Prostaglandin EP3 Receptor signaling is required to prevent insulin hypersecretion and metabolic dysfunction in a non-obese mouse model of insulin resistance
| Autor: | Darby C. Peter, Rachel J. Fenske, Michelle E. Kimple, Michael D. Schaid, Austin Reuter, Jaclyn A. Wisinski |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Blood Glucose Male medicine.medical_specialty Physiology Endocrinology Diabetes and Metabolism medicine.medical_treatment Prostaglandin 030209 endocrinology & metabolism Biology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Insulin resistance In vivo Physiology (medical) Insulin-Secreting Cells Internal medicine Diabetes mellitus Insulin Secretion medicine Animals Insulin Promoter Regions Genetic 030304 developmental biology Mice Knockout 2. Zero hunger Mice Inbred BALB C 0303 health sciences geography geography.geographical_feature_category medicine.disease Islet Phenotype Rats Mice Inbred C57BL 030104 developmental biology Endocrinology chemistry Receptors Prostaglandin E EP3 Subtype Female lipids (amino acids peptides and proteins) Beta cell Insulin Resistance Ex vivo Research Article |
| Zdroj: | Am J Physiol Endocrinol Metab |
| DOI: | 10.1101/671289 |
| Popis: | When homozygous for the LeptinOb mutation (Ob), Black-and-Tan Brachyury (BTBR) mice become morbidly obese and severely insulin resistant, and by 10 weeks of age, frankly diabetic. Previous work has shown Prostaglandin EP3 Receptor (EP3) expression and activity is up-regulated in islets from BTBR-Ob mice as compared to lean controls, actively contributing to their beta-cell dysfunction. In this work, we aimed to test the impact of beta-cell-specific EP3 loss on the BTBR-Ob phenotype by crossing Ptger3 floxed mice with the Rat insulin promoter (RIP)-CreHerr 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 beta-cell fractional area or markers of beta-cell replication ex vivo. Instead, EP3-null BTBR-lean islets had essentially uncontrolled insulin hypersecretion. The selective up-regulation of constitutively-active EP3 splice variants in islets from young, lean BTBR mice as compared to 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 vs. Balb/c males was fully consistent with their sexually-dimorphic metabolic phenotype after loss of EP3-coupled Gαz protein. Taken together, our findings provide a new dimension to the understanding of EP3 as a critical brake on insulin secretion.New and NoteworthyIslet Prostaglandin EP3 receptor (EP3) signaling is well-known as up-regulated in the pathophysiological conditions of type 2 diabetes, contributing to beta-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 beta-cell-specific knockouts.For Table of Contents Use Only |
| Databáze: | OpenAIRE |
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