Role of oligomeric amylin in impairing cardiac energy substrate metabolism

Elevated blood levels of amylin (hyperamylinemia) and consequent amylin oligomerization are key components of the metabolic syndrome. Their effects on cardiac function remain largely unknown. Recent examination of human myocardium revealed large amylin deposits in failing hearts from obese and diabetic patients, but no deposits in non-failing hearts or in failing hearts from lean, non-diabetic individuals. The major goal of our research is to assess the role of oligomeric amylin in diabetic heart failure. Our preliminary data show that amylin oligomerization at the sarcolemma alters the insulin-PI3K/Akt signaling cascade, affects mitochondrial structure and dynamics, and elevates ROS. Based on these preliminary data, this research project will test the hypotheses that amylin buildup in the heart accelerates diabetic heart failure by 1) impairing glucose and/or fat metabolism (or their balance) and 2) inducing oxidative stress. To test these hypotheses, planned work will assess cardiac energy substrate metabolism in rats transgenic for human amyloidogenic amylin (HIP rats), which accumulate oligomeric amylin in the heart, versus age- and blood glucose-matched rats that express only native non-amyloidogenic rat amylin (UCD rats), which lack deposition of amylin. Specifically, Aim 1 is focused on elucidating whether amylin oligomerization at the sarcolemma alters insulin binding to the insulin receptor, thus impairing activation of PI3K-Akt signaling cascade and GLUT4 and fatty acid transporter CD36 translocation at the sarcolemma. Planned experiments will also test whether amylin oligomers, which are highly hydrophobic molecules, preferentially bind to CD36, thus increasing CD36 presence at the sarcolemma and long-chain fatty acid uptake into myocytes. Work planned under Aim 2 will determine whether the observed increased ROS production in HIP rat cardiac myocytes is primarily the direct effect of amylin-mediated lipid peroxidation and/ or altered mitochondrial structure and function. Hence, this research proposes that amylin buildup is a key contributor to the multifactorial pathogenesis of diabetic heart disease and that mitigating amylin oligomer-mediated cardac effect will improve heart function. The use of “humanized” HIP rat model will provide critical insight into the molecular mechanisms linking pre-diabetic insulin resistance with diabetic cardiac dysfunction.