Unraveling oxyntomodulin, GLP1's enigmatic brother

Abstract

Oxyntomodulin (OXM) is a peptide secreted from the L cells of the gut following nutrient ingestion. OXM is a dual agonist of the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) combining the effects of GLP1 and glucagon to act as a potentially more effective treatment for obesity than GLP1R agonists. Injections of OXM in humans cause a significant reduction in weight and appetite, as well as an increase in energy expenditure. Activation of GCGR is classically associated with an elevation in glucose levels, which would be deleterious in patients with T2DM, but the antidiabetic properties of GLP1R agonism would be expected to counteract this effect. Indeed, OXM administration improved glucose tolerance in diet-induced obese mice. Thus, dual agonists of the GCGR and GLP1R represent a new therapeutic approach for diabetes and obesity with the potential for enhanced weight loss and improvement in glycemic control beyond those of GLP1R agonists.

Figure 1

Tissue-specific processing of proglucagon. Differential posttranslational processing of proglucagon in the pancreas and in the gut and brain. Preproglucagon is proteolytically cleaved in a tissue-specific manner by prohormone convertases 1 and 2. The numbers in the figure indicate amino acid positions in the 160-amino acid proglucagon sequence. In the pancreas, processing yields the glucagon sequence, whereas the region containing the GLP1 and GLP2 peptides is secreted as a single inactive fusion called major proglucagon fragment (MPGF) or GLP1 and GLP2. Posttranslational processing in the gut and brain results in the secretion of GLP1 and GLP2, while the glucagon sequence remains in a larger peptide, glicentin or glicentin-related pancreatic peptide (GRPP), and oxyntomodulin.

Figure 2

Sequence comparisons of GLP1(7–36) amide, glucagon(1–29), glicentin, OXM, and OXMQ3E.

Figure 3

Reported effects of oxyntomodulin.