title: Trichostatin A affects the secretion pathways of beta and intestinal endocrine cells.
abstract: Histone deacetylase inhibitors (HDACi) were recently identified as having significant clinical potential in reversing β-cell functional inhibition caused by inflammation, a shared precursor of Type 1 and Type 2 diabetes. However, HDACi are highly complex and little is known of their direct effect on important cell secretion pathways for blood glucose regulation. The aims of the present study were to investigate the effect of HDACi on insulin secretion from β-cells, GLP-1 secretion from L-cells, and recombinant insulin secretion from engineered L-cells. The β-cell line βTC-tet, L-cell line GLUTag, or recombinant insulin-secreting L-cell lines were exposed to Trichostatin A for 24h. Effects on insulin or GLP-1 mRNA, intracellular protein content, processing efficiency, and secretion were measured by real-time PCR, ELISA, and radioimmunoassay. HDACi increased secretion per viable cell in a dose-dependent manner for all cell types. Effects on mRNA levels were variable, but enhanced intracellular polypeptide content and secretion were comparable among cell types. Enhanced recombinant insulin secretion was sustained for seven days in alginate microencapsulated L-cells. HDACi enhances β- and L-cell secretion fluxes in a way that could significantly improve blood glucose regulation in diabetes patients and holds potential as a novel method for enhancing insulin-secreting non-β or β-cell grafts.
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, GA 30332, United States.
authors.forename: Aubrey R
authors.initials: AR
authors.lastname: Tiernan
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, GA 30332, United States.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Champion
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, GA 30332, United States; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, GA, United States. Electronic address: Athanassios.Sambanis@chbe.gatech.edu.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Sambanis
mesh_terms: D000818:Animals; D002460:Cell Line; D019858:Enteroendocrine Cells / Q000187:drug effects* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055571:Secretory Pathway
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007328:Insulin; D012333:RNA, Messenger; C012589:trichostatin A; D052216:Glucagon-Like Peptide 1
keywords: Diabetes; Histone deacetylase inhibitors; Intestinal endocrine cells; Regulated secretory pathway; Trichostatin A; β-cells