Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40.
Diabetes, a disease in which carbohydrate and lipid metabolism are regulated improperly by insulin, is a serious worldwide health issue. Insulin is secreted from pancreatic beta cells in response to elevated plasma glucose, with various factors modifying its secretion. Free fatty acids (FFAs) provide an important energy source as nutrients, and they also act as signalling molecules in various cellular processes, including insulin secretion. Although FFAs are thought to promote insulin secretion in an acute phase, this mechanism is not clearly understood. Here we show that a G-protein-coupled receptor, GPR40, which is abundantly expressed in the pancreas, functions as a receptor for long-chain FFAs. Furthermore, we show that long-chain FFAs amplify glucose-stimulated insulin secretion from pancreatic beta cells by activating GPR40. Our results indicate that GPR40 agonists and/or antagonists show potential for the development of new anti-diabetic drugs.
Itoh
Yasuaki
Y
Discovery Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd, Wadai 10, Tsukuba, Ibaraki 300-4293, Japan.
Kawamata
Yuji
Y
Harada
Masataka
M
Kobayashi
Makoto
M
Fujii
Ryo
R
Fukusumi
Shoji
S
Ogi
Kazuhiro
K
Hosoya
Masaki
M
Tanaka
Yasuhiro
Y
Uejima
Hiroshi
H
Tanaka
Hideyuki
H
Maruyama
Minoru
M
Satoh
Rie
R
Okubo
Shoichi
S
Kizawa
Hideki
H
Komatsu
Hidetoshi
H
Matsumura
Fumika
F
Noguchi
Yuko
Y
Shinohara
Tokuyuki
T
Hinuma
Shuji
S
Fujisawa
Yukio
Y
Fujino
Masahiko
M
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D010179:Pancreas / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D014162:Transfection
C473034:FFAR1 protein, human; D005230:Fatty Acids, Nonesterified; C473036:Ffar1 protein, mouse; C473035:G-protein-coupled receptor 40, rat; D007328:Insulin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose; D002118:Calcium