Nitric oxide: The "second messenger" of insulin

Incubation of various tissues, including heart, liver, kidney, muscle, and intestine from mice and erythrocytes or their membrane fractions from human s, with physiologic concentration of insulin resulted in the activation of a membrane-bound nitric oxide synthase (NOS). Activation of NOS and synthes is of NO were stimulated by the binding of insulin to specific receptors on the cell surface. A Lineweaver-Burk plot of the enzymatic activity demonst rated that the stimulation of NOS by insulin was related to the decrease in the K-m for L-arginine, the substrate for NOS, with a simultaneous increas e of V-max. Addition of N-G-nitro-L-arginine methyl ester (LNAME), a compet itive inhibitor of NOS, to the reaction mixture completely inhibited the ho rmone-stimulated NO synthesis in all tissues, Furthermore, NO had an insuli n-like effect in stimulating glucose transport and glucose oxidation in mus cle, a major site for insulin action. Addition of NAR;IE to the reaction mi xture completely blocked the stimulatory effect of insulin by inhibiting bo th NO production and glucose metabolism, without affecting the hormone-stim ulated tyrosine or phosphatidylinositol 3-kinases of the membrane preparati on. Injection of NO in alloxan-induced diabetic mice mimicked the effect of insulin in the control of hyperglycemia (i.e., lowered the glucose content in plasma). However, injection of NAME before the administration of insuli n to diabetic-induced and nondiabetic mice inhibited not only the insulin-s timulated increase of NO in plasma but also the glucose-lowering effect of insulin.