Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion.
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.
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan; Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
Ghupurjan
G
Gheni
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan; Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Masahito
M
Ogura
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
Masahiro
M
Iwasaki
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
Norihide
N
Yokoi
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan; Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
Kohtaro
K
Minami
Department of Biotechnology, Graduate School of Engineering, Osaka University, Yamadaoka, Suita 565-0871, Japan.
Yasumune
Y
Nakayama
Applied Environmental Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita 565-0871, Japan.
Kazuo
K
Harada
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Benoit
B
Hastoy
Alberta Diabetes Institute, University of Alberta, Faculty of Medicine & Dentistry, Edmonton, AB T6G 2E1, Canada.
Xichen
X
Wu
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
Harumi
H
Takahashi
Department of Neural Regeneration and Cell Communication, Mie University Graduate School of Medicine, Edobashi, Tsu 514-8507, Japan.
Kazushi
K
Kimura
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan; Life Science Research Center, Technology Research Laboratory, Shimadzu Corporation, Soraku-gun, Kyoto 619-0237, Japan.
Toshiya
T
Matsubara
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
Ritsuko
R
Hoshikawa
The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
Naoya
N
Hatano
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan; Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
Kenji
K
Sugawara
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan; Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
Tadao
T
Shibasaki
Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Nobuya
N
Inagaki
Department of Biotechnology, Graduate School of Engineering, Osaka University, Yamadaoka, Suita 565-0871, Japan.
Takeshi
T
Bamba
Department of Neural Regeneration and Cell Communication, Mie University Graduate School of Medicine, Edobashi, Tsu 514-8507, Japan.
Akira
A
Mizoguchi
Department of Biotechnology, Graduate School of Engineering, Osaka University, Yamadaoka, Suita 565-0871, Japan.
Eiichiro
E
Fukusaki
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Patrik
P
Rorsman
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan; The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan. Electronic address: seino@med.kobe-u.ac.jp.
Susumu
S
Seino
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005089:Exocytosis; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D054795:Incretins / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D055442:Metabolome; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D022142:Secretory Vesicles / Q000378:metabolism; D015398:Signal Transduction
D054795:Incretins; D007328:Insulin; D018698:Glutamic Acid; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose