GPR40 partial agonist MK-2305 lower fasting glucose in the Goto Kakizaki rat via suppression of endogenous glucose production
| العنوان: | GPR40 partial agonist MK-2305 lower fasting glucose in the Goto Kakizaki rat via suppression of endogenous glucose production |
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| المؤلفون: | Daniel Kosinski, Melissa Kirkland, Michelle Bunzel, Jin Cao, Robert W. Myers, Adam B. Weinglass, Kevin Knagge, Michele Pachanski, Sarah Souza, William K. Hagmann, Joel Mane, Xiaoyan Li, Maria E. Trujillo, Corin O. Miller, Paul E. Carrington, Jerry Di Salvo, Brande Thomas-Fowlkes |
| المصدر: | PLoS ONE, Vol 12, Iss 5, p e0176182 (2017) PLoS ONE |
| بيانات النشر: | Public Library of Science (PLoS), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Blood Glucose, Male, Partial Agonists, Time Factors, Physiology, medicine.medical_treatment, Drug Evaluation, Preclinical, lcsh:Medicine, Spectrum analysis techniques, Biochemistry, Receptors, G-Protein-Coupled, Tissue Culture Techniques, 0302 clinical medicine, Endocrinology, Glucose Metabolism, Medicine and Health Sciences, Glucose homeostasis, Insulin, lcsh:Science, Mice, Knockout, Multidisciplinary, Chemistry, Organic Compounds, Monosaccharides, Drugs, Fasting, Blood Sugar, Body Fluids, Blood, Liver, Physical Sciences, Carbohydrate Metabolism, Anatomy, Research Article, medicine.medical_specialty, endocrine system, Endocrine Disorders, Carbohydrates, Blood sugar, 030209 endocrinology & metabolism, CHO Cells, Carbohydrate metabolism, Partial agonist, Blood Plasma, Diabetes Mellitus, Experimental, 03 medical and health sciences, Cricetulus, NMR spectroscopy, Internal medicine, Free fatty acid receptor 1, Diabetes mellitus, medicine, Diabetes Mellitus, Animals, Humans, Hypoglycemic Agents, Benzopyrans, Rats, Wistar, Pharmacology, Diabetic Endocrinology, Organic Chemistry, lcsh:R, Chemical Compounds, Biology and Life Sciences, medicine.disease, Hormones, Rats, Research and analysis methods, 030104 developmental biology, Glucose, HEK293 Cells, Metabolism, Gluconeogenesis, Metabolic Disorders, Thiazolidinediones, lcsh:Q |
| الوصف: | GPR40 (FFA1) is a fatty acid receptor whose activation results in potent glucose lowering and insulinotropic effects in vivo. Several reports illustrate that GPR40 agonists exert glucose lowering in diabetic humans. To assess the mechanisms by which GPR40 partial agonists improve glucose homeostasis, we evaluated the effects of MK-2305, a potent and selective partial GPR40 agonist, in diabetic Goto Kakizaki rats. MK-2305 decreased fasting glucose after acute and chronic treatment. MK-2305-mediated changes in glucose were coupled with increases in plasma insulin during hyperglycemia and glucose challenges but not during fasting, when glucose was normalized. To determine the mechanism(s) mediating these changes in glucose metabolism, we measured the absolute contribution of precursors to glucose production in the presence or absence of MK-2305. MK-2305 treatment resulted in decreased endogenous glucose production (EGP) driven primarily through changes in gluconeogenesis from substrates entering at the TCA cycle. The decrease in EGP was not likely due to a direct effect on the liver, as isolated perfused liver studies showed no effect of MK-2305 ex vivo and GPR40 is not expressed in the liver. Taken together, our results suggest MK-2305 treatment increases glucose stimulated insulin secretion (GSIS), resulting in changes to hepatic substrate handling that improve glucose homeostasis in the diabetic state. Importantly, these data extend our understanding of the underlying mechanisms by which GPR40 partial agonists reduce hyperglycemia. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::26bfccec2b21e6b21432c0056bc58040 http://europepmc.org/articles/PMC5441580?pdf=render |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....26bfccec2b21e6b21432c0056bc58040 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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