Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice

Mice homozygous for a deletion in the gene encoding prohormone convertase 2 (PC2) are generally healthy but have mild hypoglycemia and flat glucose-to lerance curves. Their islets show marked alpha (A)-cell hyperplasia, sugges ting a possible defect in glucagon processing (Furuta, M., Yano, H., Zhou, A., Rouille, Y,, Holst, J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H ., and Steiner, D. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 6646-6651). In this report we have examined the biosynthesis and processing of proglucagon in isolated islets from these mice via pulse-chase labeling and find that proglucagon undergoes essentially no processing in chase periods up to 8 h in duration. Only a small percent of cleavage at the sensitive interdomain site (residues 71 and 72) appears to occur. These observations thus conclus ively demonstrate the essentiality of PC2 for the production of glucagon in the islet A-cells, Ultrastructural and immunocytochemical studies indicate the presence of large amounts of proglucagon in atypical appearing secreto ry granules in the hyperplastic and hypertrophic A-cells, along with morpho logical evidence of high rates of proglucagon secretion in PC2 null islets. These findings provide strong evidence that active glucagon is required to maintain normal blood glucose levels, counterbalancing the action of insul in at all times.