Contribution of hepatic glycogenolysis and gluconeogenesis in the defense against short-term insulin induced hypoglycemia in rats

Nascimento, Katia Fialho do; Garcia, Renata Porto Alegre; Gazola, Vilma A.F.G.; Souza, Helenir Medri de; Obici, Simoni; Bazotte, Roberto Barbosa

doi:10.1016/j.lfs.2008.02.016

Cited by 15 publications

(12 citation statements)

References 24 publications

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“…4) However, there are few studies in the prevention of nocturnal hypoglycemia. 5,6) Because rats show a suitable experimental model to study hypoglycemia [7][8][9][10] and considering the night habits of these animals, nocturnal IIH can be simulated with a diurnal pharmacological dose of Detemir insulin. Moreover, in spite the fact that glutamine dipeptide has been shown effective to promote acute glycemia recovery during long term IIH, 11) its rule to prevent prolonged hypoglycemia was not investigated.…”

Section: )mentioning

confidence: 99%

“…Moreover, in spite the fact that glutamine dipeptide has been shown effective to promote acute glycemia recovery during long term IIH, 11) its rule to prevent prolonged hypoglycemia was not investigated. Thus, by using this rat model [7][8][9][10][11] we investigated if L-alanyl-L-glutamine peptide (glutamine dipeptide) could help against prolonged IIH. The choice of glutamine dipeptide was based in the following facts: 1) glutamine dipeptide results of the combination of the most abundant blood amino acid, i.e., L-glutamine 12) and the most important liver glucose precursor, i.e., L-alanine, 13) 2) very high doses of oral glutamine dipeptide did not show acute or subchronic toxicity, 14) 3) glutamine dipeptide overcomes the intestinal catabolism of Lglutamine, 15) 4) L-alanine from glutamine dipeptide catabolism stimulates the release of glucagon.…”

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confidence: 99%

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Oral Glutamine Dipeptide Prevents against Prolonged Hypoglycemia Induced by Detemir Insulin in Rats

Felisberto-Junior

Manso

Gazola

et al. 2009

Biological & Pharmaceutical Bulletin

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Most episodes of short-term symptomatic hypoglycemia are effectively treated by the ingestion of carbohydrates 1) or glucagon injection.2) However, in spite the fact that glucose and glucagon are very effective to treat short term insulin-induced hypoglycemia (IIH), both antidotes show transitory effect 1,2) and for this reason they are not effective to prevent prolonged IIH. Moreover, patients who receive insulin therapy frequently experience prolonged IIH, particularly nocturnal hypoglycemia that represents 55-75% of severe episodes of IIH. 3)Therefore, for episodes of prolonged IIH during sleep, when the subject is unable to self-treat, new strategies to prevent IIH are necessary. 4) However, there are few studies in the prevention of nocturnal hypoglycemia. 5,6) Because rats show a suitable experimental model to study hypoglycemia [7][8][9][10] and considering the night habits of these animals, nocturnal IIH can be simulated with a diurnal pharmacological dose of Detemir insulin. Moreover, in spite the fact that glutamine dipeptide has been shown effective to promote acute glycemia recovery during long term IIH, 11) its rule to prevent prolonged hypoglycemia was not investigated. Thus, by using this rat model [7][8][9][10][11] we investigated if L-alanyl-L-glutamine peptide (glutamine dipeptide) could help against prolonged IIH. The choice of glutamine dipeptide was based in the following facts: 1) glutamine dipeptide results of the combination of the most abundant blood amino acid, i.e., L-glutamine 12) and the most important liver glucose precursor, i.e., L-alanine, 13) 2) very high doses of oral glutamine dipeptide did not show acute or subchronic toxicity, 14) 3) glutamine dipeptide overcomes the intestinal catabolism of Lglutamine, 15) 4) L-alanine from glutamine dipeptide catabolism stimulates the release of glucagon. 16,17) In addition the contribution of the liver gluconeogenesis from glutamine dipeptide and their metabolites L-alanine and L-glutamine to prevent prolonged hypoglycemia were investigated. Animals Adult male Wistar rats (180-220 g) were maintained on food and water ad libitum before the initiation of experimental procedures. The manipulation of the animals was approved by the ethical committee of the State University of Maringá, PR, Brazil (approval number 042/2006). On the day before the experiment the animals were food deprived from 5:00 p.m. All experiments were performed with overnight fasted rats (5:00 p.m.-9:00 a.m.). MATERIALS AND METHODS MaterialsExperimental Prolonged IIH A preliminary experiment to characterize the prolonged IIH after an intraperitoneal (i.p.) injection of Detemir insulin (1.0 U/kg) was done. Detemir insulin was not diluted but intraperitoneally injected (9:00 a.m.) with help of an infusion pump (Insight The role of glutamine dipeptide (GDP) to prevent against prolonged insulin induced hypoglycemia (IIH) in overnight fasted rats was investigated. The glycemia was measured 0, 2, 4, 8, and 10 h after an intraperitoneal (i.p.) injection (1 U/kg) of Detemir in...

