title: Regenerating 1 and 3b gene expression in the pancreas of type 2 diabetic Goto-Kakizaki (GK) rats.
abstract: Regenerating (REG) proteins are associated with islet development, β-cell damage, diabetes and pancreatitis. Particularly, REG-1 and REG-3-beta are involved in cell growth/survival and/or inflammation and the Reg1 promoter contains interleukin-6 (IL-6)-responsive elements. We showed by transcriptome analysis that islets of Goto-Kakizaki (GK) rats, a model of spontaneous type 2 diabetes, overexpress Reg1, 3α, 3β and 3γ, vs Wistar islets. Goto-Kakizaki rat islets also exhibit increased cytokine/chemokine expression/release, particularly IL-6. Here we analyzed Reg1 and Reg3β expression and REG-1 immuno-localization in the GK rat pancreas in relationship with inflammation. Isolated pancreatic islets and acinar tissue from male adult Wistar and diabetic GK rats were used for quantitative RT-PCR analysis. REG-1 immunohistochemistry was performed on paraffin sections with a monoclonal anti-rat REG-1 antibody. Islet cytokine/chemokine release was measured after 48 h-culture. Islet macrophage-positive area was quantified on cryostat sections using anti-CD68 and major histocompatibility complex (MHC) class II antibodies. Pancreatic exocrine-to-endocrine Reg1 and Reg3β mRNA ratios were markedly increased in Wistar vs GK rats. Conversely, both genes were upregulated in isolated GK rat islets. These findings were unexpected, because Reg genes are expressed in the pancreatic acinar tissue. However, we observed REG-1 protein labeling in acinar peri-ductal tissue close to islets and around large, often disorganized, GK rat islets, which may retain acinar cells due to their irregular shape. These large islets also showed peri-islet macrophage infiltration and increased release of various cytokines/chemokines, particularly IL-6. Thus, IL-6 might potentially trigger acinar REG-1 expression and secretion in the vicinity of large diabetic GK rat islets. This increased acinar REG-1 expression might reflect an adaptive though unsuccessful response to deleterious microenvironment.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 872, Team 6, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie, Paris 6, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Calderari
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Irminger
authors.affiliation: Equipe associée au Centre National de la Recherche Scientifique (CNRS) 4413-Unité de Biologie Fonctionnelle et Adaptative (BFA), Team 1 (Biologie et Pathologie du Pancréas Endocrine (B2PE)), Université Paris-Diderot Sorbonne-Paris-Cité, Paris, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Giroix
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia and Child and Family Research Institute, Vancouver, BC, Canada.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Ehses
authors.affiliation: Equipe associée au Centre National de la Recherche Scientifique (CNRS) 4413-Unité de Biologie Fonctionnelle et Adaptative (BFA), Team 1 (Biologie et Pathologie du Pancréas Endocrine (B2PE)), Université Paris-Diderot Sorbonne-Paris-Cité, Paris, France.
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Gangnerau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 872, Team 6, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie, Paris 6, Paris, France.
authors.forename: Josiane
authors.initials: J
authors.lastname: Coulaud
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Rickenbach
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 872, Team 6, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie, Paris 6, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauguier
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Halban
authors.affiliation: INSERM UMRS 872, Team 9, CRC, Université Pierre et Marie Curie, Paris 6, Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Serradas
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 872, Team 6, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie, Paris 6, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Homo-Delarche
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism*; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D007515:Islets of Langerhans / Q000378:metabolism*; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism*; D051847:Lithostathine / Q000235:genetics* / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D000073718:Pancreatitis-Associated Proteins; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D018925:Chemokines; D037181:Lectins, C-Type; D051847:Lithostathine; D000073718:Pancreatitis-Associated Proteins; C497616:Reg1a protein, rat