In contrast to other incretin-based therapies, glucagon-like peptide 1 receptor (GLP1R) agonists with close peptide homology to GLP1 have been shown to improve renal and cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). Now, Michael Lehrke, Peter Boor and colleagues report that GLP1 fragments have renoprotective effects.
Binding of GLP1 to GLP1R stimulates insulin production, slows gastric emptying and reduces appetite. However, GLP1 is rapidly inactivated by dipeptidyl peptidase 4 (DPP4) and cleaved into smaller fragments by neutral endopeptidase. As these fragments cannot activate GLP1R, DPP4 inhibitors and GLP1R agonists are effective therapies to lower glucose levels in patients with T2DM.
“The remarkable differences in outcomes in diabetic patients treated with different incretin-based therapies led us to hypothesize that GLP1 cleavage products have relevant biological activities independent of GLP1R,” says Lehrke. To investigate these activities the researchers overexpressed GLP1 constructs in db/db diabetic mice. They report that only overexpression of DPP4-resistant full-length GLP1 increased glucose tolerance; however, overexpression of either DPP4-resistant GLP1 or GLP1 cleavage fragments reduced kidney tubular damage in these mice.
“The renoprotective effects were glucose-independent and seemed to be mediated by immune modulation rather than by a direct effect on the kidneys,” remarks Boor. In fact, the GLP1 constructs had no effect on albuminuria or electrolyte excretion but markedly decreased the renal myeloid and T cell infiltrate, reduced the cardiac T cell infiltrate and restored the frequency of circulating T cells to normal levels. Pretreatment with GLP1, GLP1 cleavage products or the GLP1R agonist liraglutide, which mimics the peptide structure of GLP1, had similar immunomodulatory effects in a mouse model of ischaemia–reperfusion injury.
“We now plan to focus on the downstream pathways that mediate the organ-protective and immunomodulatory effects of GLP1 cleavage products and on their therapeutic potential in various diseases,” says Boor.
Moellmann, J. et al. Glucagon-like peptide-1 and its cleavage products are renoprotective in murine diabetic nephropathy. Diabetes https://doi.org/10.2337/db17-1212 (2018)
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Wang, M. GLP1 fragments protect the kidney. Nat Rev Nephrol 14, 599 (2018). https://doi.org/10.1038/s41581-018-0056-9