Glutamate Acts as a Key Signal Linking Glucose Metabolism to Incretin/cAMP Action to Amplify Insulin Secretion

• DOI: 10.1016/j.celrep.2014.09.030
• Publication Date: 2014-10-16T15:46:04Z
• Authors: Ghupurjan Gheni; Masahito Ogura; Masahiro Iwasaki; Norihide Yokoi; Kohtaro Minami; Yasumune Nakayama; Kazuo Harada; Benoit Hastoy; Xichen Wu; Harumi Takahashi; Kazushi Kimura; Toshiya Matsubara; Ritsuko Hoshikawa; Naoya Hatano; Kenji Sugawara; Tadao Shibasaki; Nobuya Inagaki; Takeshi Bamba; Akira Mizoguchi; Eiichiro Fukusaki; Patrik Rorsman; Susumu Seino
• Keywords: Male; Cytoplasm; QH301-705.5; Glutamic Acid; Incretins; Article; Exocytosis; Mice; 03 medical and health sciences; Cell Line, Tumor; Insulin-Secreting Cells; Cyclic AMP; Animals; Insulin; Biology (General); Rats, Wistar; Cells, Cultured; 2. Zero hunger; 0303 health sciences; Secretory Vesicles; Cyclic AMP-Dependent Protein Kinases; Rats; Glucose; Metabolome; Signal Transduction

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.