REGULATION BY TOLBUTAMIDE AND DIAZOXIDE OF THE ELECTRICAL-ACTIVITY INMOUSE PANCREATIC BETA-CELLS RECORDED IN-VIVO

1 The glucose-dependence of beta-cell electrical activity and the effe cts of tolbutamide and diazoxide were studied in anaesthetized mice. 2 In untreated animals there was a direct relationship between glycaemi a and the burst pattern of electrical activity. Animals with high gluc ose concentration showed continuous electrical activity. The applicati on 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 co ncentrations the electrical activity was oscillatory. The injection of tolbutamide (1800 mg kg(-1)) transformed this oscillatory pattern int o one of continuous electrical activity. The increased electrical acti vity was associated with a decrease in blood glucose concentration fro m 7.1+/-0.9 (control) to 5.5+/-1.0 mM (10 min after tolbutamide inject ion). 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 a nd transformed the oscillatory pattern into a silent one. This is cons istent with a direct stimulant effect by diazoxide on the K-ATP channe l. The use of tolbutamide or diazoxide correspondingly led to the leng thening or shortening of the active phase of electrical activity, resp ectively. This indicates that in vivo, such activity can be modulated by the relative degree of activation or inhibition of the K-ATP channe l. 5 These results indicate that under physiological conditions, tolbu tamide and diazoxide have direct and opposite effects on the electrica l activity of pancreatic beta-cells, most likely through their action on K-ATP channels. This is consistent with previous work carried out o n in vitro models and explains the drugs hypo-and hyperglycaemic effec ts.