{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T19:25:51Z","timestamp":1784921151218,"version":"3.55.0"},"reference-count":32,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2018,1,1]],"date-time":"2018-01-01T00:00:00Z","timestamp":1514764800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Objective. Histone deacytylase inhibitors (HDACis) inhibit the deacetylation of the lysine residue of proteins, including histones, and regulate the transcription of a variety of genes. Recently, HDACis have been used clinically as anti-cancer drugs and possible anti-diabetic drugs. Even though HDACis have been proven to protect the cytokine-induced damage of pancreatic beta cells, evidence also shows that high doses of HDACis are cytotoxic. In the present study, we, therefore, investigated the eff ect of HDACis on insulin secretion in a pancreatic beta cell line. Methods. Pancreatic beta cells MIN6 were treated with selected HDACis (trichostatin A, TSA; valproic acid, VPA; and sodium butyrate, NaB) in medium supplemented with 25 mM glucose and 13% heat-inactivated fetal bovine serum (FBS) for indicated time intervals. Protein expression of Pdx1 and Mafa in MIN6 cells was demonstrated by immunohistochemistry and immunocytochemistry, expression of Pdx1 and Mafa genes was measured by quantitative RT-PCR method. Insulin release from MIN6 cells and insulin cell content were estimated by ELISA kit. Superoxide production in MIN6 cells was measured using a Total ROS\/Superoxide Detection System. Results. TSA, VPA, and NaB inhibited the expression of Pdx1 and Mafa genes and their products. TSA treatment led to beta cell malfunction, characterized by enhanced insulin secretion at 3 and 9 mM glucose, but impaired insulin secretion at 15 and 25 mM glucose. Th us, TSA induced dysregulation of the insulin secretion mechanism. TSA also enhanced reactive oxygen species production in pancreatic beta cells. Conclusions. Our results showed that HDACis caused failure to suppress insulin secretion at low glucose concentrations and enhance insulin secretion at high glucose concentrations. In other words, when these HDACis are used clinically, high doses of HDACis may cause hypoglycemia in the fasting state and hyperglycemia in the fed state. When using HDACis, physicians should, therefore, be aware of the capacity of these drugs to modulate the insulin secretory capacity of pancreatic beta cells.<\/jats:p>","DOI":"10.2478\/enr-2018-0004","type":"journal-article","created":{"date-parts":[[2018,4,12]],"date-time":"2018-04-12T03:56:24Z","timestamp":1523505384000},"page":"21-26","source":"Crossref","is-referenced-by-count":15,"title":["High dose of histone deacetylase inhibitors affects insulin secretory mechanism of pancreatic beta cell line"],"prefix":"10.2478","volume":"52","author":[{"given":"Eiji","family":"Yamato","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Sciences, Mukogawa Women\u2019s University, Nishinomiya, Hyogo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2018,2,16]]},"reference":[{"key":"2026061310292577061_j_enr-2018-0004_ref_001_w2aab3b7b3b1b6b1ab1ab1Aa","doi-asserted-by":"crossref","unstructured":"Bompada P, Atac D, Luan C, Andersson R, Omella JD, Laakso EO, Wright J, Groop L, De