Systemic Metabolic Alterations Correlate with Islet-Level Prostaglandin E2 Production and Signaling Mechanisms That Predict β-Cell Dysfunction in a Mouse Model of Type 2 Diabetes
| Autor: | Brian T. Layden, Elizabeth D. Cox, Miles H Fuller, Erin Guthery, Yanlong Zhu, Chinmai Patibandla, Michael D. Schaid, Austin Reuter, Dudley W. Lamming, Joshua C. Neuman, Rachel J. Fenske, Michelle E. Kimple, Nicole E. Richardson, Ying Ge, Harpreet K Sandhu, Dawn Belt Davis, Irene M. Ong, Allan R. Brasier |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty obesity insulin secretion endocrine system diseases Endocrinology Diabetes and Metabolism lcsh:QR1-502 Prostaglandin Incretin gut microbiome 030209 endocrinology & metabolism Type 2 diabetes Biology Biochemistry lcsh:Microbiology Article prostaglandins 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Insulin resistance Downregulation and upregulation Internal medicine insulin resistance Genetic model medicine Prostaglandin E2 Molecular Biology geography geography.geographical_feature_category beta-cell function digestive oral and skin physiology Islet medicine.disease untargeted plasma metabolomics 030104 developmental biology Endocrinology chemistry inflammation lipids (amino acids peptides and proteins) type 2 diabetes medicine.drug polyunsaturated fatty acids |
| Zdroj: | Metabolites Volume 11 Issue 1 Metabolites, Vol 11, Iss 58, p 58 (2021) |
| ISSN: | 2218-1989 |
| DOI: | 10.3390/metabo11010058 |
| Popis: | The transition from &beta cell compensation to &beta cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional &beta cell mass in Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E2 (PGE2). Expression of the pancreatic islet EP3 and PGE2 synthetic enzymes and/or PGE2 excretion itself have all been shown to be upregulated in primary mouse and human islets isolated from animals or human organ donors with established T2D compared to nondiabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation&mdash a strong genetic model of T2D&mdash were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated &beta cell dysfunction. |
| Databáze: | OpenAIRE |
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