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Inhibition of cholinergic potentiation of insulin secretion from pancreatic islets by chronic elevation of glucose and fatty acids: Protection by casein kinase 2 inhibitor.

Citation
Doliba, N. M., et al. “Inhibition Of Cholinergic Potentiation Of Insulin Secretion From Pancreatic Islets By Chronic Elevation Of Glucose And Fatty Acids: Protection By Casein Kinase 2 Inhibitor.”. Molecular Metabolism, pp. 1240-1253.
Center University of Pennsylvania
Author Nicolai M Doliba, Qin Liu, Changhong Li, Pan Chen, Chengyang Liu, Ali Naji, Franz M Matschinsky
Keywords Acetylcholine, Fatty acids, glucolipotoxicity, insulin secretion, pancreatic islets
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: 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 Ca 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) Ca storage capacity; however, preserving ER Ca 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.

Year of Publication
2017
Journal
Molecular metabolism
Volume
6
Issue
10
Number of Pages
1240-1253
Date Published
12/2017
ISSN Number
2212-8778
DOI
10.1016/j.molmet.2017.07.017
Alternate Journal
Mol Metab
PMID
29031723
PMCID
PMC5641685
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