title: Control of pancreatic β cell regeneration by glucose metabolism.
abstract: Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K(ATP) channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem 91240, Israel.
authors: Shay
authors: S
authors: Porat
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Noa
authors: N
authors: Weinberg-Corem
authors: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors: Sharona
authors: S
authors: Tornovsky-Babaey
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors: Rachel
authors: R
authors: Schyr-Ben-Haroush
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Ayat
authors: A
authors: Hija
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Miri
authors: M
authors: Stolovich-Rain
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Daniela
authors: D
authors: Dadon
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Zvi
authors: Z
authors: Granot
authors: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Vered
authors: V
authors: Ben-Hur
authors: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors: Peter
authors: P
authors: White
authors: Department of Physiology, Anatomy, and Genetics, Oxford University, Oxford OX1 3QX, UK.
authors: Christophe A
authors: CA
authors: Girard
authors: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Rotem
authors: R
authors: Karni
authors: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors: Klaus H
authors: KH
authors: Kaestner
authors: Department of Physiology, Anatomy, and Genetics, Oxford University, Oxford OX1 3QX, UK.
authors: Frances M
authors: FM
authors: Ashcroft
authors: Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-0494, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-0494, USA.
authors: Mark A
authors: MA
authors: Magnuson
authors: Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors: Ann
authors: A
authors: Saada
authors: Department of Metabolic Diseases, Hoffmann-La Roche, Nutley, NJ 07110, USA.
authors: Joseph
authors: J
authors: Grimsby
authors: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. Electronic address: beng@cc.huji.ac.il.
authors: Benjamin
authors: B
authors: Glaser
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. Electronic address: yuvald@ekmd.huji.ac.il.
authors: Yuval
authors: Y
authors: Dor
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002462:Cell Membrane / Q000502:physiology; D049109:Cell Proliferation; D005941:Glucokinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006019:Glycolysis; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation; D054086:KATP Channels / Q000378:metabolism; D051379:Mice; D012038:Regeneration
chemical_list: D001786:Blood Glucose; D054086:KATP Channels; D005941:Glucokinase