Title |
Ectopic Expression of GIP in Pancreatic β-Cells Maintains Enhanced Insulin Secretion in Mice With Complete Absence of Proglucagon-Derived Peptides
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Published in |
Diabetes, January 2013
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DOI | 10.2337/db12-0294 |
Pubmed ID | |
Authors |
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 |
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 (Gcg(gfp/gfp)). The Gcg(gfp/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 Gcg(gfp/gfp) mice, and immunohistochemistry localized GIP to pancreatic β-cells of Gcg(gfp/gfp) mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcg(gfp/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 Gcg(gfp/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. |
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