PSCs and GLP-1R: occurrence in normal pancreas, acute/chronic pancreatitis and effect of their activation by a GLP-1R agonist.
There is increasing concern about the development of pancreatitis in patients with diabetes mellitus who received long-term glucagon-like peptide-1 (GLP-1) analog treatment. Its pathogenesis is unknown. The effects of GLP-1 agonists on pancreatic endocrine cells are well studied; however, there is little information on effects on other pancreatic tissues that might be involved in inflammatory processes. Pancreatic stellate cells (PSCs) can have an important role in pancreatitis, secreting various inflammatory cytokines/chemokines, as well as collagen. In this study, we investigated GLP-1R occurrence in normal pancreas, acute pancreatitis (AP)/chronic pancreatitis (CP), and the effects of GLP-1 analog on normal PSCs, their ability to stimulate inflammatory mediator secretion or proliferation. GLP-1 receptor (GLP-1R) expression/localization in normal pancreas and pancreatitis (AP/CP) tissues were evaluated with histological/immunohistochemical analysis. PSCs were isolated from male Wistar rats. GLP-1R expression and effects of GLP-1 analog on activated PSCs was examined with real-time PCR, MTS assays and western blotting. In normal pancreas, pancreatic β cells expressed GLP-1R, with only low expression in acinar cells, whereas in AP or CP, acinar cells, ductal cells and activated PSCs expressed GLP-1R. With activation of normal PSCs, GLP-1R is markedly increased, as is multiple other incretin-related receptors. The GLP-1 analog, liraglutide, did not induce inflammatory genes expression in activated PSCs, but induced proliferation. Liraglutide activated multiple signaling cascades in PSCs, and the extracellular signal-regulated kinase pathway mediated the PSCs proliferation. GLP-1Rs are expressed in normal pancreas and there is marked enhanced expression in AP/CP. GLP-1-agonist induced cell proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest chronic treatment with GLP-1R agonists could lead to proliferation/chronic activation of PSCs, which may lead to important effects in the pancreas.
1] Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan [2] Department of Cell Biology Section, NIDDK, National Institutes of Health, Bethesda, MD, USA.
Taichi
T
Nakamura
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Tetsuhide
T
Ito
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Masahiko
M
Uchida
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Masayuki
M
Hijioka
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Hisato
H
Igarashi
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Takamasa
T
Oono
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Masaki
M
Kato
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Kazuhiko
K
Nakamura
Department of Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Koichi
K
Suzuki
Department of Cell Biology Section, NIDDK, National Institutes of Health, Bethesda, MD, USA.
Robert T
RT
Jensen
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Ryoichi
R
Takayanagi
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006651:Histocytochemistry; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000069450:Liraglutide; D008297:Male; D010179:Pancreas / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058954:Pancreatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D019283:Pancreatitis, Acute Necrotizing / Q000378:metabolism*; D050500:Pancreatitis, Chronic / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D048049:Extracellular Signal-Regulated MAP Kinases