Inhibition of cholinergic potentiation of insulin secretion from pancreatic islets by chronic elevation of glucose and fatty acids: Protection by casein kinase 2 inhibitor
| العنوان: | Inhibition of cholinergic potentiation of insulin secretion from pancreatic islets by chronic elevation of glucose and fatty acids: Protection by casein kinase 2 inhibitor |
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| المؤلفون: | Franz M. Matschinsky, Pan Chen, Nicolai M. Doliba, Chengyang Liu, Ali Naji, Qin Liu, Changhong Li |
| المصدر: | Molecular Metabolism, Vol 6, Iss 10, Pp 1240-1253 (2017) Molecular Metabolism |
| بيانات النشر: | Elsevier, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, medicine.medical_specialty, lcsh:Internal medicine, Pancreatic islets, Cholinergic Agents, Hyperlipidemias, Biology, 03 medical and health sciences, Islets of Langerhans, Mice, Internal medicine, Muscarinic acetylcholine receptor, medicine, Animals, Humans, Insulin, Fatty acids, Casein Kinase II, lcsh:RC31-1245, Molecular Biology, Cells, Cultured, Insulin secretion, Cell Biology, Receptors, Muscarinic, Acetylcholine, Insulin oscillation, Glutamine, Glucolipotoxicity, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Glucose, Lipotoxicity, Diabetes Mellitus, Type 2, Hyperglycemia, Cholinergic, Original Article, Casein kinase 2, medicine.drug, Signal Transduction |
| الوصف: | Objectives Chronic hyperlipidemia and hyperglycemia are characteristic features of type 2 diabetes (T2DM) that are thought to cause or contribute to β-cell dysfunction by “glucolipotoxicity.” Previously we have shown that acute treatment of pancreatic islets with fatty acids (FA) decreases acetylcholine-potentiated insulin secretion. This acetylcholine response is mediated by M3 muscarinic receptors, which play a key role in regulating β-cell function. Here we examine whether chronic FA exposure also inhibits acetylcholine-potentiated insulin secretion using mouse and human islets. Methods Islets were cultured for 3 or 4 days at different glucose concentration with 0.5 mM palmitic acid (PA) or a 2:1 mixture of PA and oleic acid (OA) at 1% albumin (PA/BSA molar ratio 3.3). Afterwards, the response to glucose and acetylcholine were studied in perifusion experiments. Results FA-induced impairment of insulin secretion and Ca2+ signaling depended strongly on the glucose concentrations of the culture medium. PA and OA in combination reduced acetylcholine potentiation of insulin secretion more than PA alone, both in mouse and human islets, with no evidence of a protective role of OA. In contrast, lipotoxicity was not observed with islets cultured for 3 days in medium containing less than 1 mM glucose and a mixture of glutamine and leucine (7 mM each). High glucose and FAs reduced endoplasmic reticulum (ER) Ca2+ storage capacity; however, preserving ER Ca2+ by blocking the IP3 receptor with xestospongin C did not protect islets from glucolipotoxic effects on insulin secretion. In contrast, an inhibitor of casein kinase 2 (CK2) protected the glucose dependent acetylcholine potentiation of insulin secretion in mouse and human islets against glucolipotoxicity. Conclusions These results show that chronic FA treatment decreases acetylcholine potentiation of insulin secretion and that this effect is strictly glucose dependent and might involve CK2 phosphorylation of β-cell M3 muscarinic receptors. Highlights • Glucolipotoxicity impairs acetylcholine-potentiation of insulin secretion. • Glucose amplification of insulin secretion rather than triggering is damaged by FA. • Inhibitor of casein kinase 2 preserved islet function against glucolipotoxicity. |
| اللغة: | English |
| تدمد: | 2212-8778 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::467c3d5c20802c9386364a4fdc6bd0d7Test http://www.sciencedirect.com/science/article/pii/S2212877817303940Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....467c3d5c20802c9386364a4fdc6bd0d7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22128778 |
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