Glucose and alpha-ketoisocaproate induce transient inward currents in rat pancreatic beta cells

The perforated patch technique was used to study changes in membrane potential and whole-cell currents in single isolated rat pancreatic beta-cells during stimulation with glucose or alpha-ketoisocaproate. Increasing the glucose concentration from 4 to 20 mmol/l, or addition of 15 mmol/l alpha-ketoisocaproate, caused depolarization and, in most cases, initiation of action potentials. Under voltage-clamp conditions close to a potassium equilibrium potential (EK) (-60 to -70 mV) these effects were accompanied by the appearance of transient inward currents. These transient currents resembled those elicited during cell swelling in response to a 10% hypotonic bath solution, a manoeuvre which also caused beta-cell depolarization and electrical activity. Tolbutamide (0.2 mmol/l), in the absence of glucose depolarized beta-cells but did not induce transient inward currents. Nutrient-induced electrical activity and inward currents were abolished by the anion channel inhibitors 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid and 5-nitro-2-(3-phenylpropylamino) benzoic acid, compounds which also inhibited glucose-induced insulin release. It is concluded that nutrient secretagogues induce transient inward currents in isolated rat beta-cells, possibly by activating a volume-sensitive anion conductance. These inward currents could enhance the intensity of electrical, and hence secretory, activity in the beta-cell during nutrient stimulation.