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Incretins: turning the venom into the antidote

Gila monster (Heloderma suspectum) with its ‘tongue’ being composed of the incretin mimetic, exendin-4 (3D structure and amino acid sequence)

In our October 2023 issue, we feature a series of reviews that focus on incretin-based therapies. These drugs were developed following the discovery of a peptide, exendin-4, in the Gila monster’s venom in the 1990s. Being structurally similar to the incretin hormone glucagon-like peptide-1 (GLP-1), exendin-4 was found to mimic the glucose-regulating effects of incretins. The decades following this discovery have seen the generation of several incretin-based therapies and, in this issue of Diabetologia, we are excited to include eight reviews summarising the state-of-the-art knowledge about these agents. Drucker and Holst (https://doi.org/10.1007/s00125-023-05906-7) start by describing the function of GLP-1, namely glucose-dependent potentiation of insulin secretion and glucoregulatory actions, appetite reduction and cardioprotection. Nauck and Müller (https://doi.org/10.1007/s00125-023-05956-x) go on to discuss another incretin hormone: glucose-dependent insulinotropic polypeptide (GIP). GIP was not initially considered an obvious drug candidate; however, a novel drug, tirzepatide, has demonstrated that dual agonism of GLP-1 and GIP receptors produces more substantial reductions in HbA1c and body weight than selective GLP-1 receptor agonists (GLP-1RAs). Tirzepatide is but one example of a novel incretin-based therapy, with this and other advances in incretin pharmacology and drug development being summarised in the review by Tschöp et al (https://doi.org/10.1007/s00125-023-05929-0). These therapies, old and new, not only have therapeutic potential in type 2 diabetes, but also may be beneficial in other types of diabetes. In their review, Mathieu and Ahmadzai (https://doi.org/10.1007/s00125-023-05980-x) discuss the evidence for the beneficial effects of incretin-based therapies in type 1 diabetes, monogenic forms of diabetes and other conditions leading to hyperglycaemia. In terms of diabetic complications, Solini et al (https://doi.org/10.1007/s00125-023-05973-w) delve into the cardiovascular protection offered by incretin-based therapies, while Goldney et al (https://doi.org/10.1007/s00125-023-05988-3) discuss their effects on microvascular complications. Andreasen et al (https://doi.org/10.1007/s00125-023-05966-9) highlight the use of these drugs in the treatment of other metabolic diseases, specifically obesity and non-alcoholic fatty liver disease (NAFLD). Thus, the potential benefits of incretin-based therapies are clearly extensive. In contrast, however, as discussed by Karagiannis et al (https://doi.org/10.1007/s00125-023-05962-z), their uptake is restricted due to socioeconomic factors, such as affordability, accessibility, health literacy and provider bias. To extend their benefits at a societal level, a concerted effort must be made to address these issues. Looking ahead, the future holds great promise for incretin-based therapies to expand the treatment options available for individuals with metabolic disorders, offering new avenues for effective management and improved quality of life. This review set is accompanied by an editorial by Krook and Mulder (https://doi.org/10.1007/s00125-023-05987-4).

 

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