Insulin Antagonism: A Novel Role for Human Serum Transferrin

We have purified α₂-glycoprotein (α₂-GP), an insulin antagonist from human plasma which is induced by growth hormone (GH), and shown that pure α₂-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 α₂-GP and the reactivity of α₂-GP with an antitransferrin monoclonal antibody show that α₂-GP is identical to human serum transferrin. Furthermore, pure human serum transferrin and non-glycosylated recombinant human transferrin reproduce the insulin antagonist effects of α₂-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.

Key words

Insulin Antagonist - Diabetes Mellitus - Transferrin