Glucose-dependent increase in mitochondrial membrane potential, but not cytoplasmic calcium, correlates with insulin secretion in single islet cells

We examined the effects of different physiological concentrations of glucose on cytoplasmic Ca²⁺ handling and mitochondrial membrane potential (Δψ_m) and insulin secretion in single mouse islet cells. The threshold for both glucose-induced changes in Ca²⁺ and Δψ_m ranged from 6 to 8 mM. Glucose step-jumps resulted in sinusoidal oscillations of cytoplasmic Ca²⁺, whereas Δψ_m reached sustained plateaus with oscillations interposed on the top of these plateaus. The amplitude of the Ca²⁺ rise (height of the peak) did not vary with glucose concentration, suggesting a "digital" rather than "analog" character of this aspect of the oscillatory Ca²⁺ response. The average glucose-dependent elevation of cytoplasmic Ca²⁺ concentration during glucose stimulation reached saturation at 8 mM stimulatory glucose, whereas Δψ_m showed a linear glucose dose-response relationship over the range of stimulatory glucose concentrations (4-16 mM). Glucose-dependent increases in insulin secretion correlated well with Δψ_m, but not with average Ca²⁺ concentration. These data show that an ATP-dependent K⁺ channel-independent pathway is operative at the single cell level and suggest mitochondrial metabolism may be a determining factor in explaining graded, glucose concentration-dependent increases in insulin secretion.