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

Abstract

ObjectivesChronic 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.MethodsIslets 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.ResultsFA-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.ConclusionsThese 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.

Contribution of parasympathetic muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia

“…Muscarinic receptors are G protein-coupled receptors whose activity may be modulated by targeting downstream receptor kinases. For example, small molecule inhibition of casein kinase 2 (CK2) reduces agonist-induced phosphorylation of ␤-cell M 3 receptors, enhancing acetylcholine-potentiated insulin secretion from mouse and human islets, protecting mice from diet-induced diabetes (18), and protecting both mouse and human islets from lipotoxicity (8). Future studies will need to translate muscarinic signaling-targeted approaches to human models of metabolic disease and patients at risk for and affected by type 2 diabetes.…”

Protein kinase CK2: a potential therapeutic target for diverse human diseases

“…On the other hand, CK2 downregulation seemed to counteract the β-granule phosphoprotein kinesin heavy chain phosphorylation and stimulate the insulin secretion by promoting β-granule transport along microtubules in pancreatic β-cells. 284 …”

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

“…Numerous studies collectively have shown that prolonged (over 24-72 h) incubation of beta cells and islets with a high concentration of FA (0.2-0.5 mM) in the presence of glucose causes apoptosis and reduces insulin secretion (glucolipotoxicity) through activation of multiple stress pathways, including ceramide generation, ER stress, oxidative stress, mitochondrial dysfunction, and inflammation. [79][80][81] While evidence exists for each stress pathway's contribution to lipotoxicity, it remains inconclusive how these relate to the beta cell failure that occurs over decades in humans. Below, we review evidence connecting beta cell dysfunction in humans with the exposure of beta cells to lipids through recent clinical and metabolomic studies, the understanding of lipotoxicity in beta cells, and the gap in knowledge that requires future studies.…”