title: SerpinB1 Promotes Pancreatic β Cell Proliferation.
abstract: Although compensatory islet hyperplasia in response to insulin resistance is a recognized feature in diabetes, the factor(s) that promote β cell proliferation have been elusive. We previously reported that the liver is a source for such factors in the liver insulin receptor knockout (LIRKO) mouse, an insulin resistance model that manifests islet hyperplasia. Using proteomics we show that serpinB1, a protease inhibitor, which is abundant in the hepatocyte secretome and sera derived from LIRKO mice, is the liver-derived secretory protein that regulates β cell proliferation in humans, mice, and zebrafish. Small-molecule compounds, that partially mimic serpinB1 effects of inhibiting elastase activity, enhanced proliferation of β cells, and mice lacking serpinB1 exhibit attenuated β cell compensation in response to insulin resistance. Finally, SerpinB1 treatment of islets modulated proteins in growth/survival pathways. Together, these data implicate serpinB1 as an endogenous protein that can potentially be harnessed to enhance functional β cell mass in patients with diabetes.
authors.affiliation: Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Abdelfattah
authors.initials: A
authors.lastname: El Ouaamari
authors.affiliation: Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Ercument
authors.initials: E
authors.lastname: Dirice
authors.affiliation: Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Gedeon
authors.affiliation: Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Hu
authors.affiliation: Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Zhou
authors.affiliation: Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Shirakawa
authors.affiliation: Program in Cellular and Molecular Medicine at Boston Children's Hospital, 3 Blackfan Circle, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Lifei
authors.initials: L
authors.lastname: Hou
authors.affiliation: Program in Cellular and Molecular Medicine at Boston Children's Hospital, 3 Blackfan Circle, Boston, MA 02215, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Goodman
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, von Eulers väg 3, 17177 Stockholm, Sweden.
authors.forename: Christos
authors.initials: C
authors.lastname: Karampelias
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Guifeng
authors.initials: G
authors.lastname: Qiang
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA; Cardiovascular and Metabolic Diseases iMed, AstraZeneca R&D, 431 83 Mölndal, Sweden.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Boucher
authors.affiliation: Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Martinez
authors.affiliation: Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Gritsenko
authors.affiliation: Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Dario F
authors.initials: DF
authors.lastname: De Jesus
authors.affiliation: Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Sevim
authors.initials: S
authors.lastname: Kahraman
authors.affiliation: Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Bhatt
authors.affiliation: Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Smith
authors.affiliation: University Hospital Zurich, Department of Dermatology, 8006 Zurich, Switzerland.
authors.forename: Hans-Dietmar
authors.initials: HD
authors.lastname: Beer
authors.affiliation: Section on Genetics and Epidemiology, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Prapaporn
authors.initials: P
authors.lastname: Jungtrakoon
authors.affiliation: Program in Cellular and Molecular Medicine at Boston Children's Hospital, 3 Blackfan Circle, Boston, MA 02215, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Section on Clinical Research, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Allison B
authors.initials: AB
authors.lastname: Goldfine
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Chong Wee
authors.initials: CW
authors.lastname: Liew
authors.affiliation: Section on Genetics and Epidemiology, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, von Eulers väg 3, 17177 Stockholm, Sweden.
authors.forename: Olov
authors.initials: O
authors.lastname: Andersson
authors.affiliation: Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Qian
authors.affiliation: Program in Cellular and Molecular Medicine at Boston Children's Hospital, 3 Blackfan Circle, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Remold-O'Donnell
authors.affiliation: Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA. Electronic address: rohit.kulkarni@joslin.harvard.edu.
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000502:physiology*; D015398:Signal Transduction; D015027:Zebrafish
chemical_list: C522950:Serpinb1a protein, mouse; D015843:Serpins; D011972:Receptor, Insulin