title: Conditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetes.
abstract: Histone deacetylases (HDACs) are enzymes that regulate gene expression by modifying chromatin structure through removal of acetyl groups from target histones or non-histone proteins. Previous in vitro studies suggest that HDACs may be novel pharmacological targets in immune-mediated islet β-cell destruction. However, the role of specific HDAC in islet β-cell development and function remain unclear. Here, we generated a conditional islet β-cells specific HDAC3 deletion mouse model to determine the consequences of HDAC3 depletion on islet β-cell differentiation, maintenance and function. Islet morphology, insulin secretion, glucose tolerance, and multiple low-dose streptozotocin (STZ)-induced diabetes incidence were evaluated and compared between HDAC3 knockout and wild type littermate controls. Mice with β-cell-specific HDAC3 deletion displayed decreased pancreatic insulin content, disrupted glucose-stimulated insulin secretion, with intermittent spontaneous diabetes and dramatically enhanced susceptibility to STZ-induced diabetes. Furthermore, islet β-cell line, MIN6 cells with siRNA-mediated HDAC3 silence, showed decreased insulin gene transcription, which was mediated, at least partially, through the upregulation of suppressors of cytokine signaling 3 (SOCS3). These results indicate the critical role of HDAC3 in normal β-cell differentiation, maintenance and function.
authors.affiliation: Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI, USA.|Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.|Department of Dermatology, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Chen
authors.affiliation: Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI, USA.|Department of Dermatology, Henry Ford Health System, Detroit, MI, USA.|Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, China.
authors.forename: Yan-Gang
authors.initials: YG
authors.lastname: Wang
authors.affiliation: Department of Cellular Biology and Anatomy, Augusta University, GA, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI, USA.|Department of Dermatology, Henry Ford Health System, Detroit, MI, USA.|Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Qing-Sheng
authors.initials: QS
authors.lastname: Mi
authors.affiliation: Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI, USA.|Department of Dermatology, Henry Ford Health System, Detroit, MI, USA.|Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D018149:Glucose Intolerance; D005951:Glucose Tolerance Test; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010179:Pancreas / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013311:Streptozocin; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D007328:Insulin; D034741:RNA, Small Interfering; D013311:Streptozocin; D000099186:Histone Deacetylase 3
keywords: HDAC3; Pathology Section; autoimmune diabetes; glucose tolerance; insulin; knockout