Ectopic expression of GIP in pancreatic β-cells maintains enhanced insulin secretion in mice with complete absence of proglucagon-derived peptides

Ayako Fukami, Yusuke Seino, Nobuaki Ozaki, Michiyo Yamamoto, Chisato Sugiyama, Eriko Sakamoto-Miura, Tatsuhito Himeno, Yoshiko Takagishi, Shin Tsunekawa, Safina Ali, Daniel J. Drucker, Yoshiharu Murata, Yutaka Seino, Yutaka Oiso, Yoshitaka Hayashi

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19 Citations (Scopus)

Abstract

Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic α-cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and β-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock-in allele (Gcggfp/gfp). The Gcggfp/gfp mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcggfp/gfp mice, and immunohistochemistry localized GIP to pancreatic β-cells of Gcggfp/gfp mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcggfp/gfp mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcggfp/gfp mice. These results indicate that ectopic GIP expression in β-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.

Original languageEnglish
Pages (from-to)510-518
Number of pages9
JournalDiabetes
Volume62
Issue number2
DOIs
Publication statusPublished - 02-2013

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Fukami, A., Seino, Y., Ozaki, N., Yamamoto, M., Sugiyama, C., Sakamoto-Miura, E., Himeno, T., Takagishi, Y., Tsunekawa, S., Ali, S., Drucker, D. J., Murata, Y., Seino, Y., Oiso, Y., & Hayashi, Y. (2013). Ectopic expression of GIP in pancreatic β-cells maintains enhanced insulin secretion in mice with complete absence of proglucagon-derived peptides. Diabetes, 62(2), 510-518. https://doi.org/10.2337/db12-0294