Three mechanisms have been proposed by which insulin might increase the electrical potential difference across the cell membrane of some of its main target cells: stimulation of an electrogenic pump; increased permeability to K+ (PK); and decreased ratio of permeability to Na+ (PNa) compared to PK, with an absolute decrease in permeability to both ions. Our laboratory has reported that insulin-induced hyperpolarization (IIH) of rat skeletal muscle is not due to stimulation of a ouabain-inhibitable pump and that insulin decreases 42 K efflux, apparently eliminating the first two candidate mechanisms. If the remaining hypothesis is correct, when Na+ is removed from the bathing solution, insulin should depolarize, not hyperpolarize. It did. With Tris or N-methyl-D-glucamine substituted for Na+ , insulin depolarized by ∼3 mV. Ouabain had no effect. PNa decreased by >90%; PK was reduced by <40%. The main component of the immediate mechanism of IIH is the near elimination of PNa. Furthermore, when a poorly permeable cation was substituted for Na+, muscles hyperpolarized in the absence of insulin. This gave us an opportunity to test the hypothesis that hyperpolarization is a link in the insulin-transduction chain. Consistent with this hypothesis, rat muscles hyperpolarized in this manner in the absence of insulin took up more glucose than paired controls in normal Na+ solution.

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