Endocrine Abstracts

The incretin access is the descriptive term behind the observed phenomenon that one can elicit more insulin secretion from oral glucose than from an equivalent intravenous stimulus. The major causes of this are two gut hormones GIP and GLP-1.

GLP-1 is secreted in the intestine by the L cells and has effects at the beta cell, in the brain, and on gastric motility. At the beta cell it binds onto G protein receptors which activate the metabolic pathways relating to insulin secretion. Although there are some proximal effects relating to cAMP much of the effect is distal at the level of calmodulin trucking. The advantage of distal augmentation of the pathway is that the pathology of the failing beta cell seems to be circumvented thus GLP-1 is not only an insulin secretagogue but one that is glucose dependent.

GLP-1 analogues are currently under development. Those in late clinical trials include exendin 4 and liraglutide. Liraglutide in clinical trials lowers HbA1c and fasting serum glucose without concomitant weight increase. Because of its glucose dependency it seems relatively free of problems of clinical hypoglycaemia. Murine studies suggest that GLP-1 has effects on preventing apoptosis and enhancing beta cell neogenesis. The hope is therefore that these agents might truly alter the extent to which beta cells fail, but this has yet to be established in man.