Secretion, fates and actions of insulin and related products.

A large number of studies have been briefly reviewed relative to the synthesis, release, distribution, actions, degradation, and resynthesis of insulin, along with considerations of many factors influencing these activities. It is not known whether the “insulin” secreted by diabetics is normal in all regards. In these subjects there are abnormalities with respect to the rate, amount, and duration of insulin release produced by certain agents. Insulin is rapidly distributed throughout the body, but more information is required regarding its intracellular distribution in different tisues, including comparisons in diabetics with normals. Insulin is a powerful hormone that markedly influences, directly or indirectly, the activities of every tissue of the body including generation and storage of energy and regulation of its release and utilization. It exerts pronounced influences upon cell structure, growth, and proliferation. It markedly stimulates the following: (a) synthesis of DNA, RNA, and protein, (b) oxidative phosphorylation, (c) transportation into and through cells, (d) glycogen synthesis, and (e) glucose utilization, lipogenesis, antiglycogenolysis, antilipolysis, antiproteolysis, and antigluconeo-genesis. All of these functions are altered in diabetes. More investigations are required to elucidate the primacy of insulin9s actions, the interdependency of the various activities, messenger systems, etc., in diabetics as well as in normals. Insulin has been shown to act on many tissues, but studies must be extended to determine the extent and nature of its actions on all tissues. It is evident that there are many similarities of action upon various tissues, but there are also highly significant differences. Some studies have indicated abnormalities in the uptake and action of insulin in some of the peripheral tissue of diabetics. Whether there are defects in the activities of such cells that are of primary importance in the production of diabetes has not been established. Many different hormones very significantly influence the net action of insulin, but thus far it is not evident that a disturbance in their activities contributes significantly to the etiology and pathogenesis of genetic diabetes. Insulin is rapidly degraded by essentially all tissues of the body. The mechanism of degradation differs in some tissues, e.g., liver vs. adipose tissue. More study is required to ascertain in diabetics abnormalities in its degradation, qualitative and quantitative. Whereas many of the degraded products have no action like insulin, certain ones do. Moreover, in vitro studies have demonstrated that chain A and chain B can recombine—under certain conditions there is a high percentage of recombination. It is also possible for polymers to form, differing significantly in type, size, etc. Consideration is given to the possibility that NSILA constitutes one type of such polymer. It is conceivable that certain polymers would exert insulin-like action and/or could also inhibit the action of insulin; synalbumin may play such an inhibitory role. Microangiopathies have been observed in a relatively large number of prediabetics. Whether these vascular abnormalities cause significant alterations in carbohydrate metabolism has not been demonstrated. Many fascinating challenges in the field of diabetes prevail and should stimulate us to add to the brilliant contributions of Banting and Best.