Comparison of the Effects of Glibenclamide on Metabolic Parameters, GLUT1 Expression, and Liver Injury in Rats With Severe and Mild Streptozotocin-Induced Diabetes Mellitus

Jelizaveta Sokolovska,Jelena Sharipova,Olga Sugoka,Nikolajs Sjakste,Darja Isajeva,Tatjana Sjakste,Natalia Paramonova,Evita Rostoka,Sergejs Isajevs,Ivars Kalvinsh

doi:10.3390/medicina48100078

Abstract

Glucose transport via GLUT1 protein could be one of additional mechanisms of the antidiabetic action of sulfonylureas. Here, the GLUT1 gene and the protein expression was studied in rats in the course of severe and mild streptozotocin-induced diabetes mellitus and under glibenclamide treatment. Severe and mild diabetes mellitus was induced using different streptozotocin doses and standard or high fat chow. Rats were treated with glibenclamide (2 mg/kg daily, per os for 6 weeks). The therapeutic effect of glibenclamide was monitored by measuring several metabolic parameters. The GLUT1 mRNA and the protein expression in the kidneys, heart, and liver was studied by means of real-time RT-PCR and immunohistochemistry. The glibenclamide treatment decreased the blood glucose concentration and increased the insulin level in both models of severe and mild diabetes mellitus. Severe diabetes mellitus provoked an increase in both GLUT1 gene and protein expression in the kidneys and the heart, which was nearly normalized by glibenclamide. In the kidneys of mildly diabetic rats, an increase in the GLUT1 gene expression was neither confirmed on the protein level nor influenced by the glibenclamide treatment. In the liver of severely diabetic rats, the heart and the liver of mildly diabetic rats, the GLUT1 gene and the protein expression was changed independently of each other, which might be explained by abortive transcription, and pre- and posttranslational modifications of gene expression. The GLUT1 expression was found to be affected by the glucose and insulin levels and can be modulated by glibenclamide in severely and mildly diabetic rats. Glibenclamide can prevent the liver damage caused by severe hyperglycemia.

Highlights

Diabetes mellitus and its complications cause numerous health and social problems throughout the world
Severe diabetes mellitus provoked an increase in both GLUT1 gene and protein expression in the kidneys and the heart, which was nearly normalized by glibenclamide
The GLUT1 expression was found to be affected by the glucose and insulin levels and can be modulated by glibenclamide in severely and mildly diabetic rats

Summary

Introduction

Diabetes mellitus and its complications cause numerous health and social problems throughout the world. The number of patients with diabetes mellitus is constantly increasing. Both the search for novel remedies with an antidiabetic activity and comprehensive studies of the mechanisms of actions of widely used antidiabetics with a goal to widen an indication spectrum are topical problems of modern medicinal chemistry and pharmacology. The drug works by inhibiting ATP-sensitive potassium channels in pancreatic beta cells. This inhibition induces cell membrane depolarization, which results in opening of the voltage-dependent calcium channels, this causes an increase in intracellular calcium in beta cells, and stimulates insulin release as a consequence [1]. Many studies suggest that besides stimulating insulin release, sulfonylureas have

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