Lilly Lecture 1980: Insulin Resistance and Insulin Action: An In Vitro and In Vivo Perspective

Insulin is produced in the pancreatic B-cell as the primary biosynthetic product pre-proinsulin. This peptide is rapidly converted to proinsulin (MW ~ 9000) which is, in turn, converted to insulin (MW ~ 6000) plus C-peptide (MW ~ 3000) by specific proteolytic steps within the B-cell secretory granule. The normal secretory products are, therefore, insulin, an equimolar amount of C-peptide, and a small amount (~5%) of unconverted proinsulin. After a brief circulation time (t1/2 6-10 min) the hormone interacts with target tissues to exert its biologic effects. One of insulin's major biologic effects is to promote overall glucose metabolism, and abnormalities of this aspect of insulin action can lead to a number of important clinical and pathophysiologic states. Insulin resistance exists when a given, known quantity of insulin produces less than the normal expected biologic effect. Since insulin travels from the B-cell, through the circulation, to the target tissue, events at any one of these loci can influence the ultimate action of the hormone. Therefore, it is useful to categorize insulin resistance according to known etiologic mechanisms, and such a classification is presented in Table 1. Insulin resistance can be due to three general categories of causes: (1) an abnormal B-cell secretory product, (2) circulating insulin antagonists, or (3) a target tissue defect in insulin action. Within each of these categories, subclassifications exist.