Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase
ABSTRACT Insulin secretion by pancreatic beta-cells is stimulated by glucose, amino acids, and other metabolic fuels. Glutamate dehydrogenase (GDH) has been shown to play a regulatory role in this process. The importance of GDH was underscored by features of hyperinsulinemia/hyperammonemia syndrome, where a dominant mutation causes the loss of inhibition by GTP and ATP. Here we report the effects of green tea polyphenols on GDH and insulin secretion. Of the four compounds tested, epigallocatechin gallate (EGCG) and epicatechin gallate were found to inhibit GDH with nanomolar ED(50) values and were therefore found to be as potent as the physiologically important inhibitor GTP. Furthermore, we have demonstrated that EGCG inhibits BCH-stimulated insulin secretion, a process that is mediated by GDH, under conditions where GDH is no longer inhibited by high energy metabolites. EGCG does not affect glucose-stimulated insulin secretion under high energy conditions where GDH is probably fully inhibited. We have further shown that these compounds act in an allosteric manner independent of their antioxidant activity and that the beta-cell stimulatory effects are directly correlated with glutamine oxidation. These results demonstrate that EGCG, much like the activator of GDH (BCH), can facilitate dissecting the complex regulation of insulin secretion by pharmacologically modulating the effects of GDH.
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ABSTRACT: Amino acids not only participate in intermediary metabolism but also stimulate insulin-mechanistic target of rapamycin (MTOR)-mediated signal transduction which controls the major metabolic pathways. Among these is the pathway of autophagy which takes care of the degradation of long-lived proteins and of the elimination of damaged or functionally redundant organelles. Proper functioning of this process is essential for cell survival. Dysregulation of autophagy has been implicated in the etiology of several pathologies. The history of the studies on the interrelationship between amino acids, MTOR signaling and autophagy is the subject of this review. The mechanisms responsible for the stimulation of MTOR-mediated signaling, and the inhibition of autophagy, by amino acids have been studied intensively in the past but are still not completely clarified. Recent developments in this field are discussed.Amino Acids 06/2014; DOI:10.1007/s00726-014-1765-4 · 3.65 Impact Factor
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ABSTRACT: Results from epidemiological studies indicated that there exists an inverse correlation between consumption of green tea and neurodegenerative diseases including Parkinson's disease. We hypothesized that consumption of green tea would activate endogenous protective mechanisms against environmental toxin-induced cell injury, which is believed to play a causative role in the etiology of Parkinson's disease. Here, we found that epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, concentration-dependently (1 microM, 3 microM and 10 microM) reduced dichlorodiphenyl-trichloroethane (DDT) (100 microM)-induced cell death in dopaminergic neuroblastoma SHSY-5Y cells. The cell viability was determined by trypan blue exclusion assays. We also found that preconditioning the SHSY-5Y cells with EGCG by multiple, brief, prior exposures of the cells to EGCG can subsequently protect the cells from DDT-induced cell death. The EGCG-induced protective effect positively correlated with the number of exposures to EGCG. These results suggest that EGCG has a protective effect against DDT-induced cell death, and that prior exposures to EGCG activate an endogenous protective mechanism in the dopaminergic cells which can mitigate organochlorine pesticide-induced cell injury.Neuroscience Letters 10/2010; 482(3):183-7. DOI:10.1016/j.neulet.2010.06.018 · 2.06 Impact Factor
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ABSTRACT: The mTORC1-signaling pathway integrates environmental conditions into distinct signals for cell growth by balancing anabolic and catabolic processes. Accordingly, energetic stress inhibits mTORC1 signaling predominantly through AMPK-dependent activation of TSC1/2. Thus, TSC1/2-/- cells are hypersensitive to glucose deprivation, and this has been linked to increased p53 translation and activation of apoptosis. Herein, we show that mTORC1 inhibition during glucose deprivation prevented not only the execution of death, but also induction of energetic stress. mTORC1 inhibition during glucose deprivation decreased AMPK activation and allowed ATP to remain high, which was both necessary and sufficient for protection. This effect was not due to increased catabolic activities such as autophagy, but rather exclusively due to decreased anabolic processes, reducing energy consumption. Specifically, TSC1/2-/- cells become highly dependent on glutamate dehydrogenase-dependent glutamine metabolism via the TCA cycle for survival. Therefore, mTORC1 inhibition during energetic stress is primarily to balance metabolic demand with supply.Molecular cell 05/2010; 38(4):487-99. DOI:10.1016/j.molcel.2010.05.007 · 14.46 Impact Factor