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

Gheni, Ghupurjan; Ogura, Mariko; Iwasaki, Masanori; Yokoi, Norihide; Minami, Kohtaro; Nakayama, Yasumune; Harada, Kaoru; Hastoy, Benoît; Wu, Xi-Chen; Takahashi, Harumi; Kimura, Kei; Matsubara, Toshiya; Hoshikawa, Ritsuko; Hatano, Naoya; Sugawara, Kenji; Shibasaki, Tadao; Inagaki, Nobuya; Bamba, Takeshi; Mizoguchi, Akira; Fukusaki, Eiichiro; Rorsman, Patrik

doi:10.1016/j.celrep.2014.09.030

Cited by 138 publications

(160 citation statements)

References 62 publications

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“…The EGCG inhibition was associated with reduced glutamate levels, substantiating the cataplerotic activity upon glucose stimulation in human islets. Glutamate is the GDH cataplerotic product required for amplifying glucose-stimulated insulin exocytosis (Gheni et al, 2014;Maechler and Wollheim, 1999). When reverse anaplerotic activity of GDH was imposed in both mouse and human islets by the combination of glutamine + BCH, EGCG decreased insulin release, confirming previous observations in rat islets.…”

Section: Discussionsupporting

confidence: 82%

Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?

Pournourmohammadi

Grimaldi

Stridh

et al. 2017

The International Journal of Biochemistry & Cell Biology

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a b s t r a c tGlucose homeostasis is determined by insulin secretion from the ß-cells in pancreatic islets and by glucose uptake in skeletal muscle and other insulin target tissues. While glutamate dehydrogenase (GDH) senses mitochondrial energy supply and regulates insulin secretion, its role in the muscle has not been elucidated. Here we investigated the possible interplay between GDH and the cytosolic energy sensing enzyme 5 -AMP kinase (AMPK), in both isolated islets and myotubes from mice and humans. The green tea polyphenol epigallocatechin-3-gallate (EGCG) was used to inhibit GDH. Insulin secretion was reduced by EGCG upon glucose stimulation and blocked in response to glutamine combined with the allosteric GDH activator BCH (2-aminobicyclo-[2,2,1] heptane-2-carboxylic acid). Insulin secretion was similarly decreased in islets of mice with ß-cell-targeted deletion of GDH (ßGlud1 −/− ). EGCG did not further reduce insulin secretion in the mutant islets, validating its specificity. In human islets, EGCG attenuated both basal and nutrient-stimulated insulin secretion. Glutamine/BCH-induced lowering of AMPK phosphorylation did not operate in ßGlud1 −/− islets and was similarly prevented by EGCG in control islets, while high glucose systematically inactivated AMPK. In mouse C2C12 myotubes, like in islets, the inhibition of AMPK following GDH activation with glutamine/BCH was reversed by EGCG. Stimulation of GDH in primary human myotubes caused lowering of insulin-induced 2-deoxy-glucose uptake, partially counteracted by EGCG. Thus, mitochondrial energy provision through anaplerotic input via GDH influences the activity of the cytosolic energy sensor AMPK. EGCG may be useful in obesity by resensitizing insulin-resistant muscle while blunting hypersecretion of insulin in hypermetabolic states.

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Section: Discussionsupporting

confidence: 82%

Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?

Pournourmohammadi

Grimaldi

Stridh

et al. 2017

The International Journal of Biochemistry & Cell Biology

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“…Indeed, independent research groups reported glutamate uptake by insulin vesicles, rendering these granules exocytosis competent [2]. Interestingly, a recent study demonstrated that the action of glutamate is stimulated by cAMP, a second messenger induced by GLP-1, thereby unifying two signals controlling insulin secretion in pancreatic b-cells [8].…”

Section: 2mentioning

confidence: 99%

Glutamate pathways of the beta-cell and the control of insulin secretion

Maechler

2017

Diabetes Research and Clinical Practice

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InsulinGlucose Glutamate A B S T R A C T Pancreatic beta-cells secrete insulin in response to circulating glucose, thereby maintaining euglycemia. Inside the beta-cell, glucose is transformed into intracellular signals stimulating exocytosis. While calcium is an obligatory messenger, this ion is not sufficient to promote the full secretory response. Accordingly, glucose metabolism produces the additive factor glutamate that participates to an amplifying pathway of the calcium signal.Although intracellular glutamate potentiates insulin secretion, extracellular glutamate may activate ionotropic receptors. As a consequence of such activation, insulin exocytosis is slowed down. Therefore, for the beta-cell glutamate is a double-edged sword, an amplifying pathway and a negative feedback, illustrating the principle of homeostasis.

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“…Finally, the presence of depolarising agents and the allosteric K ATP channel activator diazoxide can further enhance insulin secretion in response to glucose [16]. As a result, additional factors that drive metabolism-dependent secretion, such as mitochondrial metabolites (NADPH, GTP, phosphoenol pyruvate [PEP], α-ketoglutarate [α-KG]), and other secondary glucose-derived metabolites such as glutamate [17,18] must exist.…”

Section: Introductionmentioning

confidence: 99%

LKB1 couples glucose metabolism to insulin secretion in mice

Robitaille

Faubert

et al. 2015

Diabetologia

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Aims/hypothesis Precise regulation of insulin secretion by the pancreatic beta cell is essential for the maintenance of glucose homeostasis. Insulin secretory activity is initiated by the stepwise breakdown of ambient glucose to increase cellular ATP via glycolysis and mitochondrial respiration. Knockout of Lkb1, the gene encoding liver kinase B1 (LKB1) from the beta cell in mice enhances insulin secretory activity by an undefined mechanism. Here, we sought to determine the molecular basis for how deletion of Lkb1 promotes insulin secretion. Methods To explore the role of LKB1 on individual steps in the insulin secretion pathway, we used mitochondrial functional analyses, electrophysiology and metabolic tracing coupled with by gas chromatography and mass spectrometry. Results Beta cells lacking LKB1 surprisingly display impaired mitochondrial metabolism and lower ATP levels following glucose stimulation, yet compensate for this by upregulating both uptake and synthesis of glutamine, leading to increased production of citrate. Furthermore, under low glucose conditions, Lkb1 −/− beta cells fail to inhibit acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in lipid synthesis, and consequently accumulate NEFA and display increased membrane excitability. Conclusions/interpretation Taken together, our data show that LKB1 plays a critical role in coupling glucose metabolism to insulin secretion, and factors in addition to ATP act as coupling intermediates between feeding cues and secretion. Our data suggest that beta cells lacking LKB1 could be used as a system to identify additional molecular events that connect metabolism to cellular excitation in the insulin secretion pathway.

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

Cited by 138 publications

References 62 publications

Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?

Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?

Glutamate pathways of the beta-cell and the control of insulin secretion

LKB1 couples glucose metabolism to insulin secretion in mice

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