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Cell Rep. 2014 Oct 23;9(2):661-73. doi: 10.1016/j.celrep.2014.09.030. Epub 2014 Oct 16.

Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion.

Author information

1
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.
2
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.
3
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
4
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.
5
Department of Biotechnology, Graduate School of Engineering, Osaka University, Yamadaoka, Suita 565-0871, Japan.
6
Applied Environmental Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita 565-0871, Japan.
7
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
8
Alberta Diabetes Institute, University of Alberta, Faculty of Medicine & Dentistry, Edmonton, AB T6G 2E1, Canada.
9
Department of Neural Regeneration and Cell Communication, Mie University Graduate School of Medicine, Edobashi, Tsu 514-8507, Japan.
10
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.
11
The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
12
Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
13
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.

Abstract

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.

PMID:
25373904
PMCID:
PMC4536302
DOI:
10.1016/j.celrep.2014.09.030
[Indexed for MEDLINE]
Free PMC Article

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