title: Pancreatic β-Cells Express the Fetal Islet Hormone Gastrin in Rodent and Human Diabetes.
abstract: β-Cell failure in type 2 diabetes (T2D) was recently proposed to involve dedifferentiation of β-cells and ectopic expression of other islet hormones, including somatostatin and glucagon. Here we show that gastrin, a stomach hormone typically expressed in the pancreas only during embryogenesis, is expressed in islets of diabetic rodents and humans with T2D. Although gastrin in mice is expressed in insulin+cells, gastrin expression in humans with T2D occurs in both insulin+and somatostatin+cells. Genetic lineage tracing in mice indicates that gastrin expression is turned on in a subset of differentiated β-cells after exposure to severe hyperglycemia. Gastrin expression in adult β-cells does not involve the endocrine progenitor cell regulator neurogenin3 but requires membrane depolarization, calcium influx, and calcineurin signaling. In vivo and in vitro experiments show that gastrin expression is rapidly eliminated upon exposure of β-cells to normal glucose levels. These results reveal the fetal hormone gastrin as a novel marker for reversible human β-cell reprogramming in diabetes.
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Tehila
authors.initials: T
authors.lastname: Dahan
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Ziv
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Elad
authors.initials: E
authors.lastname: Horwitz
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Hai
authors.initials: H
authors.lastname: Zemmour
authors.affiliation: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Judith
authors.initials: J
authors.lastname: Lavi
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Swisa
authors.affiliation: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Gil
authors.initials: G
authors.lastname: Leibowitz
authors.affiliation: Department of Physiology, Anatomy & Genetics, Oxford University, Oxford, U.K.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
authors.affiliation: Diabetes Research Center, Brussels Free University, Brussels, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: In't Veld
authors.affiliation: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel beng@cc.huji.ac.il yuvald@ekmd.huji.ac.il.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel beng@cc.huji.ac.il yuvald@ekmd.huji.ac.il.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D016022:Case-Control Studies; D003920:Diabetes Mellitus / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005755:Gastrins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005849:Gerbillinae; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D019864:Somatostatin-Secreting Cells / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005755:Gastrins; D009419:Nerve Tissue Proteins; C498695:NEUROG3 protein, human; C407737:Neurog3 protein, mouse