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SerpinB1 Promotes Pancreatic β Cell Proliferation*

Posted by on in 2016
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El Ouaamari A1Dirice E1Gedeon N1Hu J1Zhou JY2Shirakawa J1Hou L3Goodman J4Karampelias C5Qiang G6Boucher J7,Martinez R1Gritsenko MA2De Jesus DF1Kahraman S1Bhatt S1Smith RD2Beer HD8Jungtrakoon P9Gong Y4Goldfine AB10Liew CW6Doria A9Andersson O5Qian WJ2Remold-O'Donnell E11Kulkarni RN12. 2016. Cell Metab. 23(1):194-205. doi: 10.1016/j.cmet.2015.12.001. Epub 2015 Dec 15.
1Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
2Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
3Program 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.
4Program in Cellular and Molecular Medicine at Boston Children's Hospital, 3 Blackfan Circle, Boston, MA 02215, USA.
5Department of Cell and Molecular Biology, Karolinska Institutet, von Eulers väg 3, 17177 Stockholm, Sweden.
6Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
7Section 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.
8University Hospital Zurich, Department of Dermatology, 8006 Zurich, Switzerland.
9Section on Genetics and Epidemiology, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA.
10Section on Clinical Research, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
11Program 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.
12Islet 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.

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.

Copyright © 2016 Elsevier Inc. All rights reserved.

PMID:
 
26701651
 
[PubMed - in process] 
PMCID:
 
PMC4715773
 [Available on 2017-01-12]

*Note: Custom IgY antibodies (against SerpinB1) used in this publication were produced by Gallus Immunotech Inc. Please visit our  Custom IgY production page for more information.
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