Simvastatin Impairs Insulin Secretion by Multiple Mechanisms in MIN6 Cells

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-stim...

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Published in:PloS one 2015-11, Vol.10 (11), p.e0142902-e0142902
Main Authors: Yaluri, Nagendra, Modi, Shalem, López Rodríguez, Maykel, Stančáková, Alena, Kuusisto, Johanna, Kokkola, Tarja, Laakso, Markku
Format: Article
Language:English
Subjects:
Acetylcholine receptors (muscarinic)
Adenosine Triphosphate - chemistry
Animals
Calcium
Calcium (reticular)
Calcium - metabolism
Calcium channels
Calcium channels (voltage-gated)
Cardiovascular diseases
Cell Line
Channels
Colforsin - metabolism
Complications and side effects
Cyclic AMP - metabolism
Diabetes mellitus
Diabetes Mellitus - metabolism
Diabetes research
Disease susceptibility
Endoplasmic reticulum
Erythrocyte Membrane - metabolism
Fatty Acids - metabolism
Forskolin
Glucagon-Like Peptide-1 Receptor - metabolism
Glucose
Glucose - metabolism
Health aspects
Health risks
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use
Hypercholesterolemia
Hyperglycemia
Insulin
Insulin - metabolism
Insulin Secretion
Kinases
Male
Metabolic Syndrome - blood
Mice
Middle Aged
Molecular modelling
Pancreas
Pancreas - drug effects
Potassium
Potassium channels
Potassium channels (voltage-gated)
Pravastatin
Pravastatin - pharmacology
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - metabolism
Risk Factors
Rodents
Secretion
Signal Transduction
Simvastatin
Simvastatin - adverse effects
Simvastatin - pharmacology
Statins
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cited_by cdi_FETCH-LOGICAL-c692t-572ffca10cd902440acd891fc5bbc9019b3cf23102bc9b4b2bd281588b61a7393
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container_end_page e0142902
container_issue 11
container_start_page e0142902
container_title PloS one
container_volume 10
creator Yaluri, Nagendra
Modi, Shalem
López Rodríguez, Maykel
Stančáková, Alena
Kuusisto, Johanna
Kokkola, Tarja
Laakso, Markku
description 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
doi_str_mv 10.1371/journal.pone.0142902
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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&lt;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. 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chemistry</topic><topic>Animals</topic><topic>Calcium</topic><topic>Calcium (reticular)</topic><topic>Calcium - metabolism</topic><topic>Calcium channels</topic><topic>Calcium channels (voltage-gated)</topic><topic>Cardiovascular diseases</topic><topic>Cell Line</topic><topic>Channels</topic><topic>Colforsin - metabolism</topic><topic>Complications and side effects</topic><topic>Cyclic AMP - metabolism</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus - metabolism</topic><topic>Diabetes research</topic><topic>Disease susceptibility</topic><topic>Endoplasmic reticulum</topic><topic>Erythrocyte Membrane - metabolism</topic><topic>Fatty Acids - metabolism</topic><topic>Forskolin</topic><topic>Glucagon-Like Peptide-1 Receptor - metabolism</topic><topic>Glucose</topic><topic>Glucose - metabolism</topic><topic>Health aspects</topic><topic>Health risks</topic><topic>Humans</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use</topic><topic>Hypercholesterolemia</topic><topic>Hyperglycemia</topic><topic>Insulin</topic><topic>Insulin - 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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&lt;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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26561346</pmid><doi>10.1371/journal.pone.0142902</doi><oa>free_for_read</oa></addata></record>
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1932-6203
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subjects Acetylcholine receptors (muscarinic)
Adenosine Triphosphate - chemistry
Animals
Calcium
Calcium (reticular)
Calcium - metabolism
Calcium channels
Calcium channels (voltage-gated)
Cardiovascular diseases
Cell Line
Channels
Colforsin - metabolism
Complications and side effects
Cyclic AMP - metabolism
Diabetes mellitus
Diabetes Mellitus - metabolism
Diabetes research
Disease susceptibility
Endoplasmic reticulum
Erythrocyte Membrane - metabolism
Fatty Acids - metabolism
Forskolin
Glucagon-Like Peptide-1 Receptor - metabolism
Glucose
Glucose - metabolism
Health aspects
Health risks
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use
Hypercholesterolemia
Hyperglycemia
Insulin
Insulin - metabolism
Insulin Secretion
Kinases
Male
Metabolic Syndrome - blood
Mice
Middle Aged
Molecular modelling
Pancreas
Pancreas - drug effects
Potassium
Potassium channels
Potassium channels (voltage-gated)
Pravastatin
Pravastatin - pharmacology
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - metabolism
Risk Factors
Rodents
Secretion
Signal Transduction
Simvastatin
Simvastatin - adverse effects
Simvastatin - pharmacology
Statins
title Simvastatin Impairs Insulin Secretion by Multiple Mechanisms in MIN6 Cells
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