TY - JOUR
T1 - Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion
AU - Gheni, Ghupurjan
AU - Ogura, Masahito
AU - Iwasaki, Masahiro
AU - Yokoi, Norihide
AU - Minami, Kohtaro
AU - Nakayama, Yasumune
AU - Harada, Kazuo
AU - Hastoy, Benoit
AU - Wu, Xichen
AU - Takahashi, Harumi
AU - Kimura, Kazushi
AU - Matsubara, Toshiya
AU - Hoshikawa, Ritsuko
AU - Hatano, Naoya
AU - Sugawara, Kenji
AU - Shibasaki, Tadao
AU - Inagaki, Nobuya
AU - Bamba, Takeshi
AU - Mizoguchi, Akira
AU - Fukusaki, Eiichiro
AU - Rorsman, Patrik
AU - Seino, Susumu
N1 - Funding Information:
We thank D. Accili, F.M. Ashcroft, and G.I. Bell for critical readings of the manuscript and insightful suggestions. We also thank R.H. Edwards and Y. Moriyama for providing VGLUT1 knockout mice and anti-VGLUT1 antibody, respectively, and S. Uehara and T.N. Haase for help with animal and knockdown experiments. We are grateful to M. Iizuka, S. Hidaka, H. Kitanoya, M. Hashim, C. Seki, and T. Yamaguchi for their technical assistance, and G.K. Honkawa for assistance in preparing the manuscript. This study was supported by a CREST grant from the Japan Science and Technology Agency ; Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sport, Science and Technology, Japan ; the Wellcome Trust ; and the Canada Institutes of Health Research . This study was also supported in part by research grants from MSD K.K. and Novo Nordisk Pharma .
Publisher Copyright:
© 2014 The Authors.
PY - 2014
Y1 - 2014
N2 - Incretins, hormones released by the gut after meal ingestion, are essential for maintaining systemic glucose homeostasis by stimulating insulin secretion. The effect of incretins on insulin secretion occurs only at elevated glucose concentrations and is mediated by cAMP signaling, but the mechanism linking glucose metabolism and cAMP action in insulin secretion is unknown. We show here, using a metabolomics-based approach, that cytosolic glutamate derived from the malate-aspartate shuttle upon glucose stimulation underlies the stimulatory effect of incretins and that glutamate uptake into insulin granules mediated by cAMP/ PKA signaling amplifies insulin release. Glutamate production is diminished in an incretin-unresponsive, insulin-secreting β cell line and pancreatic islets of animal models of human diabetes and obesity. Conversely, a membrane-permeable glutamate precursor restores amplification of insulin secretion in these models. Thus, cytosolic glutamate represents the elusive link between glucose metabolism and cAMP action in incretin-induced insulin secretion.
AB - Incretins, hormones released by the gut after meal ingestion, are essential for maintaining systemic glucose homeostasis by stimulating insulin secretion. The effect of incretins on insulin secretion occurs only at elevated glucose concentrations and is mediated by cAMP signaling, but the mechanism linking glucose metabolism and cAMP action in insulin secretion is unknown. We show here, using a metabolomics-based approach, that cytosolic glutamate derived from the malate-aspartate shuttle upon glucose stimulation underlies the stimulatory effect of incretins and that glutamate uptake into insulin granules mediated by cAMP/ PKA signaling amplifies insulin release. Glutamate production is diminished in an incretin-unresponsive, insulin-secreting β cell line and pancreatic islets of animal models of human diabetes and obesity. Conversely, a membrane-permeable glutamate precursor restores amplification of insulin secretion in these models. Thus, cytosolic glutamate represents the elusive link between glucose metabolism and cAMP action in incretin-induced insulin secretion.
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U2 - 10.1016/j.celrep.2014.09.030
DO - 10.1016/j.celrep.2014.09.030
M3 - Article
C2 - 25373904
AN - SCOPUS:84919685379
SN - 2211-1247
VL - 9
SP - 661
EP - 673
JO - Cell Reports
JF - Cell Reports
IS - 2
ER -