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Section: )mentioning

confidence: 99%

Section: )mentioning

confidence: 99%

Oral Glutamine Dipeptide Prevents against Prolonged Hypoglycemia Induced by Detemir Insulin in Rats

Felisberto-Junior

Manso

Gazola

et al. 2009

Biological & Pharmaceutical Bulletin

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“…This experimental approach discards the influence of hepatic glycogen catabolism, changes in the hepatic blood flux and the variability of blood glucose precursors. 5,12 In contrast with adult hypoglycaemic rats in which the liver glucose production from L-alanine and L-lactate were increased, 22 the glucose production from these gluconeogenic substrates in livers from weaned hypoglycaemic rats was not affected by short-term IIH. On the other hand, like adult rats, 23,24 gluconeogenesis from L-glutamine which enters in this metabolic pathway after the pyruvate carboxylase step and before the phosphoenolpyruvate carboxykinase step 25 markedly rise in livers from shortterm IIH weaned rats.…”

Section: Discussionmentioning

confidence: 97%

“…In keeping with this observation, we have reported an increased rate of liver gluconeogenesis during IIH in adult rats. 11,12 Because, detailed information about hepatic gluconeogenesis in IIH weaned rats is not yet available, and considering that the transition from weaning to adult age is an unfavourable condition for gluconeogenesis 13,14 we investigated some characteristics of the hepatic gluconeogenesis in the perfused liver of weaned rats submitted to short-term IIH. Moreover, to get further information about gluconeogenesis during IIH in weaned rats, the participation …”

Section: Introductionmentioning

confidence: 99%

Evidence that L‐glutamine is better than L‐alanine as gluconeogenic substrate in perfused liver of weaned fasted rats submitted to short‐term insulin‐induced hypoglycaemia

Oliveira-Yamashita

Garcia

Felisberto-Junior

et al. 2008

Cell Biochemistry & Function

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Evidence that L-glutamine is better than L-alanine as gluconeogenic substrate in perfused liver of weaned fasted rats submitted to short-term insulin-induced hypoglycaemia Gluconeogenesis in livers from overnight fasted weaned rats submitted to short-term insulin-induced hypoglycaemia (IIH) was investigated.For this purpose, a condition of hyperinsulinemia/hypoglycaemia was obtained with an intraperitoneal (ip) injection of regular insulin (1.0 U kg À1). Control group (COG group) received ip saline. The studies were performed 30 min after insulin (IIH group) or saline (COG group) injection. The livers from IIH and COG rats were perfused with L-alanine (5 mM), L-lactate (2 mM), L-glutamine (10 mM) or glycerol (2 mM). Hepatic glucose, L-lactate and pyruvate production from L-alanine was not affected by IIH. In agreement with this result, the hepatic ability in producing glucose from L-lactate or glycerol remained unchanged (IIH group vs. COG group). However, livers from IIH rats showed higher glucose production from L-glutamine than livers from COG rats and, in the IIH rats, the production of glucose from L-glutamine was higher than that from L-alanine. The higher glucose production in livers from the IIH group, when compared with the COG group was due to its entrance further on gluconeogenic pathway. Taken together, the results suggest that L-glutamine is better than L-alanine, as gluconeogenic substrate in livers of hypoglyceaemic weaned rats.

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“…[15][16][17][18] The main advantage in comparison with diabetic rats is that normal rats maintain the integrity of the hormonal counter regulatory system and it is possible to study the participation of the liver to prevent the hypoglycemia without the interference caused by the chronic hyperglycemia of diabetic states. 19 By using these fed rats, a favorable condition to study glycogenolysis, 20 we demonstrated that hepatic glycogen concentration, and the basal activities of glycogen phosphorylase and glycogen synthase were not modified during shortterm IIH.…”

Section: Discussionmentioning

confidence: 99%

Liver glycogen metabolism during short‐term insulin‐induced hypoglycemia in fed rats

Obici

Lopes-Bertolini

Curi

et al. 2008

Cell Biochemistry & Function

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The activities of glycogen phosphorylase and synthase during infusions of glucagon, isoproterenol, or cyanide in isolated liver of fed rats submitted to short-term insulin-induced hypoglycemia (IIH) was investigated. A condition of hyperinsulinemia/hypoglycemia was obtained with an intraperitoneal injection of regular insulin (1.0 U kg(-1)). The control group received ip saline. The experiments were carried out 60 min after insulin (IIH group) or saline (COG group) injection. The rats were anesthetized and after laparotomy, blood was collected from the vena cava for glucose and insulin measurements. The liver was then infused with glucagon (1 nM), isoproterenol (2 microM), or cyanide (0.5 mM) during 20 min and a sample of the organ was collected for determination of the activities of glycogen phosphorylase and synthase 5 min after starting and 10 min after stopping the infusions. The infusions of cyanide, glucagons, and isoproterenol did not change the activities of glycogen synthase and glycogen phosphorylase. However, glycogen catabolism was decreased during the infusions of glucagon and isoproterenol in IIH rats, being more intense with isoproterenol (p < 0.05), than glucagon. It was concluded that short-term IIH promoted changes in the liver responsiveness of glycogen degradation induced by glucagon and isoproterenol without a change in the activities of glycogen phosphorylase and synthase.

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Contribution of hepatic glycogenolysis and gluconeogenesis in the defense against short-term insulin induced hypoglycemia in rats

Cited by 15 publications

References 24 publications

Oral Glutamine Dipeptide Prevents against Prolonged Hypoglycemia Induced by Detemir Insulin in Rats

Oral Glutamine Dipeptide Prevents against Prolonged Hypoglycemia Induced by Detemir Insulin in Rats

Evidence that L‐glutamine is better than L‐alanine as gluconeogenic substrate in perfused liver of weaned fasted rats submitted to short‐term insulin‐induced hypoglycaemia

Liver glycogen metabolism during short‐term insulin‐induced hypoglycemia in fed rats

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