Marinis Y. Histone acetylation of glucose-induced thioredoxin-interacting protein gene expression in pancreatic islets. Int J Biochem Cell Biol 81, 82-91, 2016.10.1016\/j.biocel.2016.10.022","DOI":"10.1016\/j.biocel.2016.10.022"},{"key":"2026061310292577061_j_enr-2018-0004_ref_002_w2aab3b7b3b1b6b1ab1ab2Aa","doi-asserted-by":"crossref","unstructured":"Butler LM, Zhou X, Xu WS, Scher HI, Rifk ind RA, Marks PA, Richon VM. Th e histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc Natl Acad Sci U S A 99, 11700-11705, 2002.10.1073\/pnas.182372299","DOI":"10.1073\/pnas.182372299"},{"key":"2026061310292577061_j_enr-2018-0004_ref_003_w2aab3b7b3b1b6b1ab1ab3Aa","doi-asserted-by":"crossref","unstructured":"Cha-Molstad H, Saxena G, Chen J, Shalev A. Glucose-stimulated expression of Txnip is mediated by carbohydrate response element-binding protein, p300, and histone H4 acetylation in pancreatic beta cells. J Biol Chem 284, 16898-16905, 2009.10.1074\/jbc.M109.010504","DOI":"10.1074\/jbc.M109.010504"},{"key":"2026061310292577061_j_enr-2018-0004_ref_004_w2aab3b7b3b1b6b1ab1ab4Aa","doi-asserted-by":"crossref","unstructured":"Christensen DP, Dahllof M, Lundh M, Rasmussen DN, Nielsen MD, Billestrup N, Grunnet LG, Mandrup-Poulsen T. Histone deacetylase (HDAC) inhibition as a novel treatment for diabetes mellitus. Mol Med 17, 378-390, 2011.10.2119\/molmed.2011.00021","DOI":"10.2119\/molmed.2011.00021"},{"key":"2026061310292577061_j_enr-2018-0004_ref_005_w2aab3b7b3b1b6b1ab1ab5Aa","doi-asserted-by":"crossref","unstructured":"Fu J, Zhang Q, Woods CG, Zheng H, Yang B, Qu W, Andersen ME, Pi J. Divergent eff ects of sulforaphane on basal and glucose-stimulated insulin secretion in b-cells: role of reactive oxygen species and induction of endogenous antioxidants. Pharm Res 30, 2248-2259, 2013.10.1007\/s11095-013-1013-8","DOI":"10.1007\/s11095-013-1013-8"},{"key":"2026061310292577061_j_enr-2018-0004_ref_006_w2aab3b7b3b1b6b1ab1ab6Aa","doi-asserted-by":"crossref","unstructured":"Halsall J, Gupta T, O\u2019Neill LP, Turner BM, Nightingale KP. Genes are oft en sheltered from the global histone hyperacetylation induced by HDAC inhibitors. PLoS One 7, e33453, 2012.10.1371\/journal.pone.0033453","DOI":"10.1371\/journal.pone.0033453"},{"key":"2026061310292577061_j_enr-2018-0004_ref_007_w2aab3b7b3b1b6b1ab1ab7Aa","doi-asserted-by":"crossref","unstructured":"Hotta M, Tashiro F, Ikegami H, Niwa H, Ogihara T, Yodoi J, Miyazaki J. Pancreatic beta cell-specifi c expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced diabetes. J. Exp Med 188, 1445-1451, 1998.10.1084\/jem.188.8.1445","DOI":"10.1084\/jem.188.8.1445"},{"key":"2026061310292577061_j_enr-2018-0004_ref_008_w2aab3b7b3b1b6b1ab1ab8Aa","doi-asserted-by":"crossref","unstructured":"Junn E, Han SH, Im JY, Yang Y, Cho EW, Um HD, Kim DK, Lee KW, Han PL, Rhee SG, Choi I. