3-Ketoglutarate generation in pancreatic B-cell mitochondria regulates insulin secretory action of amino acids and 2-keto acids

Lenzen, Sigurd; Schmidt, Wolfgang E.; Rustenbeck, Ingo; Panten, U.

doi:10.1007/bf01115002

Cited by 42 publications

(37 citation statements)

References 19 publications

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“…Our study is consistent with previous studies in which KIC-SIS was found to be blunted by transaminase inhibitors (17,18,20) and strongly supports the notion that ␣-KG generation by BCATm-catalyzed transamination of KIC/glutamate and GDH-catalyzed glutamate oxidation, which is activated by leucine, is important for KICSIS (17,20,21). It has been reported that KIC and KC, the transamination products of leucine and norleucine, respectively, stimulate insulin secretion with equal potency, whereas KMV, the transamination product of isoleucine, is a much weaker secretagogue, and KIV, the transamination product of valine, is not a secretagogue (4,9,34).…”

Section: Discussionsupporting

confidence: 82%

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Transamination Is Required for α-Ketoisocaproate but Not Leucine to Stimulate Insulin Secretion*

Zhou

Jetton

Goshorn

et al. 2010

Journal of Biological Chemistry

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It remains unclear how ␣-ketoisocaproate (KIC) and leucine are metabolized to stimulate insulin secretion. Mitochondrial BCATm (branched-chain aminotransferase) catalyzes reversible transamination of leucine and ␣-ketoglutarate to KIC and glutamate, the first step of leucine catabolism. We investigated the biochemical mechanisms of KIC and leucine-stimulated insulin secretion (KICSIS and LSIS, respectively) using Although leucine oxidation and KIC transamination were blocked in BCATm ؊/؊ islets, KIC oxidation was unaltered.These data indicate that KICSIS requires transamination of KIC and glutamate to leucine and ␣-ketoglutarate, respectively. LSIS does not require leucine catabolism and may be through leucine activation of glutamate dehydrogenase. Thus, KICSIS and LSIS occur by enhancing the metabolism of glutamine/glutamate to ␣-ketoglutarate, which, in turn, is metabolized to produce the intracellular signals such as ATP and NADPH for insulin secretion.To maintain glucose homeostasis in response to a meal, insulin secretion is precisely stimulated by nutrients such as glucose, amino acids, and free fatty acids as well as incretin hormones such as glucagon-like peptide-1. Nutrients are thought to stimulate insulin secretion through metabolic secretion coupling to generate metabolic signals, i.e. second messengers or coupling factors. Extensive research has been conducted to determine how nutrients are metabolized to generate these coupling factors, e.g. ATP and NADPH. Although leucine and ␣-ketoisocaproate (KIC) 3 are potent insulin secretagogues (1), the underlying mechanisms of leucine and KIC-stimulated insulin secretion (LSIS and KICSIS, respectively) remain elusive. A key question is whether their oxidative decarboxylation is required for induction of insulin secretion.

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Section: Discussionsupporting

confidence: 82%

“…These studies address the possible importance of ␣-KG formation via BCATm and perhaps GDH for KICSIS. In fact, the same group who proposed the catabolism mechanism later reported that intramitochondrial ␣-KG generation may regulate the insulin secretory potency of leucine and KIC (21).…”

mentioning

confidence: 99%

Transamination Is Required for α-Ketoisocaproate but Not Leucine to Stimulate Insulin Secretion*

Zhou

Jetton

Goshorn

et al. 2010

Journal of Biological Chemistry

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“…Downstream of mitochondrial activation, glutamate might play a role in exocytosis, together with permissive cytosolic Ca 2+ levels, by acting on secretory granules [13,17,49,50]. Principally, GDH is also considered important for its anaplerotic function, mediating deamination of glutamate to α-ketoglutarate [51]. Therefore, in pancreatic beta cells, the preferred directional flux of the enzyme is still under discussion [16,29,30,31,52], depending both on stimulation conditions and allosteric regulation.…”

Section: Discussionmentioning

confidence: 99%

Insulin secretion profiles are modified by overexpression of glutamate dehydrogenase in pancreatic islets

