Insulin Biosynthesis, Secretion, Structure, and Structure-Activity Relationships

Insulin plays a central role in the regulation of human metabolism. The hormone is a 51-residue anabolic protein that is secreted by the β-cells in the Islets of Langerhans. Containing two chains (A and B) connected by disulfide bonds, the mature hormone is the post-translational product of a single-chain precursor, designated proinsulin . Extensive studies of the three-dimensional structure of insulin, pioneered by D. C. Hodgkin , have enabled the development of therapeutic analogs for the treatment of the metabolic disorder diabetes mellitus (DM) . The insulin gene is the site of dominant mutations associated with DM . Although such mutations are uncommon, their molecular analysis has provided important insights into the biochemical bases of the hormone’s pathway of biosynthesis and mechanism of receptor binding . The largest class of mutations is associated with the impaired folding of proinsulin, which leads in turn to progressive endoplasmic-reticular (ER) stress, β-cell death and DM, usually with onset in the neonatal period .