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

Summary

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.

Graphical Abstract

Highlights

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  Glutamate is derived from the malate-aspartate shuttle upon glucose stimulation

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  Shuttle-derived glutamate is crucial for incretin-induced insulin secretion

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  Cytosolic glutamate is transported into insulin granules via cAMP/PKA signaling

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  Glutamate production by glucose is defective in incretin-unresponsive β cells

Abstract

Gheni et al. find that cytosolic glutamate derived from glucose through the malate-aspartate shuttle is the signal underlying incretin-induced insulin secretion. Glutamate uptake into insulin granules mediated by cAMP/PKA signaling amplifies insulin release. Thus, cytosolic glutamate acts as a signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion.