Abstract | 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: 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.
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Authors | Nicolai M Doliba, Qin Liu, Changhong Li, Pan Chen, Chengyang Liu, Ali Naji, Franz M Matschinsky |
Journal | Molecular metabolism
(Mol Metab)
Vol. 6
Issue 10
Pg. 1240-1253
(10 2017)
ISSN: 2212-8778 [Electronic] Germany |
PMID | 29031723
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved. |
Chemical References |
- Cholinergic Agents
- Fatty Acids
- Insulin
- Receptors, Muscarinic
- Casein Kinase II
- Glucose
- Acetylcholine
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Topics |
- Acetylcholine
(metabolism)
- Animals
- Casein Kinase II
(antagonists & inhibitors, metabolism)
- Cells, Cultured
- Cholinergic Agents
(metabolism, pharmacology)
- Diabetes Mellitus, Type 2
(metabolism)
- Fatty Acids
(metabolism, pharmacology)
- Glucose
(metabolism)
- Humans
- Hyperglycemia
(metabolism)
- Hyperlipidemias
(metabolism)
- Insulin
(metabolism)
- Insulin Secretion
(drug effects, physiology)
- Islets of Langerhans
(drug effects, metabolism)
- Male
- Mice
- Receptors, Muscarinic
(metabolism)
- Signal Transduction
(drug effects)
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