Insulin antagonism: a novel role for human serum transferrin.

We have purified alpha2-glycoprotein (alpha2-GP), an insulin antagonist from human plasma which is induced by growth hormone (GH), and shown that pure alpha2-GP is a potent antagonist of severe insulin-induced hypoglycemia, producing acute hyperglycemia in intact rats and ketonuria in diabetic rats. The N-terminal amino acid sequence of alpha2-GP and the reactivity of alpha2-GP with an antitransferrin monoclonal antibody show that alpha2-GP is identical to human serum transferrin. Furthermore, pure human serum transferrin and non-glycosylated recombinant human transferrin reproduce the insulin antagonist effects of alpha2-GP in rats, whereas ovotransferrin shows no such effect. The neutralization of the insulin antagonism of human serum transferrin by an anti-transferrin monoclonal antibody shows that transferrin has a new function as a potent insulin antagonist. This novel role for human serum transferrin in the regulation of glucose metabolism provides a reasonable mechanism for the diabetogenic effect of GH, and has important implications for the etiology and progression of diabetes.