Highly expressed in the β-cell, the nutrient sensor O-GlcNAc transferase (OGT) couples metabolic environment to cellular behavior through dynamic protein modifications (O-GlcNAcylation) but the role of OGT in β-cell hyperlipidemia is unknown. Here, we observed changes in islet O-GlcNAcylation in obese humans and high-fat diet (HFD, 60%) fed mice vs. lean controls, leading us to hypothesize that OGT mediates β-cell adaptations to diet-induced obesity. In a mouse model of partial β-cell OGT loss, we found that Rip-Cre; OGT f/+ (OGT Het) mice failed to develop hyperinsulinemia over 12 weeks of HFD. Only Het islets isolated from HFD mice showed deficits in stimulated insulin secretion (30 mM KCl, vs. HFD Ogt f/+). Nutrient-driven ATP was not impaired, but islets with full β-cell OGT KO (Rip-Cre; OGT f/f) showed no acute secretory potentiation to palmitate (100 μM) implicating the amplification arm of the stimulus-secretion pathway. HFD β-cell mass was similar (OGT Het vs. WT) but increased Ins+/Gcg+ cells and Ngn3 gene expression in OGT Het islets suggested functional β-cell loss through enhanced dedifferentiation. HFD hypoinsulinemia was reiterated in a tamoxifen-induced OGT loss model (Mip-Cre; OGT f/f), which also showed elevated proinsulin/insulin serum ratios (6 weeks HFD). Transcriptome analysis by RNA-sequencing of OGT KO and WT mouse islets revealed differential gene expression of proteins involved in membrane depolarization (Kcnj11, Abcc8), ER calcium (Atp2a2), lipid uptake (Lpl) and β-cell differentiation (Ucn3). An upstream analysis suggested impairments in free radical scavenging, supported by elevated levels of 4-HNE lipid peroxidation staining in post-HFD OGT Het islets. However, antioxidant supplementation of HFD chow (0.2% alpha-lipoic acid) did not rescue OGT Het in vivo deficits. These data reveal OGT as a critical mediator of β-cell adaptation to diet-induced obesity and highlight protein O-GlcNAcylation as a potential therapeutic target to prevent prediabetic progression.


A.D. Lockridge: None. S. Jo: None. N.E. Damberg: None. R. Mohan: None. E. Alejandro: None.

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