title: Simvastatin Impairs Insulin Secretion by Multiple Mechanisms in MIN6 Cells.
abstract: Statins are widely used in the treatment of hypercholesterolemia and are efficient in the prevention of cardiovascular disease. Molecular mechanisms explaining statin-induced impairment in insulin secretion remain largely unknown. In the current study, we show that simvastatin decreased glucose-stimulated insulin secretion in mouse pancreatic MIN6 β-cells by 59% and 79% (p<0.01) at glucose concentration of 5.5 mmol/l and 16.7 mmol/l, respectively, compared to control, whereas pravastatin did not impair insulin secretion. Simvastatin induced decrease in insulin secretion occurred through multiple targets. In addition to its established effects on ATP-sensitive potassium channels (p = 0.004) and voltage-gated calcium channels (p = 0.004), simvastatin suppressed insulin secretion stimulated by muscarinic M3 or GPR40 receptor agonists (Tak875 by 33%, p = 0.002; GW9508 by 77%, p = 0.01) at glucose level of 5.5 mmol/l, and inhibited calcium release from the endoplasmic reticulum. Impaired insulin secretion caused by simvastatin treatment were efficiently restored by GPR119 or GLP-1 receptor stimulation and by direct activation of cAMP-dependent signaling pathways with forskolin. The effects of simvastatin treatment on insulin secretion were not affected by the presence of hyperglycemia. Our observation of the opposite effects of simvastatin and pravastatin on glucose-stimulated insulin secretion is in agreement with previous reports showing that simvastatin, but not pravastatin, was associated with increased risk of incident diabetes.
authors.affiliation: Institute of Clinical Medicine, Internal Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Nagendra
authors.initials: N
authors.lastname: Yaluri
authors.affiliation: Institute of Clinical Medicine, Internal Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Shalem
authors.initials: S
authors.lastname: Modi
authors.affiliation: Institute of Clinical Medicine, Internal Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Maykel
authors.initials: M
authors.lastname: López Rodríguez
authors.affiliation: Institute of Clinical Medicine, Internal Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Alena
authors.initials: A
authors.lastname: Stančáková
authors.affiliation: Institute of Clinical Medicine, Internal Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.|Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.affiliation: Institute of Clinical Medicine, Internal Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Kokkola
authors.affiliation: Institute of Clinical Medicine, Internal Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.|Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D005576:Colforsin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D004910:Erythrocyte Membrane / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood; D051379:Mice; D008875:Middle Aged; D010179:Pancreas / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D019821:Simvastatin / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D005227:Fatty Acids; C473036:Ffar1 protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; C516207:Gpr119 protein, mouse; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D005576:Colforsin; D000255:Adenosine Triphosphate; D019821:Simvastatin; D000242:Cyclic AMP; D005947:Glucose; D017035:Pravastatin; D002118:Calcium