Glucagon-Like Peptide 1 and Its Cleavage Products Are Renoprotective in Murine Diabetic Nephropathy

• Published in: Diabetes (New York, N.Y.) Vol. 67; no. 11; pp. 2410 - 2419
• Main Authors: Moellmann, Julia, Klinkhammer, Barbara Mara, Onstein, Julia, Stöhr, Robert, Jankowski, Vera, Jankowski, Joachim, Lebherz, Corinna, Tacke, Frank, Marx, Nikolaus, Boor, Peter, Lehrke, Michael
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.11.2018
• Subjects: Animals; Blood Glucose - metabolism; Cell Movement - physiology; Diabetes; Diabetes mellitus; Diabetes Mellitus - metabolism; Diabetes Mellitus - pathology; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic nephropathy; Dipeptidyl-peptidase IV; GLP-1 receptor agonists; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - metabolism; Glucose; Glucose metabolism; Homology; Immunomodulation; Insulin resistance; Ischemia; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidneys; Lymphocytes T; Macrophages; Mice; Nephropathy; Peptidase; Peptides; Reperfusion
• DOI: 10.2337/db17-1212
• ISSN: 0012-1797; 1939-327X

Incretin-based therapies, including glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, are potent glucose-lowering drugs. Still, only GLP-1 receptor agonists with close peptide homology to GLP-1 (liraglutide and semaglutide) but neither exenatide-based GLP-1 receptor agonists nor DPP-4 inhibitors were found to reduce cardiovascular events. This different response might relate to GLP-1 receptor-independent actions of GLP-1 caused by cleavage products only liberated by GLP-1 receptor agonists with close peptide structure to GLP-1. To test this hypothesis, we directly compared metabolic, renal, and cardiac effects of GLP-1 and its cleavage products in diabetic db/db mice. Using an adeno-associated viral vector system, we overexpressed DPP-4-resistant GLP-1 (7-37 Mut8) and the two GLP-1 cleavage products, GLP-1 (9-37) and GLP-1 (28-37), in diabetic db/db mice. Only GLP-1 (7-37 Mut8), but none of the cleavage products, significantly improved glucose metabolism. Still, all GLP-1 constructs significantly reduced tubulointerstitial renal damage, lowered expression of the tubular injury markers, and attenuated renal accumulation of macrophages and T cells. This was associated with a systemic immunomodulatory effect, which was similarly found in an acute renal ischemia/reperfusion injury model. In conclusion, GLP-1 cleavage products proved sufficient to mediate organ-protective effects, which might help to explain differences between GLP-1 receptor agonists.