The prostaglandin E 2 EP3 receptor has disparate effects on islet insulin secretion and content in β-cells in a high-fat diet-induced mouse model of obesity.

Autor:	Neuman JC; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States.; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States., Reuter A; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States.; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States., Carbajal KA; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States.; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States., Schaid MD; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States.; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States., Kelly G; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States.; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States., Connors K; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States.; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States., Kaiser C; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States.; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States., Krause J; Department of Biology, University of Wisconsin-Lacrosse, La Crosse, Wisconsin, United States., Hurley LD; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States.; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States., Olvera A; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States.; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States., Davis DB; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States.; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States., Wisinski JA; Department of Biology, University of Wisconsin-Lacrosse, La Crosse, Wisconsin, United States., Gannon M; Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Wisconsin, United States., Kimple ME; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States.; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States.; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin, United States.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Endocrinology and metabolism [Am J Physiol Endocrinol Metab] 2024 May 01; Vol. 326 (5), pp. E567-E576. Date of Electronic Publication: 2024 Mar 13.
DOI:	10.1152/ajpendo.00061.2023
Abstrakt:	Signaling through prostaglandin E 2 EP3 receptor (EP3) actively contributes to the β-cell dysfunction of type 2 diabetes (T2D). In T2D models, full-body EP3 knockout mice have a significantly worse metabolic phenotype than wild-type controls due to hyperphagia and severe insulin resistance resulting from loss of EP3 in extra-pancreatic tissues, masking any potential beneficial effects of EP3 loss in the β cell. We hypothesized β-cell-specific EP3 knockout (EP3 βKO) mice would be protected from high-fat diet (HFD)-induced glucose intolerance, phenocopying mice lacking the EP3 effector, Gα z , which is much more limited in its tissue distribution. When fed a HFD for 16 wk, though, EP3 βKO mice were partially, but not fully, protected from glucose intolerance. In addition, exendin-4, an analog of the incretin hormone, glucagon-like peptide 1, more strongly potentiated glucose-stimulated insulin secretion in islets from both control diet- and HFD-fed EP3 βKO mice as compared with wild-type controls, with no effect of β-cell-specific EP3 loss on islet insulin content or markers of replication and survival. However, after 26 wk of diet feeding, islets from both control diet- and HFD-fed EP3 βKO mice secreted significantly less insulin as a percent of content in response to stimulatory glucose, with or without exendin-4, with elevated total insulin content unrelated to markers of β-cell replication and survival, revealing severe β-cell dysfunction. Our results suggest that EP3 serves a critical role in temporally regulating β-cell function along the progression to T2D and that there exist Gα z -independent mechanisms behind its effects. NEW & NOTEWORTHY The EP3 receptor is a strong inhibitor of β-cell function and replication, suggesting it as a potential therapeutic target for the disease. Yet, EP3 has protective roles in extrapancreatic tissues. To address this, we designed β-cell-specific EP3 knockout mice and subjected them to high-fat diet feeding to induce glucose intolerance. The negative metabolic phenotype of full-body knockout mice was ablated, and EP3 loss improved glucose tolerance, with converse effects on islet insulin secretion and content.
Databáze:	MEDLINE
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