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Pancreatic beta-cells can secrete insulin via 2 pathways characterized as KATP channel -dependent and -independent. The KATP channel-independent pathway is characterized by a rise in several potential metabolic signaling molecules, including the NADPH/NADP+ ratio and alpha-ketoglutarate (alphaKG). Prolyl hydroxylases (PHDs), which belong to the alphaKG-dependent dioxygenase superfamily, are known to regulate the stability of hypoxia-inducible factor alpha. In the current study, we assess the role of PHDs in vivo using the pharmacological inhibitor dimethyloxalylglycine (DMOG) and generated beta-cell-specific knockout (KO) mice for all 3 isoforms of PHD (beta-PHD1 KO, beta-PHD2 KO, and beta-PHD3 KO mice). DMOG inhibited in vivo insulin secretion in response to glucose challenge and inhibited the first phase of insulin secretion but enhanced the second phase of insulin secretion in isolated islets. None of the beta-PHD KO mice showed any significant in vivo defects associated with glucose tolerance and insulin resistance except for beta-PHD2 KO mice which had significantly increased plasma insulin during a glucose challenge. Islets from both beta-PHD1 KO and beta-PHD3 KO had elevated beta-cell apoptosis and reduced beta-cell mass. Isolated islets from beta-PHD1 KO and beta-PHD3 KO had impaired glucose-stimulated insulin secretion and glucose-stimulated increases in the ATP/ADP and NADPH/NADP+ ratio. All 3 PHD isoforms are expressed in beta-cells, with PHD3 showing the most distinct expression pattern. The lack of each PHD protein did not significantly impair in vivo glucose homeostasis. However, beta-PHD1 KO and beta-PHD3 KO mice had defective beta-cell mass and islet insulin secretion, suggesting that these mice may be predisposed to developing diabetes.

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Adenosine Diphosphate/metabolism Adenosine Triphosphate/metabolism Animals Apoptosis Gene Expression Regulation Glucose/metabolism Glucose Tolerance Test Homeostasis Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Insulin/*metabolism *Insulin Secretion Insulin-Secreting Cells/*metabolism Ketoglutaric Acids/metabolism Male Mice Mice, Inbred C57BL Mice, Knockout NADP/metabolism Oxidative Phosphorylation Oxygen Consumption Phenotype Prolyl Hydroxylases/*metabolism Protein Domains Protein Isoforms/*chemistry *ARNT/HIF1beta *HIF1alpha *phd *cell metabolism *hypoxia *insulin release *islet *metabolism *pancreatic beta-cell *prolyl hydroxylases