Human Islet Expression Levels of Prostaglandin E 2 Synthetic Enzymes, But Not Prostaglandin EP3 Receptor, Are Positively Correlated with Markers of β-Cell Function and Mass in Nondiabetic Obesity.

التفاصيل البيبلوغرافية
العنوان:	Human Islet Expression Levels of Prostaglandin E 2 Synthetic Enzymes, But Not Prostaglandin EP3 Receptor, Are Positively Correlated with Markers of β-Cell Function and Mass in Nondiabetic Obesity.
المؤلفون:	Truchan NA; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States., Fenske RJ; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States.; Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States., Sandhu HK; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States., Weeks AM; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States., Patibandla C; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States., Wancewicz B; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States., Pabich S; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States., Reuter A; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States., Harrington JM; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States., Brill AL; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States., Peter DC; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States., Nall R; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States., Daniels M; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States., Punt M; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States., Kaiser CE; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States., Cox ED; Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin 53792, United States., Ge Y; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States., Davis DB; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States.; Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States., Kimple ME; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.; Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, United States.; Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.
المصدر:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2021 Jun 16; Vol. 4 (4), pp. 1338-1348. Date of Electronic Publication: 2021 Jun 16 (Print Publication: 2021).
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: American Chemical Society Country of Publication: United States NLM ID: 101721411 Publication Model: eCollection Cited Medium: Internet ISSN: 2575-9108 (Electronic) Linking ISSN: 25759108 NLM ISO Abbreviation: ACS Pharmacol Transl Sci Subsets: PubMed not MEDLINE
أسماء مطبوعة:	Original Publication: Washington, DC : American Chemical Society, [2018]-
مستخلص:	Elevated islet production of prostaglandin E 2 (PGE 2 ), an arachidonic acid metabolite, and expression of prostaglandin E 2 receptor subtype EP3 (EP3) are well-known contributors to the β-cell dysfunction of type 2 diabetes (T2D). Yet, many of the same pathophysiological conditions exist in obesity, and little is known about how the PGE 2 production and signaling pathway influences nondiabetic β-cell function. In this work, plasma arachidonic acid and PGE 2 metabolite levels were quantified in a cohort of nondiabetic and T2D human subjects to identify their relationship with glycemic control, obesity, and systemic inflammation. In order to link these findings to processes happening at the islet level, cadaveric human islets were subject to gene expression and functional assays. Interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) mRNA levels, but not those of EP3, positively correlated with donor body mass index (BMI). IL-6 expression also strongly correlated with the expression of COX-2 and other PGE 2 synthetic pathway genes. Insulin secretion assays using an EP3-specific antagonist confirmed functionally relevant upregulation of PGE 2 production. Yet, islets from obese donors were not dysfunctional, secreting just as much insulin in basal and stimulatory conditions as those from nonobese donors as a percent of content. Islet insulin content, on the other hand, was increased with both donor BMI and islet COX-2 expression, while EP3 expression was unaffected. We conclude that upregulated islet PGE 2 production may be part of the β-cell adaption response to obesity and insulin resistance that only becomes dysfunctional when both ligand and receptor are highly expressed in T2D. Competing Interests: The authors declare the following competing financial interest(s): R.J.F., H.K.S., C.P., B.W., S.P., A.R., J.M.H., A.L.B., D.C.P., R.N., M.D., M.P., C.E.K., E.D.C., Y.G., D.B.D., and M.E.K. declare that they have no conflicts of interest with the contents of this article. NAT is currently a Nanomedicine Innovation Center LLC employee (46701 Commerce Center Drive, Plymouth, MI 48170). AMW is currently an Allena Pharmaceuticals employee (One Newton Executive Park, Suite 202, Newton, MA 02462). This work was completed in full during their research training with Dr. Kimple and is not related to their current positions. (© 2021 American Chemical Society.)
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معلومات مُعتمدة:	R01 DK110324 United States DK NIDDK NIH HHS; I01 BX003700 United States BX BLRD VA; R01 DK102598 United States DK NIDDK NIH HHS; UL1 TR002373 United States TR NCATS NIH HHS; I01 BX004715 United States BX BLRD VA; F31 DK109698 United States DK NIDDK NIH HHS; I01 BX001880 United States BX BLRD VA; F31 HL152647 United States HL NHLBI NIH HHS
تواريخ الأحداث:	Date Created: 20210823 Latest Revision: 20221111
رمز التحديث:	20240628
مُعرف محوري في PubMed:	PMC8369690
DOI:	10.1021/acsptsci.1c00045
PMID:	34423270
قاعدة البيانات:	MEDLINE

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تدمد:	2575-9108
DOI:	10.1021/acsptsci.1c00045