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

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0006777 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0428 (Electronic) Linking ISSN: 0012186X NLM ISO Abbreviation: Diabetologia Subsets: MEDLINE

Original Publication: Berlin Springer Verlag

Diabetes Mellitus, Type 2*/genetics ; Diabetes Mellitus, Type 2*/metabolism ; Insulin Resistance*/genetics ; Insulin-Secreting Cells*/metabolism; X-Box Binding Protein 1/*metabolism; Animals ; Cell Transdifferentiation/genetics ; Humans ; Insulin/metabolism ; Mice ; Stress, Physiological ; X-Box Binding Protein 1/genetics

Aims/hypothesis: Pancreatic beta cell dedifferentiation, transdifferentiation into other islet cells and apoptosis have been implicated in beta cell failure in 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 the unfolded protein response. XBP1 expression is reduced in islets of people with type 2 diabetes, but its role in adult differentiated beta cells is unclear. Here, we assessed the effects of Xbp1 deletion in adult beta cells and tested whether XBP1-mediated unfolded protein response makes a necessary contribution to beta cell compensation in insulin resistance states.
Methods: Mice with inducible beta cell-specific Xbp1 deletion were studied under normal (chow diet) or metabolic stress (high-fat diet or obesity) conditions. Glucose tolerance, insulin secretion, islet gene expression, alpha cell mass, beta cell mass and apoptosis were assessed. Lineage tracing was used to determine beta cell fate.
Results: Deletion of Xbp1 in adult mouse beta cells led to beta cell dedifferentiation, beta-to-alpha cell transdifferentiation and increased alpha cell mass. Cell lineage-specific analyses revealed that Xbp1 deletion deactivated beta cell identity genes (insulin, Pdx1, Nkx6.1, Beta2, Foxo1) and derepressed beta cell dedifferentiation (Aldh1a3) and alpha cell (glucagon, Arx, Irx2) genes. Xbp1 deletion in beta cells of obese ob/ob or high-fat diet-fed mice triggered diabetes and worsened glucose intolerance by disrupting insulin secretory capacity. Furthermore, Xbp1 deletion increased beta cell apoptosis under metabolic stress conditions by attenuating the antioxidant response.
Conclusions/interpretation: These findings indicate that XBP1 maintains beta cell identity, represses beta-to-alpha cell transdifferentiation and is required for beta cell compensation and prevention of diabetes in insulin resistance states.
(© 2022. The Author(s).)

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Keywords: Beta cell identity; Dedifferentiation; Endoplasmic reticulum stress; Islets; Type 2 diabetes; Unfolded protein response

0 (Insulin)
0 (X-Box Binding Protein 1)
0 (XBP1 protein, human)
0 (Xbp1 protein, mouse)

Date Created: 20220322 Date Completed: 20220510 Latest Revision: 20220716

20250114

PMC9076738

10.1007/s00125-022-05669-7

35316840