Browsing by Subject "SERCA2"

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    ISLET O-GLCNACYLATION IN THE CONTEXT OF BETA CELL SECRETORY ADAPTATION TO OBESITY
    (2020-07) Lockridge, Amber
    Obesity is the primary risk factor for the development of type 2 diabetes, primarily through the induction of insulin resistance which leads to a dysregulation of glucose homeostasis. Nevertheless, the majority of obese individuals avoid diabetic hyperglycemia by upregulating insulin output through adaptive mechanisms that tune pancreatic β-cell secretory function, insulin biosynthesis, cell growth, differentiation and proliferation in accordance with the duration of overnutrition. For example, glucose-stimulated insulin secretion of β-cell-containing islets is potentiated in mice within a few weeks of high fat diet (HFD) feeding but transitions to secretory impairment after several months, even as β-cell mass expansion continues to drive hyperinsulinemia. The cooperative dynamism of this adaptation strategy, which appears to balance insulin demand against β-cell overwork, suggests an (unknown) coordinated regulatory system that is capable of differentiating between acute, prolonged and chronic overnutrition and transducing multi-factorial cellular effects. The premise of this thesis is that post-translational protein O-GlcNAcylation, under the central control of the OGT attachment enzyme and nutrient-driven substrate supply, is well-positioned to provide this missing link. In the current studies, we found that islet O-GlcNAcylation is dynamically responsive to different phases of obesity compensation in both mice and humans, with elevations positively correlated to secretory hyperinsulinemia. β-cell specific OGT loss mice failed to develop in vivo hyperinsulinemia during early HFD and showed impairments in both HFD- and palmitate-induced in vitro potentiation of islet insulin secretion. Proinsulin processing and β-cell fate maintenance were also impaired. An unbiased RNAseq approach identified differentially expressed genes (DEGs) in βOGT KO islets, which were cross-referenced with a published transcriptome of HFD-adapted islets. Among the common DEGs, over 40% were upregulated by HFD but downregulated by OGT loss, including the ER Ca2+ ATPase SERCA2 protein. Allosteric activation of SERCA2, which was O-GlcNAcylated in both human islets and mouse β-cells, rescued palmitate-potentiation of insulin secretion in both constitutive and induced βOGT KO islets. These findings show that islet protein O-GlcNAcylation is uniquely and dynamically sensitive to obesity duration and selectively regulates hyperlipidemia-driven insulin secretory potentiation, consistent with a governing role in anti-diabetic β-cell adaptations during early obesity.