SerpinB1 Promotes Pancreatic β Cell Proliferation

Cell Metab. 2016 Jan 12;23(1):194-205. doi: 10.1016/j.cmet.2015.12.001.

Abdelfattah El Ouaamari ¹, Ercument Dirice ¹, Nicholas Gedeon ¹, Jiang Hu ¹, Jian-Ying Zhou ², Jun Shirakawa ¹, Lifei Hou ³, Jessica Goodman ⁴, Christos Karampelias ⁵, Guifeng Qiang ⁶, Jeremie Boucher ⁷, Rachael Martinez ¹, Marina A Gritsenko ², Dario F De Jesus ¹, Sevim Kahraman ¹, Shweta Bhatt ¹, Richard D Smith ², Hans-Dietmar Beer ⁸, Prapaporn Jungtrakoon ⁹, Yanping Gong ⁴, Allison B Goldfine ¹⁰, Chong Wee Liew ⁶, Alessandro Doria ⁹, Olov Andersson ⁵, Wei-Jun Qian ², Eileen Remold-O'Donnell ¹¹, Rohit N Kulkarni ¹²

Affiliations

1 Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
2 Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
3 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.
4 Program in Cellular and Molecular Medicine at Boston Children's Hospital, 3 Blackfan Circle, Boston, MA 02215, USA.
5 Department of Cell and Molecular Biology, Karolinska Institutet, von Eulers väg 3, 17177 Stockholm, Sweden.
6 Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
7 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.
8 University Hospital Zurich, Department of Dermatology, 8006 Zurich, Switzerland.
9 Section on Genetics and Epidemiology, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA.
10 Section on Clinical Research, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
11 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.
12 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.

PMID: 26701651 DOI: 10.1016/j.cmet.2015.12.001

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.

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