The stimulus-secretion coupling of glucose-induced insulin release XLVI. Physiological role of l-glutamine as a fuel for pancreatic islets

Malaisse, Willy; Sener, Abdullah; Carpinelli, Ângelo Rafael; Kowluru, Anjaneyulu; Lebrun, Philippe; Herchuelz, André; Christophe, Jean

doi:10.1016/0303-7207(80)90080-5

Cited by 106 publications

(73 citation statements)

References 33 publications

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“…This is in agreement with our observation that glutamate stimulates insulin exocytosis at permissive but not at basal Ca 2ϩ in permeabilized cells (66). Mitochondrial metabolism of glutamine/glutamate and ATP production is only weak in nonstimulated islets (73,77). This is explained by the sluggish conversion of glutamate to ␣-ketoglutarate by glutamate dehydrogenase (73).…”

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confidence: 92%

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β-Cell Mitochondria and Insulin Secretion

Wollheim¹,

Maechler²

2002

Diabetes

107

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The ␤-cell mitochondria are known to generate metabolic coupling factors, or messengers, that mediate plasma membrane depolarization and the increase in cytosolic Ca 2؉ , the triggering event in glucose-stimulated insulin secretion. Accordingly, ATP closes nucleotide-sensitive K ؉ channels necessary for the opening of voltage-gated Ca 2؉ channels. ATP also exerts a permissive action on insulin exocytosis. In contrast, GTP directly stimulates the exocytotic process. cAMP is considered to have a dual function: on the one hand, it renders the ␤-cell more responsive to glucose; on the other, it mediates the effect of glucagon and other hormones that potentiate insulin secretion. Mitochondrial shuttles contribute to the formation of pyridine nucleotides, which may also participate in insulin exocytosis. Among the metabolic factors generated by glucose, citrate-derived malonyl-CoA has been endorsed, but recent results have questioned its role. We have proposed that glutamate, which is also formed by mitochondrial metabolism, stimulates insulin exocytosis in conditions of permissive, clamped cytosolic Ca 2؉ concentrations. The evidence for the implication of these and other putative messengers in metabolism-secretion coupling is discussed in this review. Diabetes 51 (Suppl.

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confidence: 92%

“…Exposure of islets to extracellular glutamine causes a marked increase in their glutamate levels without any increase in insulin secretion (73,74). Glutamine enhances the ion NH 4 ϩ in cells, which has been shown to inhibit insulin release in both mouse and rat islets secondary to intracellular alkalinization (44,75).…”

mentioning

confidence: 99%

β-Cell Mitochondria and Insulin Secretion

Wollheim¹,

Maechler²

2002

Diabetes

107

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“…These results show that normal GDH expression levels in islets are sufficient for intermediate glucose-evoked insulin release, but are rate-limiting for optimal secretory responses to high glucose. Unlike glucose, glutamine poorly stimulates mitochondrial metabolism under normal conditions and as a result, ATP production is only weak in islets with such a stimulus [24,25,54]. Consequently, ATP generation is probably not sufficient to depolarise the plasma membrane through closure of ATP-sensitive K + channels, a process which is required for cytosolic Ca 2+ increase.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, ATP generation is probably not sufficient to depolarise the plasma membrane through closure of ATP-sensitive K + channels, a process which is required for cytosolic Ca 2+ increase. Therefore, islet glutamate levels can be markedly increased by exposure to extracellular glutamine and, because of scarce conversion of glutamate to α-ketoglutarate [24], without stimulation of insulin secretion [24,55]. Activation of GDH by L-leucine or its non-metabolisable analogue BCH increases glutamine oxidation and insulin secretion, essentially by enhancing the oxidative deamination of glutamate [25,27,28,29,32,33,56].…”

Section: Discussionmentioning

confidence: 99%

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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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Experimental study to show that growth hormone treatment before trauma increases glutamine uptake in the intestinal tract

Mjaaland

Unneberg

Jenssen

et al. 1995

Journal of British Surgery

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This study examined whether growth hormone treatment deprived the intestinal tract of glutamine after trauma. Piglets were treated with growth hormone 24 units daily 3 days before and at the start of the trauma (GH-3, n = 8) or at the start of the trauma only (GH-1, n = 8). Eight piglets acted as non-treated controls. The trauma consisted of a standardized abdominal surgical procedure. Primed constant infusions of U-14C-glutamine were given. Intestinal, hepatic, renal and hindleg glutamine fluxes were measured. Growth hormone treatment increased mean(s.e.m.) net intestinal glutamine uptake: GH-3, 39.7(9.4) and 48.7(12.7) mumol/min; GH-1, 33.2(5.5) and 25.7(12.3) mumol/min; controls, 19.5(10.3) and 2.0(15.3) mumol/min at 1 h and 5 h after trauma, respectively, (P = 0.02). The treatment increased glutamine oxidation (P = 0.025), and decreased hindleg glutamine net (P = 0.0052) and absolute release (P = 0.0063), glutamine rate of appearance (P = 0.01), and percentage of glucose coming from glutamine (P = 0.05). Growth hormone treatment before trauma increased intestinal glutamine uptake.

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The stimulus-secretion coupling of glucose-induced insulin release XLVI. Physiological role of l-glutamine as a fuel for pancreatic islets

Cited by 106 publications

References 33 publications

β-Cell Mitochondria and Insulin Secretion

β-Cell Mitochondria and Insulin Secretion

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

Experimental study to show that growth hormone treatment before trauma increases glutamine uptake in the intestinal tract

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