Die Rolle der Insulinresistenz bei der Entwicklung einer Herzinsuffizienz- Molekulare Signalwege und der Einfluss des Energiesubstratstoffwechsels

• Applicant: Professor Dr. Torsten Doenst
• Subject Area: Cardiac and Vascular Surgery
• Term: from 2009 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 148194908

Insulin resistance (IR) is a risk factor for heart failure (HF). Systemic IR is usually associated with obesity and diabetes mellitus (T2DM). Cardiac IR may develop as a consequence of chronic systemic IR. We also demonstrated cardiac IR in rats developing pressure overload HF. Here cardiac IR developed before the onset of mitochondrial dysfunction, the latter being associated with contractile dysfunction. A causal link between IR and mitochondrial dysfunction was found in mice with T2DM. Under normal conditions, insulin has a “cellular maintenance” effect on mitochondrial function. It stimulates mitochondrial biogenesis and facilitates replenishment of a moiety-depleted Krebs-cycle (anaplerosis). We hypothesize that IR accelerates and that reversing IR delays or prevents the onset of pressure overload HF. We propose that the onset of cardiac IR triggers HF through the development of mitochondrial dysfunction. We will perform aortic constriction in mice with or without IR (db/db, ob/ob, NSCL-2-/-) and assess contractile function in and ex vivo, substrate utilization rates and mitochondrial function (Specific Aim 1). We will address the underlying signaling mechanisms in vivo and in cell culture (incl. shRNA knockdown, Specific Aim 2).The results may provide a new but readily applicable approach to treat HF.

• DFG Programme: Research Grants