K(-2-ADRENERGIC EFFECTS ON GLUCOSE-INDUCED CA-I(2+) SURGES - ABERRANTBEHAVIOR IN OB() CHANNEL AND ALPHA)OB MICE/

Glucose-induced shifts in intracellular free Ca2+ concentration ([Ca2]i) were quantitatively and temporally the same in ob/ob and +/+ beta- cells. In both, epinephrine promptly and protractedly inhibited the gl ucose-induced [Ca2+]i surge via a pertussis toxin-sensitive alpha2-adr energic mechanism that was reversible by potassium depolarization. Whe n added before glucose, epinephrine blocked completely in the ob/ob be ta-cells, but in the +/+ beta-cells it produced a delayed, reduced, an d transient intracellular Ca2+ (Ca(i)2+) surge. Neither the ATP-sensit ive K+ channel blocker tolbutamide nor the large-conductance Ca2+-acti vated K+ channel (K(maxi)) blocker charybdotoxin reversed the effect o f epinephrine. Tetraethylammonium (TEA), a blocker of both the K(maxi) and the delayed-rectifier K+ channel, and forskolin attenuated the ef fect of epinephrine in +/+ but not in the ob/ob beta-cells. The data s how that 1) alpha2-adrenoreceptor activation decreases the glucose-sti mulated Ca(i)2+ surge in +/+ beta-cells primarily by activating a tolb utamide- and charybdotoxin-insensitive, TEA- and forskolin-sensitive K + channel; 2) the hypersecretion of insulin in ob/ob beta-cells is not due to enhanced glucose-induced Ca2+ influx; and 3) the ob/ob beta-ce lls are aberrant with regard to alpha2-adrenergic modulation.