Hepatocyte Growth Factor/c-Met Signaling Is Required for β-Cell Regeneration
- Juan Carlos Alvarez-Perez1,
- Sara Ernst2,
- Cem Demirci3,
- Gabriella P. Casinelli2,
- Jose Manuel D. Mellado-Gil2,
- Francisco Rausell-Palamos1,
- Rupangi C. Vasavada1 and
- Adolfo Garcia-Ocaña1⇑
- 1Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
- 2Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
- 3Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA
- Corresponding author: Adolfo Garcia-Ocaña, .
J.C.A.-P. and S.E. contributed equally to this study.
Hepatocyte growth factor (HGF) is a mitogen required for β-cell replication during pregnancy. To determine whether HGF/c-Met signaling is required for β-cell regeneration, we characterized mice with pancreatic deletion of the HGF receptor, c-Met (PancMet KO mice), in two models of reduced β-cell mass and regeneration: multiple low-dose streptozotocin (MLDS) and partial pancreatectomy (Ppx). We also analyzed whether HGF administration could accelerate β-cell regeneration in wild-type (WT) mice after Ppx. Mouse islets obtained 7 days post-Ppx displayed significantly increased c-Met, suggesting a potential role for HGF/c-Met in β-cell proliferation in situations of reduced β-cell mass. Indeed, adult PancMet KO mice displayed markedly reduced β-cell replication compared with WT mice 7 days post-Ppx. Similarly, β-cell proliferation was decreased in PancMet KO mice in the MLDS mouse model. The decrease in β-cell proliferation post-Ppx correlated with a striking decrease in D-cyclin levels. Importantly, PancMet KO mice showed significantly diminished β-cell mass, decreased glucose tolerance, and impaired insulin secretion compared with WT mice 28 days post-Ppx. Conversely, HGF administration in WT Ppx mice further accelerated β-cell regeneration. These results indicate that HGF/c-Met signaling is critical for β-cell proliferation in situations of diminished β-cell mass and suggest that activation of this pathway can enhance β-cell regeneration.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0333/-/DC1.
C.D. is currently affiliated with Pediatric Endocrinology, Connecticut Children’s Medical Center, Hartford, CT, and J.M.D.M.-G. is currently affiliated with Centro Andaluz de Biología Molecular y Medicina Regenerativa, Sevilla, Spain.
- Received February 27, 2013.
- Accepted September 21, 2013.
- © 2014 by the American Diabetes Association.
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