Introduction

Enteroglucagon is a molecule discovered in the human intestine. The historical belief was that it was an extra-pancreatic isoform of glucagon. Glucagon-like substances in the intestine were first described by Sutherland and De Duve, who identified them in preparations from the intestinal mucosa.[1] These substances came to be known as peptides with glucagon-like immunoreactivity (GLI) due to patterns of immunoreactivity shared with glucagon.[2] Subsequent sequencing studies revealed that enteroglucagons actually consisted of several different molecules derived within the L-cells (enteroendocrine cells) of the intestine by post-translational modification of the preproglucagon polypeptide.[3] L-cells or enteroendocrine cells have been localized most specifically to the ileum and the colon, although they occur sporadically in other parts of the intestine.[4]

Issues of Concern

The preproglucagon polypeptides play key roles in intestinal and systemic metabolism:

• Glicentin
• Glucagon-like peptide 1 (GLP-1)
• Glucagon-like peptide 2 (GLP-2)
• Oxyntomodulin

Cellular Level

The preproglucagon gene is the precursor to glucagon and is shared between the A-cells of the pancreatic islets of Langerhans and the L-cells of the intestine. Within the L-cells, the processing of preproglucagon polypeptide forms glicentin, glucagon-like peptides 1 and 2 (GLP-1 and GLP-2), and glicentin is then further cleaved to produce oxyntomodulin, with a leftover fragment called glicentin-related polypeptide (GRPP).[5] GLP-1 undergoes further processing, with the removal of amino acids from the N-terminus, to form the molecule, GLP-1 (7-36), which has significant effects on promoting insulin release from the pancreatic islets. This insulinotropic effect is active even at lower blood glucose levels and is much more potent than that of the glucose-dependent insulinotropic peptide (GIP, previously known as a gastric-inhibitory peptide).

Exenatide, a synthetic GLP-1 receptor agonist, was developed after the discovery of Exendin-4, a molecule of the glucagon superfamily of hormones, in the saliva of the Gila monster, which showed potent pancreatic insulinotropic effects in studies on animals, thus motivating the development of a new class of anti-diabetic medication.[6]

The gene that codes for glicentin is in the alpha-cells of the pancreas and the intestinal or intestinal L-cells—the gene on chromosome 2 (6 exons, 5 introns).

Development

In a 1991 study, researchers highlighted the presence of enteroglucagon/glicentin in a 10-week-old human fetus in pancreatic cells.

Organ Systems Involved

• Glicentin (69 amino acids) is present in alpha cells of the pancreas, intestinal L cells (duodenum, rectum, distal ileum, proximal colon, caecum, proximal jejunum). Researchers have also found the glicentin gene in the central nervous system.
• GLP-1 (30 amino acids) is also in the alpha cells of the pancreas, L cells of the intestine (proximal small intestine, colon, and distal ileum), and in the central nervous system (nucleus tractus solitaries of the brain stem).
• GLP-2 (33 amino acids) is in the L cells of the intestine (colon and distal small intestine).
• Oxyntomodulin (37 amino acids) is likewise present in the L cells of the intestine.

Function

GLP-1 belongs to a class of molecules known as “incretins,” molecules that stimulate a decrease in blood glucose levels. The release of these molecules depends on the oral intake of glucose and other nutrients. This contributes to the “incretin effect,” a phenomenon by which oral ingestion of glucose induces a greater increase in the release of insulin as opposed to an intravenous load of glucose.[7] GLP-1 also participates in the “ileal-brake” effect, a mechanism by which the small intestine, in the presence of unabsorbed nutrients, exerts negative feedback on gastric emptying and gut motility to allow better digestion and absorption of these nutrients.[8]

GLP-2 is involved in proliferative effects on small intestine mucosa.[9] These include hypertrophy of the epithelium and villi accompanied by increased mucosal blood flow at the cellular level, with evidence of hypertrophy also evident on gross anatomy in the form of increased mucosal folds and an increase in the caliber of the bowel.