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J Immunol 164, 6287-95, 2000.10.4049\/jimmunol.164.12.6287","DOI":"10.4049\/jimmunol.164.12.6287"},{"key":"2026061310292577061_j_enr-2018-0004_ref_009_w2aab3b7b3b1b6b1ab1ab9Aa","doi-asserted-by":"crossref","unstructured":"Khan S, Jena GB. Protective role of sodium butyrate, a HDAC inhibitor on beta-cell proliferation, function and glucose homeostasis through modulation of p38\/ERK MAPK and apoptotic pathways: study in juvenile diabetic rat. Chem Biol Interact 213, 1-12, 2014.10.1016\/j.cbi.2014.02.001","DOI":"10.1016\/j.cbi.2014.02.001"},{"key":"2026061310292577061_j_enr-2018-0004_ref_010_w2aab3b7b3b1b6b1ab1ac10Aa","doi-asserted-by":"crossref","unstructured":"Khan S, Jena G. Th e role of butyrate, a histone deacetylase inhibitor in diabetes mellitus: experimental evidence for therapeutic intervention. Epigenomics 7, 669-80, 2015.10.2217\/epi.15.20","DOI":"10.2217\/epi.15.20"},{"key":"2026061310292577061_j_enr-2018-0004_ref_011_w2aab3b7b3b1b6b1ab1ac11Aa","doi-asserted-by":"crossref","unstructured":"Kubicek S, Gilbert JC, Fomina-Yadlin D, Gitlin AD, Yuan Y, Wagner FF, Holson EB, Luo T, Lewis TA, Taylo B, Gupta S, Shamji AF, Wagner BK, Clemons PA, Schreiber SL. Chromatin-targeting small molecules cause class-specifi c transcriptional changes in pancreatic endocrine cells. Proc Natl Acad Sci U S A 109, 5364-5369, 2012.10.1073\/pnas.1201079109","DOI":"10.1073\/pnas.1201079109"},{"key":"2026061310292577061_j_enr-2018-0004_ref_012_w2aab3b7b3b1b6b1ab1ac12Aa","doi-asserted-by":"crossref","unstructured":"Larsen L, Tonnesen M, Ronn SG, Storling J, Jorgensen S, Mascagni P, Dinarello CA, Billestrup N, Mandrup-Poulsen T. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia 50, 779- 789, 2007.10.1007\/s00125-006-0562-3","DOI":"10.1007\/s00125-006-0562-3"},{"key":"2026061310292577061_j_enr-2018-0004_ref_013_w2aab3b7b3b1b6b1ab1ac13Aa","doi-asserted-by":"crossref","unstructured":"Llanos P, Contreras-Ferrat A, Barrientos G, Valencia M, Mears D, Hidalgo C. Glucose-Dependent Insulin Secretion in Pancreatic \u03b2-Cell Islets from Male Rats Requires Ca2+ Release via ROS-Stimulated Ryanodine Receptors. PLoS One 10, e0129238, 2015.10.1371\/journal.pone.0129238","DOI":"10.1371\/journal.pone.0129238"},{"key":"2026061310292577061_j_enr-2018-0004_ref_014_w2aab3b7b3b1b6b1ab1ac14Aa","doi-asserted-by":"crossref","unstructured":"Lundh M, Christensen DP, Damgaard Nielsen M, Richardson SJ, Dahllof MS, Skovgaard T, Berthelsen J, Dinarello CA, Stevenazzi A, Mascagni P, Grunnet G, Morgan NG, Mandrup-Poulsen T. Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are diff erentially regulated in the islets of type 1 diabetic children. Diabetologia 55, 2421-2431, 2012.10.1007\/s00125-012-2615-0","DOI":"10.1007\/s00125-012-2615-0"},{"key":"2026061310292577061_j_enr-2018-0004_ref_015_w2aab3b7b3b1b6b1ab1ac15Aa","doi-asserted-by":"crossref","unstructured":"Lundh M, Galbo T, Poulsen SS, Mandrup-Poulsen T. Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats. Diabetes, Obes Metab 17, 703-707, 2015.10.1111\/dom.12470","DOI":"10.1111\/dom.12470"},{"key":"2026061310292577061_j_enr-2018-0004_ref_016_w2aab3b7b3b1b6b1ab1ac16Aa","doi-asserted-by":"crossref","unstructured":"Manal M, Chandrasekar MJN, Gomathi Priya J, Nanjan MJ. Inhibitors of histone deacetylase as antitumor agents: A critical review. Bioorg Chem 67, 18-42, 2016.10.1016\/j.bioorg.2016.05.005","DOI":"10.1016\/j.bioorg.2016.05.005"},{"key":"2026061310292577061_j_enr-2018-0004_ref_017_w2aab3b7b3b1b6b1ab1ac17Aa","doi-asserted-by":"crossref","unstructured":"Marks PA. Histone deacetylase inhibitors: a chemical genetics approach to understanding