Biosynthesis of Insulin and Glucagon: A View of the Current State of the Art

Abstract

It is now well established that insulin biosynthesis proceeds through a precursor molecule, proinsulin. This single polypeptide chain form has been identified as a ribosomal product in the microsomal fraction from islet tissues. The newly synthesized peptide chain, after folding and thiol oxidation, is transferred to the Golgi apparatus where it begins to undergo proteolytic processing to insulin and packaging into secretory granules. The secretion from the cells of significant amounts of newly synthesized material by exocytosis begins only one hour or more after biosynthesis and this process is regulated by several factors, including glucose. Foci of current attention discussed in this paper include (1) the possible existence of larger precursor forms than proinsulin, especially short-lived biosynthetic transients with extended NH2-termini analogous to the recently described immunoglobulin L chain and proparathyroid hormone precursors; (2) the large-scale production of insulin by chemical or genetic engineering approaches; (3) isolation of beta-cell plasma membranes; (4) regulatory mechanisms for the biosynthesis and secretion of insulin, the possible role of mRNA modification in this process, and effects of somatostatin on insulin biosynthesis and secretion; (5) studies on the secretion, metabolism and clinical usefulness of the proinsulin C-peptide; (6) finally, the biosynthesis of glucagon and other peptide hormones and the general significance of precursor forms.