title: Pancreatic stellate cells reduce insulin expression and induce apoptosis in pancreatic β-cells.
abstract: Islet fibrosis, pancreatic β-cell dysfunction, and β-cell apoptosis are features of pancreatic diabetes and type 2 diabetes; however, the underlying mechanisms remain largely unknown. We hypothesized that pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, might affect the phenotype of pancreatic β-cells. α-Smooth muscle actin (a marker of activated PSC)-positive cells were found within and around the fibrotic islets. Indirect co-culture with PSCs reduced insulin expression and induced apoptosis in RIN-5F pancreatic β-cells. Induction of β-cell apoptosis was associated with activation of the caspase pathway and mitochondrial depolarization. Diphenylene iodonium, an inhibitor of PSC activation, inhibited islet fibrosis and protected islets in vivo. Our findings suggest a novel mechanism linking PSCs, islet fibrosis, and diabetes mellitus.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kikuta
authors.forename: Atsushi
authors.initials: A
authors.lastname: Masamune
authors.forename: Shin
authors.initials: S
authors.lastname: Hamada
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takikawa
authors.forename: Eriko
authors.initials: E
authors.lastname: Nakano
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D005355:Fibrosis; D015870:Gene Expression; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology*; D058954:Pancreatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000199:Actins; D015415:Biomarkers; D020169:Caspases; D007004:Hypoglycemic Agents; D007328:Insulin; D009861:Onium Compounds; C498862:Acta2 protein, rat; C007517:diphenyleneiodonium