cellular functions. Biochim Biophys Acta 1799, 717-725, 2010.10.1016\/j.bbagrm.2010.05.008","DOI":"10.1016\/j.bbagrm.2010.05.008"},{"key":"2026061310292577061_j_enr-2018-0004_ref_018_w2aab3b7b3b1b6b1ab1ac18Aa","doi-asserted-by":"crossref","unstructured":"Minn AH, Hafele C, Shalev A. Th ioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces beta-cell apoptosis. Endocrinology 146, 2397-2405, 200510.1210\/en.2004-1378","DOI":"10.1210\/en.2004-1378"},{"key":"2026061310292577061_j_enr-2018-0004_ref_019_w2aab3b7b3b1b6b1ab1ac19Aa","doi-asserted-by":"crossref","unstructured":"Miyazaki J, Araki K, Yamato E, Ikegami H, Asano T, Shibasaki Y, Oka Y, Yamamura K. Establishment of a pancreatic beta cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms. Endocrinology 127, 126-32, 1990.10.1210\/endo-127-1-126","DOI":"10.1210\/endo-127-1-126"},{"key":"2026061310292577061_j_enr-2018-0004_ref_020_w2aab3b7b3b1b6b1ab1ac20Aa","doi-asserted-by":"crossref","unstructured":"Newbold A, Falkenberg KJ, Prince HM, Johnstone RW. How do tumor cells respond to HDAC inhibition? FEBS J 283, 4032-4046, 2016.10.1111\/febs.13746","DOI":"10.1111\/febs.13746"},{"key":"2026061310292577061_j_enr-2018-0004_ref_021_w2aab3b7b3b1b6b1ab1ac21Aa","doi-asserted-by":"crossref","unstructured":"Pi J, Bai Y, Zhang Q, Wong V, Floering LM, Daniel K, Reece, JM, Deeney JT, Andersen ME, Corkey BE, Collins S. Reactive oxygen species as a signal in glucose-stimulated insulin secretion. Diabetes 56, 1783-1791, 2007.10.2337\/db06-1601","DOI":"10.2337\/db06-1601"},{"key":"2026061310292577061_j_enr-2018-0004_ref_022_w2aab3b7b3b1b6b1ab1ac22Aa","doi-asserted-by":"crossref","unstructured":"Plaisance V, Rolland L, Gmyr V, Annicotte JS, Kerr-Conte J, Pattou F, Abderrahmani A. Th e class I histone deacetylase inhibitor MS-275 prevents pancreatic beta cell death induced by palmitate. J Diabetes Res 2014, 195739, 2014.10.1155\/2014\/195739","DOI":"10.1155\/2014\/195739"},{"key":"2026061310292577061_j_enr-2018-0004_ref_023_w2aab3b7b3b1b6b1ab1ac23Aa","doi-asserted-by":"crossref","unstructured":"Saadeh M, Ferrante TC, Kane A, Shirihai O, Corkey BE, Deeney JT. Reactive oxygen species stimulate insulin secretion in rat pancreatic islets: studies using mono-oleoyl-glycerol. PLoS One 7, e30200, 2012.10.1371\/journal.pone.0030200","DOI":"10.1371\/journal.pone.0030200"},{"key":"2026061310292577061_j_enr-2018-0004_ref_024_w2aab3b7b3b1b6b1ab1ac24Aa","doi-asserted-by":"crossref","unstructured":"Schulze PC, Yoshioka J, Takahashi T, He Z, King GL, Lee RT. Hyperglycemia promotes oxidative stress through inhibition of thioredoxin function by thioredoxin-interacting protein. J Biol Chem 279, 30369-30374, 2004.10.1074\/jbc.M400549200","DOI":"10.1074\/jbc.M400549200"},{"key":"2026061310292577061_j_enr-2018-0004_ref_025_w2aab3b7b3b1b6b1ab1ac25Aa","doi-asserted-by":"crossref","unstructured":"Sharma S, Taliyan R. Histone deacetylase inhibitors: Future therapeutics for insulin resistance and type 2 diabetes. Pharmacol Res 113, 320-326, 2016.10.1016\/j.phrs.2016.09.009","DOI":"10.1016\/j.phrs.2016.09.009"},{"key":"2026061310292577061_j_enr-2018-0004_ref_026_w2aab3b7b3b1b6b1ab1ac26Aa","doi-asserted-by":"crossref","unstructured":"Susick L, Veluthakal R, Suresh MV, Hadden T, Kowluru