lineage tracing was used determine fate. Results Deletion mouse led beta-to-alpha increased mass. Cell lineage-specific analyses revealed that deactivated identity genes (insulin, Pdx1 , Nkx6.1 Beta2 Foxo1 ) derepressed dedifferentiation ( Aldh1a3 (glucagon, Arx Irx2 genes. obese ob/ob high-fat diet-fed mice triggered diabetes worsened glucose intolerance by disrupting secretory capacity. Furthermore, conditions attenuating antioxidant Conclusions/interpretation These findings indicate maintains identity, represses required for prevention Graphical abstract