Overexpression of GPR40 in pancreatic beta-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice.
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.


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.
Nagasumi
Kae
K
Pharmaceutical Research Division, Pharmacology [corrected] Research Laboratories I, Takeda Pharmaceutical Company Limited, Osaka, Japan. nagasumi_kae@takeda.co.jp
Esaki
Ritsuko
R
Iwachidow
Kimihiko
K
Yasuhara
Yoshitaka
Y
Ogi
Kazuhiro
K
Tanaka
Hideyuki
H
Nakata
Mitsugu
M
Yano
Takashi
T
Shimakawa
Kozo
K
Taketomi
Shigehisa
S
Takeuchi
Koji
K
Odaka
Hiroyuki
H
Kaisho
Yoshihiko
Y
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000502:physiology; D012016:Reference Values
D001786:Blood Glucose; D017931:DNA Primers; C106262:FFAR3 protein, human; D005230:Fatty Acids, Nonesterified; C473036:Ffar1 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D012313:RNA; D005947:Glucose