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1.
Biol Chem ; 404(4): 339-353, 2023 03 28.
Article in English | MEDLINE | ID: mdl-36571487

ABSTRACT

Ion channels play an important role for regulation of the exocrine and the endocrine pancreas. This review focuses on the Ca2+-regulated K+ channel KCa3.1, encoded by the KCNN4 gene, which is present in both parts of the pancreas. In the islets of Langerhans, KCa3.1 channels are involved in the regulation of membrane potential oscillations characterizing nutrient-stimulated islet activity. Channel upregulation is induced by gluco- or lipotoxic conditions and might contribute to micro-inflammation and impaired insulin release in type 2 diabetes mellitus as well as to diabetes-associated renal and vascular complications. In the exocrine pancreas KCa3.1 channels are expressed in acinar and ductal cells. They are thought to play a role for anion secretion during digestion but their physiological role has not been fully elucidated yet. Pancreatic carcinoma, especially pancreatic ductal adenocarcinoma (PDAC), is associated with drastic overexpression of KCa3.1. For pharmacological targeting of KCa3.1 channels, we are discussing the possible benefits KCa3.1 channel inhibitors might provide in the context of diabetes mellitus and pancreatic cancer, respectively. We are also giving a perspective for the use of a fluorescently labeled derivative of the KCa3.1 blocker senicapoc as a tool to monitor channel distribution in pancreatic tissue. In summary, modulating KCa3.1 channel activity is a useful strategy for exo-and endocrine pancreatic disease but further studies are needed to evaluate its clinical suitability.


Subject(s)
Diabetes Mellitus, Type 2 , Islets of Langerhans , Pancreatic Neoplasms , Humans , Pancreas , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms
2.
Mol Pharmacol ; 97(3): 202-211, 2020 03.
Article in English | MEDLINE | ID: mdl-31911428

ABSTRACT

Bile acids such as chenodeoxycholic acid (CDC) acutely enhance insulin secretion via the farnesoid X receptor (FXR). Statins, which are frequently prescribed for patients with type 2 diabetes who suffer from dyslipidemia, are known for their diabetogenic risk and are reported to interact with the FXR. Our study investigates whether this interaction is relevant for beta cell signaling and plays a role for negative effects of statins on glycemic control. Experiments were performed with islets and islet cells from C57BL/6N wild-type and FXR-knockout (KO) mice. Culturing islets with atorvastatin (15 µM) for 24 hours decreased glucose-stimulated insulin secretion by approximately 30% without affecting ATP synthesis. Prolonged exposure for 7 days lowered the concentration necessary for impairment of insulin release to 150 nM. After 24-hour culture with atorvastatin, the ability of CDC (500 nM) to elevate [Ca2+]c was diminished and the potentiating effect on insulin secretion was completely lost. Mevalonate largely reduced the negative effect of atorvastatin. Nuclear activity of FXR was reduced by atorvastatin in a mouse FXR reporter assay. The atorvastatin-induced decrease in insulin release was also present in FXR-KO mice. Although not a prerequisite, FXR seems to influence the degree of damage caused by atorvastatin depending on its interaction with CDC: Preparations responding to CDC with an increase in insulin secretion under control conditions were less impaired by atorvastatin than preparations that were nonresponsive to CDC. Extended stimulation of FXR by the synthetic agonist GW4064, which is suggested to induce translocation of FXR from the cytosol into the nucleus, increased the inhibitory effect of atorvastatin. In conclusion, atorvastatin inhibits insulin release and prevents positive effects of bile acids on beta cell function. Both interactions may contribute to progression of type 2 diabetes mellitus. SIGNIFICANCE STATEMENT: This study shows that the diabetogenic risk of statins is coupled to the activity of farnesoid X receptor (FXR)-dependent signaling pathways in beta cells. On the one hand, statins abolish the insulinotropic effects of bile acids and on the other hand, FXR determines the level of impairment of islet function by the statin.


Subject(s)
Atorvastatin/metabolism , Bile Acids and Salts/metabolism , Diabetes Mellitus, Type 2/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Insulin-Secreting Cells/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Animals , Atorvastatin/adverse effects , Bile Acids and Salts/antagonists & inhibitors , Cells, Cultured , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/prevention & control , Dose-Response Relationship, Drug , Female , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Insulin/metabolism , Insulin-Secreting Cells/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Risk Factors
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