title: Short term exposure of beta cells to low concentrations of interleukin-1β improves insulin secretion through focal adhesion and actin remodeling and regulation of gene expression.
abstract: Type 2 diabetes involves defective insulin secretion with islet inflammation governed in part by IL-1β. Prolonged exposure of islets to high concentrations of IL-1β (>24 h, 20 ng/ml) impairs beta cell function and survival. Conversely, exposure to lower concentrations of IL-1β for >24 h improves these same parameters. The impact on insulin secretion of shorter exposure times to IL-1β and the underlying molecular mechanisms are poorly understood and were the focus of this study. Treatment of rat primary beta cells, as well as rat or human whole islets, with 0.1 ng/ml IL-1β for 2 h increased glucose-stimulated (but not basal) insulin secretion, whereas 20 ng/ml was without effect. Similar differential effects of IL-1β depending on concentration were observed after 15 min of KCl stimulation but were prevented by diazoxide. Studies on sorted rat beta cells indicated that the enhancement of stimulated secretion by 0.1 ng/ml IL-1β was mediated by the NF-κB pathway and c-JUN/JNK pathway acting in parallel to elicit focal adhesion remodeling and the phosphorylation of paxillin independently of upstream regulation by focal adhesion kinase. Because the beneficial effect of IL-1β was dependent in part upon transcription, gene expression was analyzed by RNAseq. There were 18 genes regulated uniquely by 0.1 but not 20 ng/ml IL-1β, which are mostly involved in transcription and apoptosis. These results indicate that 2 h of exposure of beta cells to a low but not a high concentration of IL-1β enhances glucose-stimulated insulin secretion through focal adhesion and actin remodeling, as well as modulation of gene expression.
authors.affiliation: From the Department of Genetic Medicine and Development, University Medical Centre, University of Geneva, 1211 Geneva 4, Switzerland Caroline.Arous@unige.ch.
authors.forename: Caroline
authors.initials: C
authors.lastname: Arous
authors.affiliation: From the Department of Genetic Medicine and Development, University Medical Centre, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Pedro G
authors.initials: PG
authors.lastname: Ferreira
authors.affiliation: From the Department of Genetic Medicine and Development, University Medical Centre, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.affiliation: From the Department of Genetic Medicine and Development, University Medical Centre, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Halban
mesh_terms: D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D053583:Interleukin-1beta / Q000008:administration & dosage* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051419:Paxillin / Q000096:biosynthesis; D061251:Primary Cell Culture; D051381:Rats
chemical_list: D000199:Actins; D007328:Insulin; D053583:Interleukin-1beta; D051419:Paxillin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose
keywords: Actin; Actin Remodeling; Beta cell (B-cell); ERK1/2; Focal Adhesions; Gene Transcription; Insulin Secretion; Interleukin-1β; c-JUN N-terminal kinase (JNK)