Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.celrep.2014.09.030

Type

Journal article

Journal

Cell Rep

Publication Date

23/10/2014

Volume

9

Pages

661 - 673

Keywords

Animals, Cell Line, Tumor, Cells, Cultured, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cytoplasm, Exocytosis, Glucose, Glutamic Acid, Incretins, Insulin, Insulin-Secreting Cells, Male, Metabolome, Mice, Rats, Rats, Wistar, Secretory Vesicles, Signal Transduction