Abolition of the expression of inhibitory guanine nucleotide regulatory protein G_i activity in diabetes

Many cell-surface receptors for hormones appear to exert their effects on target cells by interacting with specific guanine nucleotide binding regulatory proteins (G-proteins) which couple receptors to their second-messenger signal generation systems. A common intracellular second messenger, which is used by many hormones, is cyclic AMP. This is produced by adenylate cyclase, whose activity is controlled by two G-proteins, G_s which mediates stimulatory effects and G_i inhibitory effects on adenylate cyclase activity¹. In liver, the hormone glucagon increases intracellular cAMP concentrations by activating adenylate cyclase by a G_s-mediated process. This effect of glucagon is antagonised by the hormone insulin, although the molecular mechanism by which insulin elicits its actions is obscure. However, insulin receptors exhibit a tyrosyl kinase activity² and appear to interact with G-proteins^2,3, perhaps by causing phosphorylation of them⁴. In type I diabetes, circulating insulin levels are abnormally low, giving rise to gross perturbations of metabolism as well as to a variety of complications such as ionic disturbances, neuropathies of the nervous system, respiratory and cardiovascular aberrations and predispostion to infection⁵. We show here that experimentally-induced type I diabetes leads to the loss of expression of G{ in rat liver. As it has been suggested that G_i may couple receptors to K⁺- channels^6,7 as well as mediating the inhibition of adenylate cyclase, aberrations in the control of expression of this key regulatory protein in type I diabetes may be expected to lead to pleiotropic effects.