دورية أكاديمية
أعرض في EDS

Prostaglandin EP3 receptor signaling is required to prevent insulin hypersecretion and metabolic dysfunction in a non-obese mouse model of insulin resistance.

التفاصيل البيبلوغرافية
العنوان: Prostaglandin EP3 receptor signaling is required to prevent insulin hypersecretion and metabolic dysfunction in a non-obese mouse model of insulin resistance.
المؤلفون: Wisinski JA; Department of Biology, University of Wisconsin-LaCrosse, La Crosse, Wisconsin., Reuter A; Research Service, William S. Middleton Memorial VA Hospital, Madison, Wisconsin.; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin., Peter DC; Research Service, William S. Middleton Memorial VA Hospital, Madison, Wisconsin.; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin., Schaid MD; Research Service, William S. Middleton Memorial VA Hospital, Madison, Wisconsin.; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin.; Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin., Fenske RJ; Research Service, William S. Middleton Memorial VA Hospital, Madison, Wisconsin.; Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin., Kimple ME; Research Service, William S. Middleton Memorial VA Hospital, Madison, Wisconsin.; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin.; Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin.; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.
المصدر: American journal of physiology. Endocrinology and metabolism [Am J Physiol Endocrinol Metab] 2021 Oct 01; Vol. 321 (4), pp. E479-E489. Date of Electronic Publication: 2021 Jul 06.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901226 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1555 (Electronic) Linking ISSN: 01931849 NLM ISO Abbreviation: Am J Physiol Endocrinol Metab Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Bethesda, MD. : American Physiological Society
مواضيع طبية MeSH: Insulin Resistance* , Insulin Secretion*, Blood Glucose/*metabolism , Insulin/*metabolism , Insulin-Secreting Cells/*pathology , Receptors, Prostaglandin E, EP3 Subtype/*physiology, Animals ; Female ; Insulin-Secreting Cells/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Promoter Regions, Genetic ; Rats
مستخلص: When homozygous for the Leptin Ob mutation (Ob), Black-and-Tan Brachyury (BTBR) mice become morbidly obese and severely insulin resistant, and by 10 wk of age, frankly diabetic. Previous work has shown prostaglandin EP3 receptor (EP3) expression and activity is upregulated in islets from BTBR-Ob mice as compared with lean controls, actively contributing to their β-cell dysfunction. In this work, we aimed to test the impact of β-cell-specific EP3 loss on the BTBR-Ob phenotype by crossing Ptger3 floxed mice with the rat insulin promoter (RIP)-Cre Herr driver strain. Instead, germline recombination of the floxed allele in the founder mouse-an event whose prevalence we identified as directly associated with underlying insulin resistance of the background strain-generated a full-body knockout. Full-body EP3 loss provided no diabetes protection to BTBR-Ob mice but, unexpectedly, significantly worsened BTBR-lean insulin resistance and glucose tolerance. This in vivo phenotype was not associated with changes in β-cell fractional area or markers of β-cell replication ex vivo. Instead, EP3-null BTBR-lean islets had essentially uncontrolled insulin hypersecretion. The selective upregulation of constitutively active EP3 splice variants in islets from young, lean BTBR mice as compared with C57BL/6J, where no phenotype of EP3 loss has been observed, provides a potential explanation for the hypersecretion phenotype. In support of this, high islet EP3 expression in Balb/c females versus Balb/c males was fully consistent with their sexually dimorphic metabolic phenotype after loss of EP3-coupled Gα z protein. Taken together, our findings provide a new dimension to the understanding of EP3 as a critical brake on insulin secretion. NEW & NOTEWORTHY Islet prostaglandin EP3 receptor (EP3) signaling is well known as upregulated in the pathophysiological conditions of type 2 diabetes, contributing to β-cell dysfunction. Unexpected findings in mouse models of non-obese insulin sensitivity and resistance provide a new dimension to our understanding of EP3 as a key modulator of insulin secretion. A previously unknown relationship between mouse insulin resistance and the penetrance of rat insulin promoter-driven germline floxed allele recombination is critical to consider when creating β-cell-specific knockouts.
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معلومات مُعتمدة: R01 DK102598 United States DK NIDDK NIH HHS; T32 DK007665 United States DK NIDDK NIH HHS; F31 DK109698 United States DK NIDDK NIH HHS; R01 DK076488 United States DK NIDDK NIH HHS; I01 BX003700 United States BX BLRD VA; K01 DK080845 United States DK NIDDK NIH HHS
فهرسة مساهمة: Keywords: G protein-coupled receptor; animal model; beta cell (β-cell); insulin resistance; insulin secretion
المشرفين على المادة: 0 (Blood Glucose)
0 (Insulin)
0 (Ptger3 protein, mouse)
0 (Receptors, Prostaglandin E, EP3 Subtype)
تواريخ الأحداث: Date Created: 20210707 Date Completed: 20211108 Latest Revision: 20220225
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC8560379
DOI: 10.1152/ajpendo.00051.2021
PMID: 34229444
قاعدة البيانات: MEDLINE
الوصف
تدمد:1522-1555
DOI:10.1152/ajpendo.00051.2021