A. Regulatory roles for histone deacetylation in IL-1betainduced nitric oxide release in pancreatic beta-cells. J Cell Mol Med 12, 1571-1583, 2008.10.1111\/j.1582-4934.2007.00171.x","DOI":"10.1111\/j.1582-4934.2007.00171.x"},{"key":"2026061310292577061_j_enr-2018-0004_ref_027_w2aab3b7b3b1b6b1ab1ac27Aa","doi-asserted-by":"crossref","unstructured":"Tiernan AR, Champion JA, Sambanis A. Trichostatin A aff ects the secretion pathways of beta and intestinal endocrine cells. Exp Cell Res 330, 212-21, 2015.10.1016\/j.yexcr.2014.09.031","DOI":"10.1016\/j.yexcr.2014.09.031"},{"key":"2026061310292577061_j_enr-2018-0004_ref_028_w2aab3b7b3b1b6b1ab1ac28Aa","doi-asserted-by":"crossref","unstructured":"Ungerstedt J, Du Y, Zhang H, Nair D, Holmgren A. In vivo redox state of Human thioredoxin and redox shift by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Free Radic Biol Med 53, 2002-2007, 2012.10.1016\/j.freeradbiomed.2012.09.019","DOI":"10.1016\/j.freeradbiomed.2012.09.019"},{"key":"2026061310292577061_j_enr-2018-0004_ref_029_w2aab3b7b3b1b6b1ab1ac29Aa","doi-asserted-by":"crossref","unstructured":"Xu G, Chen J, Jing G, Shalev A. Th ioredoxin-interacting protein regulates insulin transcription through microRNA-204. Nat Med 19, 1141-1146, 2013.10.1038\/nm.3287","DOI":"10.1038\/nm.3287"},{"key":"2026061310292577061_j_enr-2018-0004_ref_030_w2aab3b7b3b1b6b1ab1ac30Aa","doi-asserted-by":"crossref","unstructured":"Yamamoto M, Yamato E, Toyoda S, Tashiro F, Ikegami H, Yodoi J, Miyazaki J. Transgenic expression of antioxidant protein thioredoxin in pancreatic beta cells prevents progression of type 2 diabetes mellitus. Antioxid Redox Signal 10, 43-49, 2008.10.1089\/ars.2007.1586","DOI":"10.1089\/ars.2007.1586"},{"key":"2026061310292577061_j_enr-2018-0004_ref_031_w2aab3b7b3b1b6b1ab1ac31Aa","doi-asserted-by":"crossref","unstructured":"Yamato E, Tashiro F, Miyazaki J. Microarray analysis of novel candidate genes responsible for glucose-stimulated insulin secretion in mouse pancreatic \u03b2 cell line MIN6. PLoS One 8, e61211, 2013.10.1371\/journal.pone.0061211","DOI":"10.1371\/journal.pone.0061211"},{"key":"2026061310292577061_j_enr-2018-0004_ref_032_w2aab3b7b3b1b6b1ab1ac32Aa","doi-asserted-by":"crossref","unstructured":"Zhang J, Zhong Q. Histone deacetylase inhibitors and cell death. Cell Mol Life Sci 71, 3885-901, 2014.10.1007\/s00018-014-1656-6","DOI":"10.1007\/s00018-014-1656-6"}],"container-title":["Endocrine Regulations"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/content.sciendo.com\/view\/journals\/enr\/52\/1\/article-p21.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/reference-global.com\/pdf\/10.2478\/enr-2018-0004","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T10:29:44Z","timestamp":1781346584000},"score":1,"resource":{"primary":{"URL":"https:\/\/reference-global.com\/article\/10.2478\/enr-2018-0004"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,1]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,2,16]]},"published-print":{"date-parts":[[2018,1,1]]}},"alternative-id":["10.2478\/enr-2018-0004"],"URL":"https:\/\/doi.org\/10.2478\/enr-2018-0004","relation":{},"ISSN":["1336-0329"],"issn-type":[{"value":"1336-0329","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,1]]}}}