TITLE

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

AUTHOR(S)
Tan, Carina P.; Yue Feng; Yun-Ping Zhou; Eiermann, George J.; Petrov, Aleksandr; Zhou, Changyou; Lin, Songnian; Salituro, Gino; Meinke, Peter; Mosley, Ralph; Akiyama, Taro E.; Einstein, Monica; Kumar, Sanjeev; Berger, Joel P.; Mills, Sander G.; Thornberry, Nancy A.; Lihu Yang; Howard, Andrew D.
PUB. DATE
August 2008
SOURCE
Diabetes;Aug2008, Vol. 57 Issue 8, p2211
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
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[sup -/-]). RESULTS--Small-molecule GPR40 agonists significantly enhanced GDIS in isolated islets and improved glucose tolerance in wild-type mice but not in GPR40[sup -/-] mice. While a 72-h exposure to FFAs in tissue culture significantly impaired GDIS in islets from both wild-type and GPR40[sup -/-] 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. Diabetes 57:2211-2219, 2008
ACCESSION #
34109609

 

Related Articles

  • Humanized mice for the study of type 1 and type 2 diabetes. Greiner, Dale L.; Brehm, Michael A.; Hosur, Vishnu; Harlan, David M.; Powers, Alvin C.; Shultz, Leonard D. // Annals of the New York Academy of Sciences;Dec2011, Vol. 1245 Issue 1, p55 

    The availability of immunodeficient mice engrafted with functional human immune systems and islets permits in vivo study of human diabetes without putting patients at risk.

  • High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Srivastava, Ankita; Yano, Jason; Hirozane, Yoshihiko; Okada, Kengo; Kefala, Georgia; Snell, Gyorgy; Lane, Weston; Ivetac, Anthony; Jennings, Andy; Gruswitz, Franz; Aertgeerts, Kathleen; Nguyen, Jasmine // Nature;9/4/2014, Vol. 513 Issue 7516, p124 

    Human GPR40 receptor (hGPR40), also known as free fatty-acid receptor 1 (FFAR1), is a G-protein-coupled receptor that binds long-chain free fatty acids to enhance glucose-dependent insulin secretion. Novel treatments for type-2 diabetes mellitus are therefore possible by targeting hGPR40 with...

  • Activation of GPR40 as a Therapeutic Target for the Treatment of Type 2 Diabetes. BURANT, CHARLES F. // Diabetes Care;Aug2013 Supplement, Vol. 36 Issue S2, pS175 

    The stimulation of insulin secretion by glucose can be modulated by multiple nutritive, hormonal, and pharmacological inputs. Fatty acids potentiate insulin secretion through the generation of intracellular signaling molecules and through the activation of cell surface receptors. The...

  • Impact of Adenoviral Transduction With SREBP1c or AMPK on Pancreatic Islet Gene Expression Profile. Diraison, Frederique; Motakis, Efthimios; Parton, Laura E.; Nason, Guy P.; Leclerc, Isabelle; Rutter, Guy A. // Diabetes;Dec2004 Supplement, Vol. 53, pS84 

    Accumulation of triglyceride in islets may contribute to the loss of glucose-stimulated insulin secretion (GSIS) in some forms of type 2 diabetes (Diraison et al., Biochem J 373:769-778, 2004). Here, we use adenoviral vectors and oligonucleotide microarrays to determine the effects of the forced...

  • Presence of GAD Antibodies During Gestational Diabetes Mellitus Predicts Type 1 Diabetes. Nilsson, Charlotta; Ursing, Dag; Törn, Carina; Åberg, Anders; Landin-Olsson, Mona // Diabetes Care;Aug2007, Vol. 30 Issue 8, p1968 

    OBJECTIVE -- We sought to study the frequency of β-cell-specific autoantibody markers in women with gestational diabetes mellitus (GDM) and to follow these women to estimate the risk of later development of type 1 diabetes. RESEARCH DESIGN AND METHODS--Of 385 pregnant women with GDM during...

  • Phenotypic Characterization of LEA Rat: A New Rat Model of Nonobese Type 2 Diabetes. Tadashi Okamura; Xiang Yuan Pei; Ichiro Miyoshi; Yukiko Shimizu; Rieko Takanashi-Yanobu; Yasumasa Mototani; Takao Kanai; Jo Satoh; Noriko Kimura; Noriyuki Kasai // Journal of Diabetes Research;2013, p1 

    Animal models have provided important information for the genetics and pathophysiology of diabetes. Here we have established a novel, nonobese rat strain with spontaneous diabetes, Long-Evans Agouti (LEA) rat derived from Long-Evans (LE) strain. The incidence of diabetes in the males was 10% at...

  • Sitagliptin Improves Glycemic Control and Restores Islet Cell Mass and Function in a Rodent Model of Type 2 Diabetes. Mu, James; Woods, John; Yun-Ping Zhou; Petrov, Aleksandr; Zhihuali; Yue Feng; Zycband, Emanuel; Eiermann, George J.; Howard, Andrew; Cai Li; Thornberry, Nancy A.; Zhang, Bei B. // Diabetes;Jun2007 Supplement 1, Vol. 56, pA550 

    Inhibition of dipeptidyl peptidase-4 (DPP-4) activity has been shown to improve glycemic control by prolonging and potentiating the actions of incretin hormones such as GLP-1 and GIP. In this study, we compared the effects of chronic treatment of sitagliptin, a potent and selective DPP-4...

  • Chronic Activation of Liver X Receptor Induces β-Cell Apoptosis Through Hyperactivation of Lipogenesis. Choe, Sung S.; Choi, A. H.; Kim, Kang H.; Chung, Jun-Jae; Park, Jiyoung; Lee, Ju W.; Lee, Kyeong-Min; Lee, In-Kyu; Kim, Jae B. // Diabetes;Jun2007 Supplement 1, Vol. 56, pA409 

    Liver X receptor (LXR)-α and LXR-β play important roles in fatty acid metabolism and cholesterol homeostasis. Although the function of LXR in the liver, intestine, fat, and macrophage is well established, its role in the pancreatic β-cell has not been clearly defined. In this study, we...

  • Enhancement of GSIS by Oleate Requires Increased LC-CoA, Ca2+, and PKC Activity. Yaney, Gordon; Corkey, Richard; Terala, Deepti; Kirber, Michael // Diabetes;Jun2007 Supplement 1, Vol. 56, pA433 

    Lipids are essential for normal glucose-stimulated insulin release (GSIS). Islets depleted of triglyceride stores exhibit markedly reduced GSIS when assayed in vitro. This defect is corrected by the addition of exogenous free fatty acids (FFA). Paradoxically, chronic elevation of serum FFA also...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics