Enteroglucagons (GLP-1, GLP-2, and Others)

VIVO Pathophysiology

Enteroglucagons (GLP-1, GLP-2, and Others)

The preproglucagon protein is the precursor to glucagon and is synthesized in both the alpha-cells of the pancreatic islets of Langerhans and the L-cells of the small and large intestine. Within L-cells, the processing of preproglucagon polypeptide forms a group of peptide hormones collectively referred to as “enteroglucagon”. These peptides include glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) and a peptide called glicentin. Glicentin is then further cleaved to yield yet another peptide called oxyntomodulin. Yes, this is a complex set of proteolytic events that produce an entire family of peptide hormones involved not only in energy metabolism but intestinal growth and function. Here we will focus on GLP-1 and GLP-2.

GLP-1

GLP-1 is a 30 amino acid peptide sythesized in both pancreatic alpha cells and L cells scattered throughout the epithelium of the intestinal tract. GLP-1 and glucose-dependent insulinotropic peptide are collectively known as "incretins", gastrointestinal hormones that stimulate a decrease in blood glucose levels in response to oral intake of glucose and fatty acids. This incretin effect of GLP-1 can be attributed to its ability to stimulate secretion of insulin and coincidentally suppress secretion of glucagon. GLP-1 also has some inhibitory effects on gastric emptying and intestinal motility. Finally, GLP-1 acts on the brain to promote a sensation of satiation or decreased hunger.

Please re-read the previous paragraph. Note that GLP-1 has activities of potentially huge importance to medicine. There is immense excitment and investment in use of GLP-1 agonists for treating and managing several prevalent human diseases and multiple products are now marketed for those purposes. Two prominent examples:

Diabetes mellitus involves deficiency in secretion of insulin or in insulin resistance. The ability of GLP-1 to stimulate insulin release clearly has potential benefit in such conditions.
Obesity is obviously a highly complex condition, and the ability of GLP-1 to suppress hunger and hence food intake offers promise for controlling this increasingly common health challenge.

GLP-2

GLP-2 is a 33 amino acid peptide co-secreted with GLP-1 by intestinal L-cells; it is also produced in the brainstem. Like other incretins, GLP-2 is secreted in response to the presence of nutrients, mostly glucose and fatty acids. It has halflife of only a few minutes and is rapidly destroyed by the peptidase DPP4.

Unlike GLP-1, GLP-2 does not modulate insulin release or significantly influence glucose homeostasis. Rather, its predominant effects appears to be on intestinal function itself:

Promotion of intestinal growth and repair. It also seems to be a significant anti-inflammatory factor in the intestine and supports the co-called gastrointestinal barrier.
Stimulation of nutrient uptake by intestinal epithelial cells. For example, GLP-2 stimultes expression of hexose transporters in intestinal epithelial cells.

Another similarity of GLP-2 and GLP-1 is their shared ability to inhibit food intake by activities in the brain and exploitation of this effect is again of interest for pharmacologic control of conditions like obesity.

References

Amato A, Baldassano S, Mulè F. GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity. J Endocrinol. 2016; 229:R57-66.

Beutler LR. GLP-1 physiology and pharmacology along the gut-brain axis. J Clin Invest. 2026; 136:e194744.

Müller TD, Finan B, Bloom SR, D'Alessio D, Drucker DJ, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019; 30:72-130.

Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab. 2018; Suppl 1:5-21.

Rehfeld JF. The Origin and Understanding of the Incretin Concept. Front Endocrinol (Lausanne). 2018; 9:387.

Raffort J, Lareyre F, Massalou D, Fénichel P, Panaïa-Ferrari P, Chinetti G. Insights on glicentin, a promising peptide of the proglucagon family. Biochem Med (Zagreb). 2017; 27:308-324.

Gastric Inhibitory Peptide

Gastrointestinal Hormones: Introduction and Index

Updated April 2026. Send comments to Richard.Bowen@colostate.edu