Isoform-specific Roles of Prolyl Hydroxylases in the Regulation of Pancreatic ß-Cell Function.
Endocrinology
; 163(1)2022 01 01.
Article
em En
| MEDLINE
| ID: mdl-34718519
ABSTRACT
Pancreatic ß-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 α-ketoglutarate (αKG). Prolyl hydroxylases (PHDs), which belong to the αKG-dependent dioxygenase superfamily, are known to regulate the stability of hypoxia-inducible factor α. In the current study, we assess the role of PHDs in vivo using the pharmacological inhibitor dimethyloxalylglycine (DMOG) and generated ß-cell-specific knockout (KO) mice for all 3 isoforms of PHD (ß-PHD1 KO, ß-PHD2 KO, and ß-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 ß-PHD KO mice showed any significant in vivo defects associated with glucose tolerance and insulin resistance except for ß-PHD2 KO mice which had significantly increased plasma insulin during a glucose challenge. Islets from both ß-PHD1 KO and ß-PHD3 KO had elevated ß-cell apoptosis and reduced ß-cell mass. Isolated islets from ß-PHD1 KO and ß-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 ß-cells, with PHD3 showing the most distinct expression pattern. The lack of each PHD protein did not significantly impair in vivo glucose homeostasis. However, ß-PHD1 KO and ß-PHD3 KO mice had defective ß-cell mass and islet insulin secretion, suggesting that these mice may be predisposed to developing diabetes.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Isoformas de Proteínas
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Células Secretoras de Insulina
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Prolil Hidroxilases
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Secreção de Insulina
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Insulina
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article