The role of phosphoenolpyruvate in insulin secretion: the effect of L-phenylalanine

Chatterton, Tracey A.; Reynolds, Charles H.; Lazarus, Norman R.; Pogson, Christopher I.

doi:10.1007/bf01951926

Cited by 3 publications

(3 citation statements)

References 30 publications

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“…The present study supports previous observations that Phe has no effect on glucose-stimulated insulin release (Chatterton et al 1984, Landgraf et al 1974, Panten & Langer 1981, but is extended to demonstrate a small effect of this amino acid in the presence of Gln (Table I). This effect is, however, unlikely to be mediated by an activation of islet glutamate dehydrogenase activity since Phe neither in the present (Table z), nor in a previous (Panten & Langer 1981) study, affected islet GDH activity.…”

Section: Discussionsupporting

confidence: 92%

“…I n the present study we have studied the effects of L-phenylalanine, and L-serine and their methyl ester derinatives on insulin release and islet GDH activity. L-Phenylalanine was studied because most investigations suggest it has no effect on insulin release (Chatterton et al 1984, Landgraf et al 1974, Panten Langer 1981 , Panten & Langer 1981. We reasoned that if L-phenylalanine methyl ester stimulated insulin release and islet GDH activity, it would strongly support the hypothesis that a signal for insulin release might be derived from the activation of this enzyme.…”

mentioning

confidence: 99%

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Potentiation of insulin release in response to amino acid methyl esters correlates to activation of islet glutamate dehydrogenase activity

Kofod

Lernmark

Hedeskov

1986

Acta Physiologica Scandinavica

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Column perifusion of mouse pancreatic islets was used to study the ability of amino acids and their methyl esters to influence insulin release and activate islet glutamate dehydrogenase activity. In the absence of L-glutamine, L-serine and the methyl ester of L-phenylalanine, but neither L-phenylalanine nor L-serine methyl ester, stimulate insulin secretion. In the presence of L-glutamine, however, the effect of L-serine was additive, while the methyl esters of L-serine and L-phenylalanine as well as native L-phenylalanine, potentiated the glucose-stimulated release of insulin. Measurements of islet glutamate dehydrogenase activity showed that only the two methyl esters of L-phenylalanine and L-serine activated the enzyme. It is concluded that the mechanism by which methyl esters of amino acids potentiate insulin release is most likely to be mediated by the activation of pancreatic beta-cell glutamate dehydrogenase activity.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Potentiation of insulin release in response to amino acid methyl esters correlates to activation of islet glutamate dehydrogenase activity

Kofod

Lernmark

Hedeskov

1986

Acta Physiologica Scandinavica

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“…However, the emphasis on PEP as a second messenger waned upon the reports of K ATP -dependent insulin secretion and that PEPCK (at least PEPCK-C) was not present in islets (13, 55). Furthermore, although phenylalanine nearly doubled PEP levels, it did not increase GSIS, suggesting cytosolic PEP per se was not sufficient to augment insulin release (56). In agreement, overexpression of Escherichia coli PEPCK in the cytosol of islets actually reduced glucose-stimulated increases in insulin synthesis (secretion was not measured) (57).…”

Section: Discussionmentioning

confidence: 99%

Phosphoenolpyruvate Cycling via Mitochondrial Phosphoenolpyruvate Carboxykinase Links Anaplerosis and Mitochondrial GTP with Insulin Secretion

Stark

Pasquel

Turcu

et al. 2009

Journal of Biological Chemistry

135

159

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Pancreatic β-cells couple the oxidation of glucose to the secretion of insulin. Apart from the canonical KATP-dependent glucose-stimulated insulin secretion (GSIS), there are important KATP-independent mechanisms involving both anaplerosis and mitochondrial GTP (mtGTP). How mtGTP that is trapped within the mitochondrial matrix regulates the cytosolic calcium increases that drive GSIS remains a mystery. Here we have investigated whether the mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) is the GTPase linking hydrolysis of mtGTP made by succinyl-CoA synthetase (SCS-GTP) to an anaplerotic pathway producing phosphoenolpyruvate (PEP). Although cytosolic PEPCK (PEPCK-C) is absent, PEPCK-M message and protein were detected in INS-1 832/13 cells, rat islets, and mouse islets. PEPCK enzymatic activity is half that of primary hepatocytes and is localized exclusively to the mitochondria. Novel 13C-labeling strategies in INS-1 832/13 cells and islets measured substantial contribution of PEPCK-M to the synthesis of PEP. As high as 30% of PEP in INS-1 832/13 cells and 41% of PEP in rat islets came from PEPCK-M. The contribution of PEPCK-M to overall PEP synthesis more than tripled with glucose stimulation. Silencing the PEPCK-M gene completely inhibited GSIS underscoring its central role in mitochondrial metabolism-mediated insulin secretion. Given that mtGTP synthesized by SCS-GTP is an indicator of TCA flux that is crucial for GSIS, PEPCK-M is a strong candidate to link mtGTP synthesis with insulin release through anaplerotic PEP cycling.

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Ingestion of Leucine + Phenylalanine with Glucose Produces an Additive Effect on Serum Insulin but Less than Additive Effect on Plasma Glucose

Iverson

Gannon

Nuttall

2013

Journal of Amino Acids

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Most individual amino acids stimulate insulin secretion and attenuate the plasma glucose response when ingested with glucose. We determined whether ingestion of two amino acids simultaneously with glucose would result in an additive effect on the glucose area response compared with ingestion of amino acids individually. Leucine and phenylalanine were chosen because they were two of the most potent glucose-lowering amino acids when given individually. Eight healthy subjects were studied on four separate days. Test meals were given at 0800. The first meal was a water control. Subjects then received 25 g glucose or leucine + phenylalanine (1 mmol/kg fat free body mass each) ±25 g glucose in random order. Glucose, insulin and glucagon were measured frequently for 2.5 hours thereafter. Net areas under the curves were calculated using the mean fasting value as baseline. The insulin response to leucine + phenylalanine was additive. In contrast, the decrease in glucose response to leucine + phenylalanine + glucose was less than additive compared to the individual amino acids ingested with glucose. Interestingly, the insulin response to the combination was largely due to the leucine component, whereas the glucose response was largely due to the phenylalanine component. Glucose was unchanged when leucine or phenylalanine, alone or in combination, was ingested without glucose. This trial is registered with ClinicalTrials.gov NCT01471509.

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The role of phosphoenolpyruvate in insulin secretion: the effect of L-phenylalanine

Cited by 3 publications

References 30 publications

Potentiation of insulin release in response to amino acid methyl esters correlates to activation of islet glutamate dehydrogenase activity

Potentiation of insulin release in response to amino acid methyl esters correlates to activation of islet glutamate dehydrogenase activity

Phosphoenolpyruvate Cycling via Mitochondrial Phosphoenolpyruvate Carboxykinase Links Anaplerosis and Mitochondrial GTP with Insulin Secretion

Ingestion of Leucine + Phenylalanine with Glucose Produces an Additive Effect on Serum Insulin but Less than Additive Effect on Plasma Glucose

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