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GLP-1 receptor independent pathways: emerging beneficial effects of GLP-1 breakdown products

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Abstract

The glucagon-like peptide-1 (GLP-1) axis has emerged as a major therapeutic target for the treatment of type 2 diabetes and, recently, of obesity. The insulinotropic activity of the native incretin hormone GLP-1(7–36)amide, which is mainly exerted through a unique G protein-coupled receptor (GLP-1R), is terminated via enzymatic cleavage by dipeptidyl peptidase-IV that generates a C-terminal GLP-1 metabolite GLP-1(9–36)amide, the major circulating form in plasma. GLP-1(28–36)amide and GLP-1(32–36)amide are further cleavage products derived from GLP-1(7–36)amide and GLP-1(9–36)amide by the action of a neutral endopeptidase known as neprilysin. Until recently, GLP-1-derived metabolites were generally considered metabolically inactive. However, emerging evidence indicates that GLP-1 byproducts have insulinomimetic activities that may contribute to the pleiotropic effects of GLP-1 independently of the canonical GLP-1R. The recent studies reporting the beneficial effects of the administration of these metabolites in vivo and in vitro are the focus of this review. Collectively, these results suggest that GLP-1 metabolites inhibit hepatic glucose production, exert antioxidant cardio- and neuroprotective actions, reduce oxidative stress in vasculature and have both anti-apoptotic and proliferative effects in pancreatic β-cells, putatively by the modulation of mitochondrial functions. These findings have implication in energy homeostasis, obesity and its associated metabolic and cardiovascular complications as well as incretin-based therapies for the treatment of diabetes and obesity.

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Authors and Affiliations

  1. Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy

    Valeria Guglielmi & Paolo Sbraccia

  2. Internal Medicine Unit and Obesity Center, University Hospital Policlinico Tor Vergata, Rome, Italy

    Valeria Guglielmi & Paolo Sbraccia

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  1. Valeria Guglielmi
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Correspondence to Paolo Sbraccia.

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This work was supported by a grant from the Ministero della Salute (Project n. 45/RF-2013-02357791).

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Valeria Guglielmi declares that she has no conflict of interest. Paolo Sbraccia declares that he has no conflict of interest.

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Guglielmi, V., Sbraccia, P. GLP-1 receptor independent pathways: emerging beneficial effects of GLP-1 breakdown products. Eat Weight Disord 22, 231–240 (2017). https://doi.org/10.1007/s40519-016-0352-y

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