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

  • Valeria Guglielmi
  • Paolo SbracciaEmail author


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.


GLP-1 metabolites Dipeptidyl peptidase IV Neprilysin GLP-1(9–36)amide GLP-1(28–36)amide GLP-1(32–36)amide 


Compliance with ethical standards


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

Conflict of interest

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

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study formal consent is not required.


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Systems MedicineUniversity of Rome Tor VergataRomeItaly
  2. 2.Internal Medicine Unit and Obesity CenterUniversity Hospital Policlinico Tor VergataRomeItaly

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