Circulating Amylin Amyloid Oligomers Accumulate in the Heart and Induce Cardiomyocyte Dysfunction in a Rat Model of Type-2 Diabetes

Abstract

Amylin amyloid deposition is generally considered a pancreatic disorder and a hallmark of type-2 diabetes. Recently, amylin amyloids were also found in failing hearts from obese and type-2 diabetic patients, suggesting a possible contribution to cardiac dysfunction. Here, we investigate the mechanism of cardiac amylin accumulation and consequent effects on myocyte structure and function in rats transgenic for human amylin. In this model, we observed that soluble amylin oligomers are released from the pancreas in the blood and accumulate in the heart. Amylin oligomers attach to the sarcolemma and raises the intracellular Ca2+ ([Ca2+]i) leading to myocyte dysfunction. In contrast, rats expressing same level of wild-type, non-amyloidogenic rat amylin showed normal cardiac myocyte structure and function. To test whether the rise of [Ca2+]i is an amylin oligomer-mediated effect, we measured Ca2+ transients in intact cardiac myocytes incubated with exogenous human/rat amylin. 50 μM of human amylin, which rapidly forms oligomers, increased substantially the amplitude of cardiac myocyte Ca2+ transients, while same concentration of rat amylin had no significant effects. Passive trans-sarcolemmal Ca2+ leak was substantially larger in myocytes incubated with human amylin vs. control, implying that amylin oligomers alter the structural integrity of the sarcolemma and increase sarcolemmal permeability to Ca2+. In conclusion, our data show that amylin oligomers circulate through the blood, accumulate in the heart, and alter cardiac myocyte function by disrupting Ca2+ homeostasis. The results suggest that circulating amylin oligomers should be targeted for pharmacological interventions to prevent heart dysfunction in patients with obesity and insulin resistance.