Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Kolesnik,E.
Effects of Modern Antidiabetic Concepts on Myocardial Function
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [Dissertation] Medical University of Graz;2019. pp.101
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- Autor*innen der Med Uni Graz:
- Kolesnik Ewald
- Betreuer*innen:
- Pelzmann Brigitte
- Rainer Peter
- von Lewinski Dirk
- Altmetrics:
- Abstract:
- Background and Aim: In type-2 diabetes mellitus dipeptidyl peptidase (DPP) 4 inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists and sodium dependent glucose transporter 2 (SGLT2) represent modern antidiabetic concepts. Mandatory cardiovascular outcome trials revealed diverging results ranging from beneficial to neutral with hints of possible harmful effects. Direct effects of these modern antidiabetic effects on myocardium have never been assessed, therefore this thesis aims on filling this gap of evidence. Material and Methods: Isolated human atrial (n = 146) and ventricular (n = 30) muscle strips were electrically stimulated at 1 Hz and functional effects (developed force, diastolic tension, relaxation parameters) of modern antidiabetic concepts were assessed. Therefore, muscle strips were treated with increasing concentrations of the DPP4 inhibitors saxagliptin, alogliptin, or sitagliptin and the SGLT2 inhibitors empagliflozin, dapagliflozin, and T-1095. In another set of experiments, muscle strips were treated with a single dose of the GLP-1 receptor agonists exenatide and GLP-1(7–36) amide, the GLP-1 receptor antagonist GLP 1(9–36) amide, isoproterenol, and increasing concentrations of calcium in the presence of either glucose or pyruvate. Furthermore, the acute effect of saxagliptin on action potentials (APs, elicited by a stimulation frequency of 1 Hz) were measured in guinea pig ventricles (GPV; n = 16) using whole-cell patch-clamp technique. Results: DPP4 inhibitors induced arrhythmic events in a same extend in almost half of the tested muscle strips. Here, saxagliptin induced a significant negative inotropic effect while alogliptin induced a significant prolongation of the relaxation time RT90. Furthermore, saxagliptin prolonged action potential duration and decreased the repolarizing potassium outward current density in GPV cells. Administration of exenatide and GLP-1(7–36) amide, but not GLP-1(9–36) amide, led to a transient positive inotropic effect in the presence of pyruvate and glucose. This effect tended to be more pronounced in glucose-treated muscle strips, while both isoproterenol and calcium exerted a strong positive inotropic effect with no difference regarding the energy substrate. The SGLT2 inhibitors empagliflozin and dapagliflozin exerted no functional effects on human atrial and ventricular muscle strips, while T-1095 induced a significant negative inotropic effect. Conclusion: The results of this thesis provide an insight in direct effects of modern antidiabetic concepts on human myocardium and may serve as basis for further investigations. At least DPP4 inhibitors and GLP-1 receptor agonists interact strongly with myocardium. The presented data may help to explain discrepant outcomes of clinical trials.