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The potential antidiabetic activity of some alpha-2 adrenoceptor antagonists
A O Abdel-Zaher1, I T Ahmed, A D El-Koussi
1Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
Abstract:
The effect of alpha-2 adrenoceptor antagonists, yohimbine and efaroxan, on the plasma glucose and insulin levels was studied in non-diabetic control, type-I (insulin-dependent) and type-II (non-insulin-dependent) diabetic rats. Pretreatment with either yohimbine or efaroxan potentiated glucose-induced insulin release in non-diabetic control rats and produced an improvement of the oral glucose tolerance and potentiated glucose-induced insulin release in type-II but not in type-I diabetic rats. Treatment with either yohimbine or efaroxan reduced the plasma glucose level and increased the plasma insulin level of non-diabetic control and type-II diabetic rats but not of type-I diabetic rats. Effects of efaroxan were more marked. Pretreatment of non-diabetic control and type-II diabetic rats with either yohimbine or efaroxan inhibited clonidine-induced hyperglycaemia and suppressed or reversed clonidine-induced hypoinsulinaemia. Also, pretreatment of these animals with either yohimbine or efaroxan enhanced the hypoglycaemic and insulinotropic effects of glibenclamide. The combination of glibenclamide and efaroxan led to a synergistic increase in insulin secretion, while that of glibenclamide and yohimbine led to an additive increase. The hyperglycaemic effect of diazoxide in non-diabetic control and type-II diabetic rats was inhibited by pretreatment with either yohimbine or efaroxan. The hypoinsulinaemic effect of diazoxide in these animals was antagonized and reversed by pretreatment with yohimbine and efaroxan, respectively. In type-I diabetic rats, there was no change in the plasma glucose and insulin levels induced by the treatment of animals with each of clonidine or diazoxide alone or in combination with either yohimbine or efaroxan. Glibenclamide produced a slight decrease in the plasma glucose level of type-I diabetic rats, at the end of the 120 min period of investigation but there was no change in the plasma insulin level. Pretreatment of these animals with either yohimbine or efaroxan produced no change in glibenclamide effects. Additionally, bath application of efaroxan or glibenclamide inhibited the relaxant effects of different concentrations of diazoxide on the isolated norepinephrine-contracted aortic strips, while the application of yohimbine produced insignificant changes. The combination of glibenclamide and efaroxan led to complete inhibition of the relaxant effects of different concentrations of diazoxide, while that of glibenclamide and yohimbine did not produce such an effect. It is concluded that yohimbine, via blockade of postsynaptic alpha-2 adrenoceptors, and efaroxan, via blockade of postsynaptic alpha-2 adrenoceptors and adenosine triphosphate-sensitive potassium channels in the pancreatic beta-cell membrane, produce insulinotropic and subsequent hypoglycaemic effects.
Insights
Alpha-2 adrenoceptor antagonists, yohimbine and efaroxan, improve glucose tolerance and insulin release in type-II diabetic rats. These compounds show potential for managing type-II diabetes by enhancing insulin secretion and lowering glucose levels.
Area of Science:
- Pharmacology
- Endocrinology
- Diabetology
Background:
- Alpha-2 adrenoceptors play a role in regulating insulin secretion and glucose homeostasis.
- Dysregulation of these receptors is implicated in the pathophysiology of type-II diabetes.
Purpose of the Study:
- To investigate the effects of alpha-2 adrenoceptor antagonists, yohimbine and efaroxan, on plasma glucose and insulin levels in diabetic and non-diabetic rats.
- To explore the potential of these antagonists as therapeutic agents for type-II diabetes.
Main Methods:
- Administration of yohimbine and efaroxan to non-diabetic control, type-I, and type-II diabetic rats.
- Measurement of plasma glucose and insulin levels following drug administration and glucose challenge.
- Assessment of responses to other agents like clonidine, glibenclamide, and diazoxide.
Main Results:
- Yohimbine and efaroxan improved oral glucose tolerance and potentiated glucose-induced insulin release in type-II diabetic rats.
- Both antagonists reduced plasma glucose and increased plasma insulin in non-diabetic and type-II diabetic rats, with efaroxan showing more pronounced effects.
- These agents inhibited clonidine-induced hyperglycemia and enhanced the effects of glibenclamide, suggesting a synergistic insulinotropic action.
Conclusions:
- Yohimbine and efaroxan exert insulinotropic and hypoglycemic effects primarily through blockade of postsynaptic alpha-2 adrenoceptors.
- Efaroxan's effects are further mediated by blocking ATP-sensitive potassium channels in pancreatic beta-cells.
- These findings highlight the therapeutic potential of alpha-2 adrenoceptor antagonists in managing type-II diabetes.
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