Journal
CELL METABOLISM
Volume 23, Issue 1, Pages 194-205Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2015.12.001
Keywords
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Funding
- NIH [RO1 DK67536, RO1 DK103215, RO1 DK55523, RO1 HL066548, R21 AI103407]
- Boston Children's Hospital
- Societe Francophone du Diabete
- Association Francaise des Diabetiques
- American Diabetes Association
- JDRF [3-APF-2014-182-A-N]
- Juvenile Diabetes Research Foundation/Sanofi Aventis Strategic Alliance [17-2011-644, P30 DK036836]
- Ragnar Soderbergs Foundation
- Swedish Research Council
- Department of Energy
- DOE [DE-AC05-76RL0 1830]
- [R01 DK 074795]
- [P41 GM103493]
- [UC4 DK104167]
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Although compensatory islet hyperplasia in response to insulin resistance is a recognized feature in diabetes, the factor(s) that promote beta 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 beta cell proliferation in humans, mice, and zebrafish. Small-molecule compounds, that partially mimic serpinB1 effects of inhibiting elastase activity, enhanced proliferation of beta cells, and mice lacking serpinB1 exhibit attenuated beta 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 beta cell mass in patients with diabetes.
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