Regulation by tolbutamide and diazoxide of the electrical activity in mouse pancreatic beta-cells recorded in vivo

Abstract

1. The glucose-dependence of beta-cell electrical activity and the effects of tolbutamide and diazoxide were studied in anaesthetized mice. 2. In untreated animals there was a direct relationship between glycaemia and the burst pattern of electrical activity. Animals with high glucose concentration showed continuous electrical activity. The application of insulin led to a steady decrease in blood glucose concentration and a transition from continuous to oscillatory activity at 7.7+/-0.1 mM glucose (mean+/-s.d.) and a subsequent transition from oscillatory to silent at 4.7+/-0.6 mM glucose. 3. At physiological blood glucose concentrations the electrical activity was oscillatory. The injection of tolbutamide (1800 mg kg[-1]) transformed this oscillatory pattern into one of continuous electrical activity. The increased electrical activity was associated with a decrease in blood glucose concentration from 7.1+/-0.9 (control) to 5.5+/-1.0 mM (10 min after tolbutamide injection). The effects of tolbutamide are consistent with a direct blocking effect on the K(ATP) channel that leads to membrane depolarization. 4. The injection of diazoxide (6000 mg kg[-1]) hyperpolarized the cells and transformed the oscillatory pattern into a silent one. This is consistent with a direct stimulant effect by diazoxide on the K(ATP) channel. The use of tolbutamide or diazoxide correspondingly led to the lengthening or shortening of the active phase of electrical activity, respectively. This indicates that in vivo, such activity can be modulated by the relative degree of activation or inhibition of the K(ATP) channel. 5. These results indicate that under physiological conditions, tolbutamide and diazoxide have direct and opposite effects on the electrical activity of pancreatic beta-cells, most likely through their action on K(ATP) channels. This is consistent with previous work carried out on in vitro models and explains the drugs hypo- and hyperglycaemic effects.