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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood Glucose / metabolism
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Blotting, Western
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Butadienes / pharmacology
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Cell Proliferation / drug effects*
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Cells, Cultured
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Connective Tissue Growth Factor
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Diabetes Mellitus, Type 2 / blood
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Diabetes Mellitus, Type 2 / physiopathology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibrosis
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Gene Expression / drug effects
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Glucose / metabolism
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Glucose / pharmacology*
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Hyperglycemia / physiopathology
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Hyperinsulinism / physiopathology
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Immediate-Early Proteins / metabolism
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Insulin / blood
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Insulin / pharmacology*
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Intercellular Signaling Peptides and Proteins / metabolism
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Islets of Langerhans / drug effects
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Islets of Langerhans / metabolism
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Islets of Langerhans / pathology
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MAP Kinase Signaling System / drug effects
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Male
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Nitriles / pharmacology
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Pancreas / drug effects*
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Pancreas / metabolism
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Pancreas / pathology
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Phosphorylation / drug effects
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Rats
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Rats, Sprague-Dawley
Substances
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Blood Glucose
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Butadienes
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CCN2 protein, rat
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Enzyme Inhibitors
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Immediate-Early Proteins
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Insulin
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Intercellular Signaling Peptides and Proteins
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Nitriles
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U 0126
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Connective Tissue Growth Factor
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Extracellular Signal-Regulated MAP Kinases
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Glucose