Regulation of Hepatic Glutaminase in the Streptozotocin-Induced Diabetic Rat

Sa, Squires; Hs, Ewart; McCarthy, C. F.; Me, Brosnan; Jt, Brosnan

doi:10.2337/diab.46.12.1945

Cited by 12 publications

(6 citation statements)

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“…Type 2 diabetes was pratically without action on the hepatic L-glutamine metabolism with the important exception of L-alanine production which was increased (see below). All these conclusions are opposed to the notions that were drawn from measurements of L-glutamine metabolism in isolated hepatocytes in which the accumulation of metabolites was measured after 30 minutes, i.e., without following the response over the entire incubation time [ 17 , 20 ].…”

Section: Discussionmentioning

confidence: 89%

“…Its activity changes under certain pathological conditions, such as diabetes, for example [ 15 , 16 ]. In streptozotocin-induced diabetic rats (type 1 diabetes), increases of up to 12-fold have been reported [ 17 ]. Consistently, in diabetes, the liver switches from release to net uptake of L-glutamine [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…In accordance to this, an increased L-glutamine utilization was observed in hepatocytes isolated from streptozotocin-induced diabetic rats [ 16 ]. However, the experiments with isolated hepatocytes have been done by measuring either 14 CO 2 accumulation in the presence of L-[ 14 C]glutamine [ 17 ] or glucose accumulation during 30 minutes [ 20 ]. The latter, especially, does not allow to differentiate between glycogenolysis and gluconeogenesis, an important detail if one considers that the fasting glycogen content of livers from type 1 diabetic rats is usually high [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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The Metabolic Responses to L-Glutamine of Livers from Rats with Diabetes Types 1 and 2

et al. 2016

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There are several claims about the beneficial effects of supplementing L-glutamine to both type 1 and type 2 diabetes. The purpose of the present study was to provide detailed knowledge about the fate of this amino acid in the liver, the first organ that receives the compound when ingested orally. The study was done using the isolated perfused rat liver, an experimental system that preserves the microcirculation of the organ and that allows to measured several parameters during steady-state and pre steady-state conditions. L-Glutamine was infused in the portal vein (5 mM) and several parameters were monitored. Livers from type 1 diabetic rats showed an accelerated response to L-glutamine infusion. In consequence of this accelerated response livers from type 1 diabetic rats presented higher rates of ammonia, urea, glucose and lactate output during the first 25–30 minutes following L-glutamine infusion. As steady-state conditions approached, however, the difference between type 1 diabetes and control livers tended to disappear. Measurement of the glycogen content over a period of 100 minutes revealed that, excepting the initial phase of the L-glutamine infusion, the increased glucose output in livers from type 1 diabetic rats was mainly due to accelerated glycogenolysis. Livers from type 2 diabetic rats behaved similarly to control livers with no accelerated glucose output but with increased L-alanine production. L-Alanine is important for the pancreatic β-cells and from this point of view the oral intake of L-glutamine can be regarded as beneficial. Furthermore, the lack of increased glucose output in livers from type 2 diabetic rats is consistent with observations that even daily L-glutamine doses of 30 g do not increase the glycemic levels in well controlled type 2 diabetes patients.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Metabolic Responses to L-Glutamine of Livers from Rats with Diabetes Types 1 and 2

et al. 2016

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“…Feeding rats a high-protein diet for four days is known to increase circulating levels of glucagon in plasma (28) more than threefold. Treatment of isolated hepatocytes with glucagon is known to stimulate the glycine cleavage system (20), glutaminase (36), and phenylalanine oxidation (12). The principal focus of this investigation is to determine whether the catabolism of arginine and ornithine in the perfused rat liver is subject to longterm regulation by the level of dietary protein and/or acute regulation by glucagon.…”

mentioning

confidence: 99%

Catabolism of arginine and ornithine in the perfused rat liver: effect of dietary protein and of glucagon

O'Sullivan

Brosnan

2000

American Journal of Physiology-Endocrinology and Metabolism

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The rates of oxidation of arginine and ornithine that occurred through a reaction pathway involving the enzyme ornithine aminotransferase (EC 2.6.1.13) were determined using (14)C-labeled amino acids in the isolated nonrecirculating perfused rat liver. At physiological concentrations of these amino acids, their catabolism is subject to chronic regulation by the level of protein consumed in the diet. (14)CO(2) production from [U-(14)C]ornithine (0.1 mM) and from [U-(14)C]arginine (0.2 mM) was increased about fourfold in livers from rats fed 60% casein diets for 3-4 days. The catabolism of arginine in the perfused rat liver, but not that of ornithine, is subject to acute regulation by glucagon (10(-7) M), which stimulated arginine catabolism by approximately 40%. Dibutyryl cAMP (0.1 mM) activated arginine catabolism to a similar extent. In retrograde perfusions, glucagon caused a twofold increase in the rate of arginine catabolism, suggesting an effect of glucagon on arginase in the perivenous cells.

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“…However, whether GLS1 contributes to angiogenesis by other stimuli or in other organs remains to be established. Given that GLS activity is elevated in diabetes [63,64], the use of GLS1 inhibitors may provide a novel approach in treating diabetic retinopathy. Finally, neovascularization in atherosclerotic lesions plays a major role in plaque growth by increasing the influx of lipoproteins and leukocytes into the lesion [65].…”

Section: Discussionmentioning

confidence: 99%

Glutaminase-1 stimulates the proliferation, migration, and survival of human endothelial cells

Peyton

Liu

Yan

et al. 2018

Biochemical Pharmacology

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Glutaminase-1 (GLS1) is a mitochondrial enzyme found in endothelial cells (ECs) that metabolizes glutamine to glutamate and ammonia. Although glutaminolysis modulates the function of human umbilical vein ECs, it is not known whether these findings extend to human ECs beyond the fetal circulation. Furthermore, the molecular mechanism by which GLS1 regulates EC function is not defined. In this study, we show that the absence of glutamine in the culture media or the inhibition of GLS1 activity or expression blocked the proliferation and migration of ECs derived from the human umbilical vein, the human aorta, and the human microvasculature. GLS1 inhibition arrested ECs in the G/G phase of the cell cycle and this was associated with a significant decline in cyclin A expression. Restoration of cyclin A expression via adenoviral-mediated gene transfer improved the proliferative, but not the migratory, response of GLS1-inhibited ECs. Glutamine deprivation or GLS1 inhibition also stimulated the production of reactive oxygen species and this was associated with a marked decline in heme oxygenase-1 (HO-1) expression. GLS1 inhibition also sensitized ECs to the cytotoxic effect of hydrogen peroxide and this was prevented by the overexpression of HO-1. In conclusion, the metabolism of glutamine by GLS1 promotes human EC proliferation, migration, and survival irrespective of the vascular source. While cyclin A contributes to the proliferative action of GLS1, HO-1 mediates its pro-survival effect. These results identify GLS1 as a promising therapeutic target in treating diseases associated with aberrant EC proliferation, migration, and viability.

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Regulation of Hepatic Glutaminase in the Streptozotocin-Induced Diabetic Rat

Cited by 12 publications

References 0 publications

The Metabolic Responses to L-Glutamine of Livers from Rats with Diabetes Types 1 and 2

The Metabolic Responses to L-Glutamine of Livers from Rats with Diabetes Types 1 and 2

Catabolism of arginine and ornithine in the perfused rat liver: effect of dietary protein and of glucagon

Glutaminase-1 stimulates the proliferation, migration, and survival of human endothelial cells

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