Insulin Depolarization of Skeletal Muscle in Absence of External Na⁺

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⁺ (P_K); and decreased ratio of permeability to Na⁺ (P_Na) compared to P_K, 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. P_Na decreased by >90%; P_K was reduced by <40%. The main component of the immediate mechanism of IIH is the near elimination of P_Na. 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.