Abstract
SummaryIncretins, 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.
Highlights
We find that cytosolic glutamate derived from the malate-aspartate shuttle upon glucose stimulation is transported into insulin granules by cAMP/protein kinase A (PKA) signaling, which leads to amplification of insulin granule exocytosis
Like primary pancreatic b cells, MIN6-K8 cells secrete insulin in response to both glucose and the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), whereas MIN6K20 cells respond to glucose, but not to the incretins (Figures 1A, S1A, and S1B)
Since incretin-induced insulin secretion is glucose dependent, we considered the possibility that the impaired incretin responsiveness of MIN6-K20 cells results from compromised ‘‘metabolism-cAMP coupling.’’ We addressed this possibility by conducting a metabolome analysis of MIN6-K8 and MIN6-K20 cells stimulated by glucose (16.7 mM) (Table S1)
Summary
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. Cytosolic glutamate acts as a signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion.
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