Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice.
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.


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.
Tan
Carina P
CP
Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, New Jersey, USA.
Feng
Yue
Y
Zhou
Yun-Ping
YP
Eiermann
George J
GJ
Petrov
Aleksandr
A
Zhou
Changyou
C
Lin
Songnian
S
Salituro
Gino
G
Meinke
Peter
P
Mosley
Ralph
R
Akiyama
Taro E
TE
Einstein
Monica
M
Kumar
Sanjeev
S
Berger
Joel P
JP
Mills
Sander G
SG
Thornberry
Nancy A
NA
Yang
Lihu
L
Howard
Andrew D
AD
D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism / Q000473:pathology; D004041:Dietary Fats / Q000008:administration & dosage; D005227:Fatty Acids / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000502:physiology
D001786:Blood Glucose; D004041:Dietary Fats; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D015544:Inositol 1,4,5-Trisphosphate