Dual Functional Role of Membrane Depolarization/Ca2+ Influx in Rat Pancreatic B-Cell

Abstract

Transient exposure of rat pancreatic B-cell to 50 mM K+ ([K+50]) makes exocytosis unresponsive to further depolarization, i.e., stimulation with 100 mM K+ or 1 uM glyburide, which closes the ATP-sensitive K+ (K+ATP) channel, simultaneously with [K+50] does not produce any greater insulin secretion compared with [K+50] alone. In sharp contrast, 16.7 mM glucose ([G16.7]) applied simultaneously with [K+50] elicits an insulin response markedly greater than that produced by [K+50] alone, which is not attenuated by 100 uM diazoxide, an inhibitor of K+ATP channel closure. [G16.7]-induced insulin secretion at the basal K+ concn of 4.7 mM was greatly (93%) suppressed by 100 uM diazoxide. Insulin secretion induced by [K+50] plus [G16.7] ([K+50 + G16.7]) was markedly suppressed (70%) by 1 uM nifedipine, a Ca(2+)-channel blocker and was completely abolished by 2 mM 2-cyclohexen-1-one, which reportedly decreases reduced glutathione level and blocks glucokinase. This finding indicates that insulin release induced by [K+50 + G16.7] is not due to leakage produced by toxic stimuli but to activation of exocytosis. When graded concentrations (25 and 50 mM) of K+ were applied simultaneously with [G16.7] in the presence of 100 uM diazoxide, insulin response was clearly dependent on K+ concentration, indicating that the physiological range of membrane depolarization also activates the glucose-responsive effector. Membrane depolarization/Ca2+ influx directly stimulates hormone exocytosis on one hand and activates the K+ATP channel-independent glucose-responsive effector or effectors on the other in the B-cell. The nature of the glucose-responsive effector or effectors remains to be established.

Glucose Stimulates Glucagon Release in Single Rat α-Cells by Mechanisms that Mirror the Stimulus-Secretion Coupling in β-Cells

“…Under these experimental conditions, where the membrane potential is clamped and action potential firing is suppressed, glucose enhanced glucagon secretion in a dosedependent manner (EC 50 ϭ 3.1 mm). This effect must have occurred independent of K ATP -channel closure because this pathway is bypassed under these conditions (35,36). This contrasts to a clear and dose-dependent inhibition of glucagon secretion from parallel experiments in which the islets were exposed to increasing glucose concentrations in normal KRBH buffer containing 4.7 mm K ϩ and no added diazoxide (Fig.…”

Antidiabetic activity and toxicity of Zizyphus spina-christi leaves

“…The ability of sulfonylureas to block the beta-cell K ATP channels directly explains their stimulatory effect on insulin secretion (Satin, 1996;Doyle and Egan, 2003). On the other hand, diazoxide was found to inhibit insulin release by selectivity opening of K ATP channels of pancreatic beta-cells, leading to hyperpolarization of the plasma membrane (Dunne, 1989;Sato et al, 1992;Dabrowski et al, 2003).…”

Induction of insulin secretion by an aqueous extract of Tabernanhte iboga Baill. (Apocynaceae) in rat pancreatic islets of Langerhans

“…In beta cell insulin secretory activity, calcium entry plays a key role (Boschero et al, 1990;Sato et al, 1992;Rorsman, 1997;Van Eylen et al, 1998). Thus, to further study the involvement of calcium, the effect of the extract was investigated in conditions designed to minimize the rate of Ca 2+ influx into islet cells (in the presence of cobalt or in the absence of calcium from medium).…”