SerpinB1 Promotes Pancreatic β Cell Proliferation

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

Research output: Contribution to journalArticle

90 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)194-205
Number of pages12
JournalCell Metabolism
Volume23
Issue number1
DOIs
StatePublished - Jan 12 2016

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Physiology
  • Cell Biology

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  • Cite this

    El Ouaamari, A., Dirice, E., Gedeon, N., Hu, J., Zhou, J. Y., Shirakawa, J., Hou, L., Goodman, J., Karampelias, C., Qiang, G., Boucher, J., Martinez, R., Gritsenko, M. A., De Jesus, D. F., Kahraman, S., Bhatt, S., Smith, R. D., Beer, H. D., Jungtrakoon, P., ... Kulkarni, R. N. (2016). SerpinB1 Promotes Pancreatic β Cell Proliferation. Cell Metabolism, 23(1), 194-205. https://doi.org/10.1016/j.cmet.2015.12.001