Hepatocyte Growth Factor/c-Met Signaling Is Required for β-Cell Regeneration

  1. Adolfo Garcia-Ocaña1
  1. 1Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
  2. 2Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
  3. 3Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA
  1. Corresponding author: Adolfo Garcia-Ocaña, adolfo.g.ocana{at}mssm.edu.
  1. J.C.A.-P. and S.E. contributed equally to this study.

Abstract

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.

Footnotes

  • Received February 27, 2013.
  • Accepted September 21, 2013.

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  1. Diabetes vol. 63 no. 1 216-223
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