Oral glutamine dipeptide prevents against prolonged hypoglycemia induced by Detemir insulin in rats.
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 insulin. Because the lowest glycemia was obtained 4 h after insulin administration, the experiments were done at this time. The hypoglycemia obtained 4 h after insulin injection was partially prevented with increasing oral doses of GDP (1.56, 3.12, 6.25, 12.5 mg/kg). The best result was obtained with 12.5 mg/kg. However, from this dose (25.0, 50.0, 100.0 mg/kg), the values of glycemia progressively decreased (p<0.05). The effect of GDP to prevent prolonged IIH was mediated, partly at least, by an intensification of liver gluconeogenesis. Moreover, the increased portal availability of GDP, L-alanine and L-glutamine after GDP administration also contributed to the IIH prevention, since the rate of gluconeogenesis progressively augmented with the infusion of increasing concentrations of these substances. However, after getting the maximal value, the rate of liver gluconeogenesis decreased (p<0.05) if a more elevated concentration of L-alanine or L-glutamine was infused. On the other hand, the liver gluconeogenesis during the infusion of increasing concentrations of GDP was unchanged. Because, GDP did not directly inhibit liver gluconeogenesis, but an inhibition of this metabolic pathway was observed with low ammonia concentrations (from 0.062 mM) it is possible that the ammonia from the catabolism of GDP by extra hepatic tissues could inhibit liver gluconeogenesis. This mechanism could help to explain the lower glycemia obtained with more elevated doses of oral GDP.
Felisberto-Junior
Antonio Machado
AM
Department of Pharmacy and Pharmacology, State University of Maringá, PR, Brazil.
Manso
Fernando Canas
FC
Gazola
Vilma Aparecida Ferreira de Godoi
VA
Obici
Simoni
S
Geisler
Sandonaid Andrei
SA
Bazotte
Roberto Barbosa
RB
D000409:Alanine / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects; D005973:Glutamine / Q000008:administration & dosage* / Q000494:pharmacology*; D007003:Hypoglycemia / Q000139:chemically induced* / Q000517:prevention & control*; D007004:Hypoglycemic Agents; D007328:Insulin / Q000031:analogs & derivatives*; D000069057:Insulin Detemir; D049528:Insulin, Long-Acting; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014508:Urea / Q000378:metabolism
D001786:Blood Glucose; D004151:Dipeptides; D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D005973:Glutamine; D000069057:Insulin Detemir; D014508:Urea; D000409:Alanine