Carobbio¹,

Ishihara²,

Fernández-Pascual

et al. 2004

Diabetologia

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Aims/hypothesis. Glutamate dehydrogenase (GDH) is a mitochondrial enzyme playing a key role in the control of insulin secretion. However, it is not known whether GDH expression levels in beta cells are ratelimiting for the secretory response to glucose. GDH also controls glutamine and glutamate oxidative metabolism, which is only weak in islets if GDH is not allosterically activated by L-leucine or (+/−)-2-aminobicyclo-[2,2,1]heptane-2-carboxylic acid (BCH). Methods. We constructed an adenovirus encoding for GDH to overexpress the enzyme in the beta-cell line INS-1E, as well as in isolated rat and mouse pancreatic islets. The secretory responses to glucose and glutamine were studied in static and perifusion experiments. Amino acid concentrations and metabolic parameters were measured in parallel.Results. GDH overexpression in rat islets did not change insulin release at basal or intermediate glucose (2.8 and 8.3 mmol/l respectively), but potentiated the secretory response at high glucose concentrations (16.7 mmol/l) compared to controls (+35%). Control islets exposed to 5 mmol/l glutamine at basal glucose did not increase insulin release, unless BCH was added with a resulting 2.5-fold response. In islets overexpressing GDH glutamine alone stimulated insulin secretion (2.7-fold), which was potentiated 2.2-fold by adding BCH. The secretory responses evoked by glutamine under these conditions correlated with enhanced cellular metabolism. Conclusions/interpretation. GDH could be rate-limiting in glucose-induced insulin secretion, as GDH overexpression enhanced secretory responses. Moreover, GDH overexpression made islets responsive to glutamine, indicating that under physiological conditions this enzyme acts as a gatekeeper to prevent amino acids from being inappropriate efficient secretagogues. [Diabetologia (2004) 47:266-276]

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“…Thus, without BCATm in liver, leucine will be spared from so-called "first-pass" metabolism. As mentioned in the previous studies (47,50), the lack of effect of norleucine on insulin secretion suggests that different mechanisms may be responsible for the effects of BCAA/␣-keto acids in islet cells [e.g., described by Xu et al (70)] and other peripheral tissues. Future studies will be required to determine whether leucine and/or ␣-ketoisocaproate mediate these effects and for a complete understanding of the complex signaling pathways that mediate the effects of the nutritional signaling molecules.…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats

Lynch

Hutson

Patson

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

118

102

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Acute administration of leucine and norleucine activates the mammalian target of rapamycin (mTOR) cell-signaling pathway and increases rates of protein synthesis in a number of tissues in fasted rats. Although persistent stimulation of mTOR signaling is thought to increase protein synthetic capacity, little information is available concerning the effects of chronic administration of these agonists on protein synthesis, mTOR signal transduction, or leucine metabolism. Hence, we developed a model of chronic leucine/norleucine supplementation via drinking water and examined the effects of chronic (12 days) supplementation on protein synthesis in adipose tissue, kidney, heart, liver, and skeletal muscle from ad libitum-fed rats. The relative concentration of proteins involved in mTOR signaling and the two initial steps in leucine oxidation were also examined. Leucine or norleucine supplementation was accompanied by increased rates of protein synthesis in adipose tissue, liver, and skeletal muscle, but not in heart or kidney. Supplementation was not associated with increases in the anabolic hormones insulin or insulin-like growth factor I. Chronic supplementation did not cause apparent adaptation in either components of the mTOR cell-signaling pathway that respond to leucine (mTOR, ribosomal protein S6 kinase, and eukaryotic initiation factor 4E-binding protein-1) or the first two steps in leucine metabolism (the mitochondrial isoform of branched-chain amino acid transaminase, branched-chain keto acid dehydrogenase, and branched-chain keto acid dehydrogenase kinase), which may be involved in terminating the signal from leucine. These results suggest that provision of leucine or norleucine supplementation via the drinking water results in stimulation of postprandial protein synthesis in adipose tissue, skeletal muscle, and liver without notable adaptive changes in signaling proteins or metabolic enzymes.

show abstract

3-Ketoglutarate generation in pancreatic B-cell mitochondria regulates insulin secretory action of amino acids and 2-keto acids

Cited by 42 publications

References 19 publications

Transamination Is Required for α-Ketoisocaproate but Not Leucine to Stimulate Insulin Secretion*

Transamination Is Required for α-Ketoisocaproate but Not Leucine to Stimulate Insulin Secretion*

Insulin secretion profiles are modified by overexpression of glutamate dehydrogenase in pancreatic islets

Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats

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