Commentary: a comparison of glucagon‐like peptides 1 and 2

Abstract

The enteroendocrine system has been broadly neglected by gastroenterologists, but has finally arrived in mainstream therapeutics. However, this epiphany occurred in diabetes and obesity, where extensive research is driven by huge markets and unmet clinical needs. In this thorough review, Janssen et al. describe the glucagon-like peptides (GLP).1 GLP-1 analogues now have accepted roles in managing common metabolic conditions. The side effects are principally gastrointestinal, and there is experimental evidence to suggest that GLP-1 (and peptide-YY) is mechanistically involved in the impact of bariatric surgery.2 Recently discovered receptors expressed by enteroendocrine cells (EEC) sense luminal nutrients, and the gut will offer exciting new therapeutic targets. What of EEC in gastrointestinal diseases though? Research outside the review has increasingly identified EEC roles in key diseases, e.g. IBD, infection. Innate immune components have been localised to EEC,3 and potential roles have been highlighted by genomic approaches.4 This raises intriguing possibilities that EEC may be involved in host defences and pathogenesis. It is highly likely that EEC play a part in the dysregulation of appetite when the gut is inflamed. Infection and experimental enteritis increase cholecystokinin (CCK) activity.5, 6 Blockade of CCK1 receptors improves feeding,6 and a vagal anti-inflammatory circuit has been proposed.7 Similarly, increased L-cell numbers or activity might contribute to anorectic symptoms in Crohn's disease.8, 9 We have also reported that dipeptidyl peptidase 4, the enzyme that degrades GLP-1/2, is significantly downregulated in active Crohn's disease.10 This would enhance effects of GLP-1 on appetite and potentiate the intestinotrophic properties of GLP-2. Its protective effects on the epithelial barrier probably occur by stabilisation of tight junctions.11 We predict that enteroendocrine functions and targets will be increasingly discovered in the alimentary system, and suggest that gastroenterologists need to reclaim and research this highly complex yet neglected system. Declaration of personal and funding interests: None.