The role of cyclic AMP in the control of carbohydrate metabolism.

Abstract

Cyclic AMP plays an important role in the regulation of metabolism generally. Emphasis in the present review has been placed on carbohydrate metabolism, but lipid metabolism has also been discussed to some extent. The chief role of cyclic AMP in several tissues seems to be to facilitate or promote the mobilization of glucose and fatty acid reserves. In the liver, glucagon and the catecholamines cause an increase in the intracellular level of cyclic AMPby stimulating adenyl cyclase. This increase in the level of .cyclic AMP leads to a net increase in hepatic glucose production by at least three mechanisms: stimulation of phosphorylase activation, suppression of glycogen synthetase activity, and stimulation of gluconeogenesis. The catecholamines also stimulate adenyl cyclase in muscle and adipose tissue. Among the principal effects of cyclic AMP in these tissues are glycogenolysis in muscle and lipolysis in adipose tissue. Another role of cyclic AMP is to enhance or promote the release of insulin from pancreatic beta cells. Insulin then travels to the liver and adipose tissue to suppress the accumulation of cyclic AMP, and may also antagonize the action of cyclic AMP in muscle. Cyclic AMP is thus seen to mediate the actions of several catabolic hormones as well as promote the release of an anabolic hormone which acts in part by opposing cyclic AMP. Since cyclic AMP is involved in the release as well as several of the actions of insulin, the possible role of cyclic AMP in diabetes has been discussed. Human diabetes mellitus is recognized as the result of a basic genetic defect, the nature of which is undefined. One line of evidence implicates basement membrane thickening as an early event in the patho genesis of diabetes. Further study of the formation and breakdown of the basement membrane may therefore lead to a better understanding of the genetic defect. Whether or not cyclic AMP plays a regulatory role in basement membrane synthesis is presently unknown. Another defect recognizable in prediabetics is faulty insulin release in response to glucose infusion. This could be secondary to basement membrane thickening, but there is also evidence that the cyclic AMP mechanism may be defective. At another level, the role of cyclic AMP is more obvious: insulin deficiency leaves unopposed the actions of hormones which stimulate the production of cyclic AMP, thereby contributing to the glucose plethora and ketosis so often seen in the later stages of the disease.