The role of the entero-insular axis in insulin secretion

Abstract

The concept of an entero-insular axis has its origins in the 19th Century, after the observation that greater amounts of glucose could be given orally rather than intravenously without producing glycosuria. However, convincing evidence that the gut is able to modify the insulin response to an oral glucose load was produced by two groups of investigators in the 1960s, who showed that oral glucose is much more effective in raising circulating insulin levels than intravenous glucose given in amounts sufficient to produce similar degrees of hyperglycaemia [ 1, 21. The term ‘entero-insular axis’ embraces all those gut factors which contribute to enhanced insulin secretion after ingestion of a meal [3]. Gastrointestinal hormones, collectively termed ‘incretins’ [4], were regarded until recently as the major transmitters of messages from the gut to the pancreatic islets apart from absorbed substrates themselves and their metabolites. It is now apparent that the entero-insular axis possesses an important neural as well as an endocrine component. Both appear to work against the ‘set’ determined by the circulating glucose concentration. The endocrine arm of the enteroinsular axis is better characterized, although far from completely understood. The following focuses on this arm, its role in the regulation of insulin secretion and the possible pathophysiological significance of its modification by dietary changes. Investigators in the 1960s had assumed that higher circulating levels of insulin were synonymous with increased insulin secretion. This assumption has more recently been questioned as a result of comparing peripheral venous plasma insulin and C-peptide responses to oral and intravenous glucose. Observations [ 51 that the increased plasma insulin response to hyperglycaemia resulting from oral versus intravenous glucose was not accompanied by a comparable increase in plasma C-peptide, led to the conclusion that the higher plasma insulin levels seen after oral glucose were due to a decreased fractional hepatic extraction of insulin rather than increased insulin secretion. Further work, based on matching the degree of hyperglycaemia in arterialized rather than venous blood, which is more representative of the stimulus to insulin secretion at B-cell level, has shown that the incretin effect is mediated by both increased secretion and decreased clearance of insulin in normal human subjects [6]. Nevertheless, the observable effect of oral carbohydrate on peripheral insulin levels can be largely accounted for by augmented insulin secretion, particularly when large carbohydrate loads are taken orally [ 71. Many peptides have been isolated from intestinal and nervous tissue which have the ability to stimulate insulin