Nutrient sensor O-GlcNAc transferase maintains pancreatic beta-cell identity, in part, through positive regulation of pancreatic duodenal homeobox 1

Type 2 diabetes (T2D) is a metabolic condition characterized by hyperglycemia and reduced functional beta-cell mass in the context of insulin resistance. O-GlcNAc transferase (Ogt) is a nutrient sensitive enzyme that is highly expressed in the pancreatic islets. It is the sole enzyme that catalyzes the addition of an O-GlcNAc sugar moiety onto Ser and Thr residues of its target proteins, affecting their localization, stability, and function. We previously demonstrated that expression of Ogt in the developing pancreatic epithelium is indispensable for the formation of both the endocrine and exocrine pancreas compartments. Genetic deletion of Ogt in the islet progenitors and in the pancreatic beta-cell, specifically, both result in progressive diabetes and reductions in levels of transcription factor pancreatic duodenal homeobox 1 (Pdx1), a target of Ogt and a master regulator of mature pancreatic beta-cell identity and function. Studies in humans and in animal models have implicated beta-cell dedifferentiation, in addition to ER stress induced apoptosis, as a driver of the loss of functional beta-cell mass in the pathogenesis of T2D. Thus, we hypothesized that Ogt maintains pancreatic beta-cell function and identity, in part, through positive regulation of Pdx1. Using islets from human donors, we demonstrate that islets from T2D individuals exhibit reduced global O-GlcNAc levels, in addition to significantly lower levels of both Ogt and Pdx1. In mice, deletion of Ogt in the entire islet (OgtKOEndo) results in increased levels of insulin and glucagon co-expressing (bihormonal) cells, as well as aberrant Pdx1 localization. Furthermore, beta-cell specific Ogt haploinsufficiency (OgtHETIns) also results in increased bihormonal cells upon metabolic challenge, with elevated islet levels of lipid peroxidation marker 4-hydroxynonenal (4-HNE) and increased islet transcripts of Neurogenin 3 (Ngn3), suggesting the induction of oxidative stress and the perturbation of cell maturity. Similarly, mice lacking both alleles of Ogt in beta-cells (OgtKOIns) exhibit elevated levels of bihormonal cells, as well as lower islet Pdx1 levels, aberrant Pdx1 localization, and increased immunoreactivity for dedifferentiation marker, CD81. Genetic overexpression of Pdx1 in the absence of Ogt (OgtKOIns; PdxTg) results in a partial rescue of bihormonal cell levels. To elucidate the mechanism through which Ogt regulates Pdx1, we performed molecular experiments using MIN6 cells treated with small molecule Ogt-inhibitor, OSMI-1, and found that Ogt positively regulates both Pdx1 transcription and protein stability. Together, these results highlight the role of Ogt in the maintenance of functional beta-cell mass and identity through regulation of the beta-cell oxidative stress response and the stabilization of its transcription factor target, Pdx1. Funding: R01DK115720, T32GM140936, T32 HL166142 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.