Glicentin shows some glucagon-like activity, while the roles of oxyntomodulin and GRPP in humans are unclear at present.[10][11] However, studies are ongoing to determine their effects on diabetes and obesity. According to some authors, oxyntomodulin reduces the sense of appetite, increases metabolism, and helps maintain systemic glucose homeostasis.

Mechanism

GLP-1 acts on the GLP-1 receptor (GLP-1R), which belongs to the class of G-protein coupled receptors (GPCRs).[12] The GLP-1R has a Gs subunit responsible for activating the intracellular enzyme adenylyl cyclase, which is the catalyst for the conversion of ATP to cAMP. This molecule is the second messenger for GLP-1 and GLP-2 and mediates further downstream effects of these peptides.

After release, GLP-1 is degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) to GLP-1 (9–36) amide.[13] DPP-4 is widely expressed by endothelial cells on their surface, especially those neighboring GLP-1 secretion sites, and also degrades other bioactive peptides such as GIP. DPP-4 is also present in high levels on hepatocytes, and the liver degrades much of the remaining GLP-1. Thus, very little GLP-1 leaves the intestine intact, and even less makes it to the systemic circulation.[12]

Neutral endopeptidase 24.11 (NEP 24.11) is another enzyme that catabolizes GLP-1. It is a zinc metallopeptidase and is expressed in several locations, particularly in the kidneys. However, its contribution to GLP-1 degradation only becomes clear following inhibition of DPP-4, as otherwise most of the GLP-1 reaching the kidneys is already degraded by DPP-4.[14]

Proteolysis by DPP-4 limits the half-life of endogenous GLP-1 to 1-5 minutes. Analogs of GLP-1 in clinical use are thus chemically modified to be resistant to the effects of this enzyme, and therefore have much longer half-lives than endogenous GLP-1 (e.g., liraglutide, exenatide). Another mechanism of prolonging the actions of GLP-1, apart from degradation-resistant synthetic analogs, is the inhibition of their degradation by the action of the class of drugs called DPP-4 inhibitors (e.g., sitagliptin, saxagliptin, vildagliptin).

Related Testing

The role of preproglucagon is still under study and with probable different clinical applications, but, currently, there is no routine test performed in the clinical setting.

Pathophysiology

Enteroglucagon was once implicated in the pathogenesis of diabetes after pancreatectomy. These have also been described in a rare functional pancreatic neuroendocrine tumor, which may be located in the pancreas itself or in the small intestine, where they correlate with slight intestinal hypertrophy. A case report exists describing trophic effects of enteroglucagon (now known to be due to GLP-2) in a patient with an endocrine tumor in the kidney.[15]

Clinical Significance

GLP-1 analogs are now used in the management of diabetes.[16] These agents can potentiate endogenous insulin release in response to oral glucose loads with only a minor risk of hypoglycemia compared to sulfonylureas. Examples include long-acting GLP-1 agonists such as liraglutide, which are resistant to degradation by the enzyme dipeptidyl-peptidase-4 (DPP-4), and short-acting agonists like lixisenatide. Exenatide, another GLP-1 agonist, is available as both an immediate-release and an extended-release formulation.

DPP-4 inhibitors inhibit the degradation of endogenous GLP-1 by DPP-4 and thus increase the half-life of the endogenous product. Examples include sitagliptin, saxagliptin, and linagliptin, among others. The efficacy of linagliptin may be adversely affected by CYP3A4 or P-glycoprotein inducers such as rifampin or St. John’s wort, thus requiring the use of alternative agents that are not pharmacodynamically affected by changes in CYP-450 drug metabolism.[17]

GLP-2 analogs are currently emerging as a treatment for short-bowel syndrome due to their trophic effects on the small intestine.[18] Currently, teduglutide, a novel GLP-2 analog, is being tested for use in this condition, seen in patients who have undergone extensive small bowel resection and subsequently lack sufficient small bowel absorptive area to keep up with the production of digestive juices and intake of foods and fluids.[19]