Overexpression of GPR40 in Pancreatic β-Cells Augments Glucose-Stimulated Insulin Secretion and Improves Glucose Tolerance in Normal and Diabetic Mice

  1. Kae Nagasumi1,
  2. Ritsuko Esaki2,
  3. Kimihiko Iwachidow2,
  4. Yoshitaka Yasuhara2,
  5. Kazuhiro Ogi3,
  6. Hideyuki Tanaka3,
  7. Mitsugu Nakata2,
  8. Takashi Yano2,
  9. Kozo Shimakawa2,
  10. Shigehisa Taketomi4,
  11. Koji Takeuchi1,
  12. Hiroyuki Odaka1 and
  13. Yoshihiko Kaisho2
  1. 1Pharmaceutical Research Division, Pharmacological Research Laboratories I, Takeda Pharmaceutical Company Limited, Osaka, Japan; the
  2. 2Pharmaceutical Research Division, Strategic Research Planning Department, Takeda Pharmaceutical Company Limited, Osaka, Japan;
  3. 3the Pharmaceutical Research Division, Frontier Research Laboratories, Takeda Pharmaceutical Company Limited, Ibaraki, Japan; and
  4. 4Hamari Chemicals, Osaka, Japan.
  1. Corresponding author: Kae Nagasumi, nagasumi_kae{at}takeda.co.jp.

Abstract

OBJECTIVE GPR40 is a G protein–coupled receptor regulating free fatty acid–induced insulin secretion. We generated transgenic mice overexpressing the hGPR40 gene under control of the mouse insulin II promoter and used them to examine the role of GPR40 in the regulation of insulin secretion and glucose homeostasis.

RESEARCH DESIGN AND METHODS Normal (C57BL/6J) and diabetic (KK) mice overexpressing the hGPR40 gene under control of the insulin II promoter were generated, and their glucose metabolism and islet function were analyzed.

RESULTS In comparison with nontransgenic littermates, hGPR40 transgenic mice exhibited improved oral glucose tolerance with an increase in insulin secretion. Although islet morphologic analysis showed no obvious differences between hGPR40 transgenic and nontransgenic mice, isolated islets from hGPR40 transgenic mice had enhanced insulin secretion in response to high glucose (16 mmol/l) compared with those from nontransgenic mice, and they both had similar low glucose (3 mmol/l)-stimulated insulin secretion. In addition, hGPR40 transgenic islets significantly increased insulin secretion against a naturally occurring agonist palmitate in the presence of 11 mmol/l glucose. hGPR40 transgenic mice were also found to be resistant to high-fat diet–induced glucose intolerance, and hGPR40 transgenic mice harboring KK background showed augmented insulin secretion and improved oral glucose tolerance compared with nontransgenic littermates.

CONCLUSIONS Our results suggest that GPR40 may have a role in regulating glucose-stimulated insulin secretion and plasma glucose levels in vivo and that pharmacological activation of GPR40 may provide a novel insulin secretagogue beneficial for the treatment of type 2 diabetes.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Please see accompanying commentary, p. 1035.

    • Received September 5, 2008.
    • Accepted February 2, 2009.
  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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