The Role of Glicentin and Oxyntomodulin in Human Metabolism: New Evidence and New Directions

Posttranslational processing of proglucagon leads to the formation of glucagon-like peptide-1 (GLP-1), oxyntomodulin, and glicentin, which are secreted by enteroendocrine L-cells, and of glucagon, which is secreted by pancreatic alpha cells (1). Over the past decade, several GLP-1 receptor analogs have been developed and have transformed the treatment of type 2 diabetes (T2DM) and obesity (1-3). Oxyntomodulin, which contains the glucagon sequence with a carboxyterminal extension, is a dual agonist of glucagon and GLP-1 receptors that may act additively to GLP-1 to reduce food intake and appetite (2). Clinical studies with oxyntomodulin either alone or in combination with other gastrointestinal hormones (GLP-1, peptide tyrosine-tyrosine [PYY], etc.) are currently being performed (2). Glicentin, which contains the sequence of oxyntomodulin (and thus also of glucagon) with an N-terminal extension, has as of yet no clearly defined physiological role, and its receptor remains unknown. In a new article published in the Journal of Clinical Endocrinology and Metabolism (4), Nielsen et al investigated the postprandial responses of 5 important gastrointestinal hormones (GLP-1, ghrelin, PYY, oxyntomodulin, glicentin) in relation to weight loss, energy intake, and food preferences after Roux-en-Y bypass or sleeve gastrectomy in patients with morbid obesity. They demonstrate that glicentin and oxyntomodulin are the best predictors of weight loss (superior to GLP-1, PYY, or ghrelin), with the postprandial changes of these hormones 6 months after surgery explaining statistically 22% of the weight loss variability observed 18 months postoperatively. Postprandial changes of glicentin and oxyntomodulin are also associated with decreased preference for energy-dense foods in an ad libitum buffet meal test, which may be mediating their effects on weight loss and metabolism. The variability in weight loss evaluated statistically increased when considering jointly more than 1 of the hormones (ie, glicentin and PYY [44%] and ghrelin [51%]; glicentin-PYY-GLP1-oxyntomodulin [53%] and ghrelin [60%]), although authors did not fully clarify whether these figures reflect crude (r2) or multivariable adjusted variability (adjusted r2) with the latter being always more conservative. These results are in agreement with and extend recent findings of another study in 2 independent cohorts of patients undergoing gastric banding, Roux-en-Y bypass, or sleeve gastrectomy (5), which also showed superiority of the postprandial blood levels of glicentin and oxyntomodulin compared to GLP-1 at predicting long-term weight loss after bariatric surgery. The results of these studies suggest that beyond GLP-1, other products of proglucagon peptide may be playing a valuable, and probably even stronger, role either as simple predictors and/or as true physiological modulators of body weight loss. This provides strong experimental support to ongoing efforts to develop combination treatments of GLP-1 with more than 1 gastrointestinal hormones. There are certain issues that need to be fully addressed though. First, the results of these studies have to be validated in prospective clinical studies with predefined outcomes. Second, given the strong collinearity (4,5) mainly of glicentin with oxyntomodulin but also both of them with GLP-1, it is not possible to combine many hormones as independent variables in linear regression models in most studies, let alone those with small sample sizes. Third, due to the high molecular similarity of these molecules, the specificity, sensitivity, cross-reactivity, and reference range of assays measuring proglucagon products have been repeatedly questioned. Nielsen et al have used in-house enzyme-linked immunosorbent assays that have been developed and validated with mass-spectrometric methods, which are not yet widely available. The second study has used novel commercially available assays (oxyntomodulin from Ansh and glicentin from Mercodia) that according to the manufacturers have been extensively validated for cross-reactivity between the different proglucagon products (5). Despite the different study designs and populations, meal compositions, and assay ranges between the 2 studies, the direction and magnitude of the postprandial changes of the hormones in both studies demonstrate striking similarities, leading to similar conclusions. However, for the field to move forward significantly, the independent validations of the available assays and international standardization of the reference ranges are needed for all assays of products of the proglucagon peptide. Fourth, the high molecular similarity of these molecules suggests also that their actions may overlap. Additional molecular, mechanistic, and human physiology studies are thus needed. Especially for glicentin, we know that it may stimulate insulin secretion, gastrointestinal motility, and gut growth (1) and that it is detected in the brain (6). We don’t know whether it binds on a specific receptor or its affinity with GLP-1, GLP-2, glucose‐dependent insulinotropic polypeptide, or glucagon receptor. We also do not know whether it acts in the brain or whether it can regulate appetite, energy expenditure, or lipid metabolism in animals or humans. Finally, we don’t know whether pharmacologic administration of glicentin alone, or in combination with other gastrointestinal hormones, may have any metabolic effect in animal models of obesity, T2DM, or nonalcoholic fatty liver disease. Independently of any physiological or therapeutic role, glicentin, due to its longer half-life, may be able to serve as a more reliable marker of L-cell function compared to GLP-1. In that case, its diagnostic or prognostic value should be further tested in obesity and its comorbidities. For example, its levels after bariatric surgery could be used to identify patients who will eventually have a more robust response vs those that will need more intense postoperative care to achieve sufficient weight loss or could predict other metabolic outcomes in the long term (4,5). Along these lines, it was recently demonstrated that postprandial response of glicentin, but not of any other proglucagon peptide, is impaired in early stages of NAFLD, which suggests that glicentin may be useful for the noninvasive diagnosis of the disease (7). Similarly, a progressive reduction of the glicentin/glucagon ratio in OGTT is observed in children when moving from lean phenotype to obesity with normal, impaired glucose tolerance or T2DM (8) and that, in turn, may be used to justify more intensive follow-ups or guide treatment decisions. In conclusion, current evidence suggests that oxyntomodulin and glicentin may be useful markers of L-cell function and metabolic health. Future studies should aim to validate and further improve the available assays for their detection and standardization of their reference ranges, to validate their biomarker potential in prospective clinical studies and in different metabolic conditions (obesity, insulin resistance, T2DM, nonalcoholic fatty liver disease) and to investigate the role, if any, of glicentin in energy regulation, glucose homeostasis, and treatment of metabolic diseases. Disclosure Summary: CSM is a shareholder and consultant for Coherus Inc. and Pangea Inc., has served on advisory boards for Novo Nordisk, has received funding through his institution by Novo Nordisk and Esai, and serves as consultant for Regeneron and Ansh Inc. NP has nothing to disclose. Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.