Abstract 12006: Patients with Obesity and Type-2 Diabetes Present Cardiac IAPP Accumulation: A Source of Cardiomyocyte Ca2+ Dysregulation
Patients with obesity and insulin resistance/hypeinsulinemia have elevated circulating levels of islet amyloid polypeptide (IAPP), an amyloidogenic protein making up the amyloid deposits within pancreas and kidneys. It is increasingly appreciated that the toxic form of amyloidogenic proteins is not amyloid but small oligomers that attach to membranes and alter cellular Ca2+ homeostasis. We assessed the hypothesis that IAPP oligomers accumulate within the heart in patients with obesity and insulin resistance and alter cardiomyocyte Ca2+ cycling.
Using an anti-IAPP antibody, we compared the level of accumulation and characteristic size distribution of IAPP oligomers in failing and non-failing hearts (N=53) from patients with obesity and type-2 diabetes and from lean, healthy subjects. We found large IAPP amyloid oligomers (>32 kDa) and plaques in failing hearts from patients with obesity and diabetes, but not in hearts from lean, healthy individuals. Smaller (<32kDa) IAPP oligomers were even elevated in non-failing hearts from overweight/obese patients, suggesting an early stage of accumulation. We used Sprague-Dawley rats transgenic for human IAPP (HIP rats; N=14) to investigate how cardiac IAPP accumulation affects cardiomyocyte function. Sprague-Dawley rats expressing only the native rat IAPP isoform, which does not form amyloids, were used as negative controls (N=16). In cardiac myocytes from HIP rats, we found larger amplitude and slower relaxation of Ca2+ transients, elevated diastolic Ca2+ level, sarcoplasmic reticulum Ca-ATPase remodeling and hypertrophy. In contrast, control rats expressing the same level of non-amyloidogenic rat IAPP have normal cardiomyocyte function.
In conclusion, these data demonstrate that IAPP oligomers accumulate within the heart in patients with overweight/obesity and type-2 diabetes. Cardiac IAPP accumulation promotes myocardial toxicity by altering cardiomyocyte Ca2+ regulation in a rat model.
- © 2011 by American Heart Association, Inc.