Selective Small-Molecule Agonists of G Protein–Coupled Receptor 40 Promote Glucose-Dependent Insulin Secretion and Reduce Blood Glucose in Mice

  1. Carina P. Tan1,
  2. Yue Feng1,
  3. Yun-Ping Zhou1,
  4. George J. Eiermann2,
  5. Aleksandr Petrov2,
  6. Changyou Zhou3,
  7. Songnian Lin3,
  8. Gino Salituro4,
  9. Peter Meinke3,
  10. Ralph Mosley3,
  11. Taro E. Akiyama1,
  12. Monica Einstein1,
  13. Sanjeev Kumar4,
  14. Joel P. Berger1,
  15. Sander G. Mills3,
  16. Nancy A. Thornberry1,
  17. Lihu Yang3 and
  18. Andrew D. Howard1
  1. 1Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, New Jersey
  2. 2Department of In Vivo Sciences, Merck Research Laboratories, Rahway, New Jersey
  3. 3Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey
  4. 4Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey
  1. Corresponding authors: Dr. Andrew D. Howard, howarda{at}, and Dr. Yun-Ping Zhou, yunping_zhou{at}


OBJECTIVE— Acute activation of G protein–coupled receptor 40 (GPR40) by free fatty acids (FFAs) or synthetic GPR40 agonists enhances insulin secretion. However, it is still a matter of debate whether activation of GPR40 would be beneficial for the treatment of type 2 diabetes, since chronic exposure to FFAs impairs islet function. We sought to evaluate the specific role of GPR40 in islets and its potential as a therapeutic target using compounds that specifically activate GPR40.

RESEARCH DESIGN AND METHODS— We developed a series of GPR40-selective small-molecule agonists and studied their acute and chronic effects on glucose-dependent insulin secretion (GDIS) in isolated islets, as well as effects on blood glucose levels during intraperitoneal glucose tolerance tests in wild-type and GPR40 knockout mice (GPR40−/−).

RESULTS— Small-molecule GPR40 agonists significantly enhanced GDIS in isolated islets and improved glucose tolerance in wild-type mice but not in GPR40−/− mice. While a 72-h exposure to FFAs in tissue culture significantly impaired GDIS in islets from both wild-type and GPR40−/− mice, similar exposure to the GPR40 agonist did not impair GDIS in islets from wild-type mice. Furthermore, the GPR40 agonist enhanced insulin secretion in perfused pancreata from neonatal streptozotocin-induced diabetic rats and improved glucose levels in mice with high-fat diet–induced obesity acutely and chronically.

CONCLUSIONS— GPR40 does not mediate the chronic toxic effects of FFAs on islet function. Pharmacological activation of GPR40 may potentiate GDIS in humans and be beneficial for overall glucose control in patients with type 2 diabetes.


  • Published ahead of print at on 13 May 2008.

    C.P.T. and Y.F. contributed equally to this article.

    R.M. is currently affiliated with Pharmasset, Princeton, New Jersey.

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    • Accepted May 7, 2008.
    • Received January 30, 2008.
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  1. Diabetes vol. 57 no. 8 2211-2219
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