Diabetologie und Stoffwechsel 2014; 9 - P241
DOI: 10.1055/s-0034-1375098

The GLP-1 metabolite (9 – 37) improves myocardial function in the TAC model by reducing myocardial hypertrophy and improving glucose uptake

J Möllmann 1, R Stöhr 1, W Coumans 2, O Winz 3, AT Vogg 3, HJ Kaiser 3, C Lebherz 1, FM Mottaghy 3, JJ Luiken 2, JF Glatz 2, N Marx 1, M Lehrke 1
  • 1Medizinische Klinik I, Kardiologie, Aachen, Germany
  • 2Dept. of Genetics and Cell Biology, Maastricht, Netherlands
  • 3Klinik für Nuklearmedizin, Aachen, Germany

Purpose: Diastolic dysfunction and myocardial hypertrophy are signs of hypertensive cardiomyopathy. GLP-1(7 – 37) is an incretin hormone which is released in response to nutritional stimuli from the gut and improves glucose metabolism by increasing glucose dependent insulin secretion from the pancreas. GLP-1(7 – 37) is rapidly cleaved to its inactive metabolite GLP-1(9 – 37) which can't bind to the GLP-1 receptor and doesn't cause insulin secretion. Nevertheless both peptides have been found to hold cardioprotective actions.

Methods and Results: To investigate the effects of GLP-1 on hypertensive cardiomyopathy we injected C57BL/6J mice with an AAV vector overexpressing GLP-1(7 – 37), GLP-1(9 – 37) or LacZ (control) (n = 15/group). Cardiac hypertrophy was induced by transversal aortic constriction (TAC). Overexpression of GLP-1(7 – 37) led to the expected improvement of glucose metabolism (p < 0.01) while GLP-1(9 – 37) had no effect. Both peptides reduced myocardial hypertrophy (p < 0.01; n = 5 – 10/group) and reduced myocardial collagen content (gomori stain and PCR all p < 0.05; n = 6 – 8/group) and apoptosis (caspase-3 p < 0.05). Only GLP-1(9 – 37) led to a significant improvement of diastolic myocardial function (dp/dt-min) while reducing LVEDP (all p < 0.05; n = 13/group under dobutamin-stress by millar catheter). This was accompanied by a significant reduction of myocardial F18-FDG-glucose uptake (p < 0.05; n = 11/group in the PET) in GLP-1(9 – 37) expressing mice and reduced expression of the glucose transporters GLUT1 (p < 0.01) and GLUT4 (p < 0.01). In addition, GLP-1(9 – 37) expressing mice were found to hold increased ACC-phosphrylation (p < 0.05) pointing to activation of AMPK as a possible mechanism.

Conclusion: GLP-1(9 – 37) improves hypertrophic cardiomyopathy in the TAC model by reducing myocardial glucose uptake, ventricular hypertrophy, myocardial collagen content and apoptosis.