title: Hyperglycemia and hyperinsulinemia have additive effects on activation and proliferation of pancreatic stellate cells: possible explanation of islet-specific fibrosis in type 2 diabetes mellitus.
abstract: Pancreatic islet fibrosis observed in Type 2 diabetes is one of the major factors leading to progressive beta-cell loss and dysfunction. Despite its importance, the mechanism of islet-restricted fibrogenesis associated with pancreatic stellate cell (PSC) activation and proliferation remains to be defined. Therefore, we studied whether the islet-specific environment represented by hyperglycemia and hyperinsulinemia had additive effects on the activation and proliferation of cultured rat PSCs. Cells were stimulated to activate and proliferate with glucose and insulin, either individually or concomitantly. Both stimuli promoted PSC proliferation and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation independently, but an additive effect was also demonstrated. Blockade of ERK signaling by the mitogen-activated protein kinase kinase (MEK) inhibitor, U0126, suppressed both glucose- and insulin-induced ERK 1/2 phosphorylation and PSC proliferation. Glucose and insulin-induced ERK 1/2 phosphorylation also stimulated connective tissue growth factor gene expression. Thus, hyperglycemia and hyperinsulinemia are two crucial mitogenic factors that activate and proliferate PSCs, and the presence of both states will amplify this response.
authors.affiliation: Immunology & Cell Biology Core Laboratory, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Oak-Kee
authors.initials: OK
authors.lastname: Hong
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Lee
authors.forename: Marie
authors.initials: M
authors.lastname: Rhee
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Ko
authors.forename: Jae-Hyoung
authors.initials: JH
authors.lastname: Cho
authors.forename: Yoon-Hee
authors.initials: YH
authors.lastname: Choi
authors.forename: Ki-Ho
authors.initials: KH
authors.lastname: Song
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Son
authors.forename: Kun-Ho
authors.initials: KH
authors.lastname: Yoon
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D006943:Hyperglycemia / Q000503:physiopathology; D006946:Hyperinsulinism / Q000503:physiopathology; D017874:Immediate-Early Proteins / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D002070:Butadienes; C526316:CCN2 protein, rat; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D009570:Nitriles; C113580:U 0126; D055513:Connective Tissue Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose