Department of Pharmacology, University of California-Davis, 451 Health Sciences Drive, Davis, CA 95616, USA.
Circ Res. 2012 Feb 17;110(4):598-608. doi: 10.1161/CIRCRESAHA.111.258285. Epub 2012 Jan 24.
Hyperamylinemia is common in patients with obesity and insulin resistance, coincides with hyperinsulinemia, and results in amyloid deposition. Amylin amyloids are generally considered a pancreatic disorder in type 2 diabetes. However, elevated circulating levels of amylin may also lead to amylin accumulation and proteotoxicity in peripheral organs, including the heart.
To test whether amylin accumulates in the heart of obese and type 2 diabetic patients and to uncover the effects of amylin accumulation on cardiac morphology and function.
We compared amylin deposition in failing and nonfailing hearts from lean, obese, and type 2 diabetic humans using immunohistochemistry and Western blots. We found significant accumulation of large amylin oligomers, fibrils, and plaques in failing hearts from obese and diabetic patients but not in normal hearts and failing hearts from lean, nondiabetic humans. Small amylin oligomers were even elevated in nonfailing hearts from overweight/obese patients, suggesting an early state of accumulation. Using a rat model of hyperamylinemia transgenic for human amylin, we observed that amylin oligomers attach to the sarcolemma, leading to myocyte Ca(2+) dysregulation, pathological myocyte remodeling, and diastolic dysfunction, starting from prediabetes. In contrast, prediabetic rats expressing the same level of wild-type rat amylin, a nonamyloidogenic isoform, exhibited normal heart structure and function.
Hyperamylinemia promotes amylin deposition in the heart, causing alterations of cardiac myocyte structure and function. We propose that detection and disruption of cardiac amylin buildup may be both a predictor of heart dysfunction and a novel therapeutic strategy in diabetic cardiomyopathy.
在肥胖和胰岛素抵抗患者中，高胰淀素血症很常见，与高胰岛素血症同时发生，并导致淀粉样沉积。通常认为淀粉样蛋白在 2 型糖尿病中是一种胰腺疾病。然而，循环中升高的胰淀素水平也可能导致外周器官（包括心脏）中的淀粉样蛋白蓄积和蛋白毒性。
检测肥胖和 2 型糖尿病患者心脏中是否有胰淀素蓄积，并揭示胰淀素蓄积对心脏形态和功能的影响。
我们通过免疫组织化学和 Western blot 比较了来自瘦、肥胖和 2 型糖尿病患者的衰竭和非衰竭心脏中的胰淀素沉积。我们发现，在肥胖和糖尿病患者的衰竭心脏中，存在大量的淀粉样蛋白寡聚物、纤维和斑块的明显蓄积，但在正常心脏和瘦、非糖尿病患者的衰竭心脏中没有。即使在超重/肥胖患者的非衰竭心脏中，小的淀粉样蛋白寡聚物也升高，表明存在早期蓄积状态。在人胰淀素转基因的大鼠高胰淀素血症模型中，我们观察到淀粉样蛋白寡聚物附着在肌膜上，导致肌细胞 Ca(2+) 失调、病理性肌细胞重塑和舒张功能障碍，始于 prediabetes。相比之下，表达相同水平野生型大鼠胰淀素（一种非淀粉样形成同工型）的 prediabetic 大鼠表现出正常的心脏结构和功能。
高胰淀素血症促进了心脏中的胰淀素沉积，导致心肌细胞结构和功能的改变。我们提出，检测和破坏心脏中的胰淀素蓄积可能既是心脏功能障碍的预测指标，也是糖尿病心肌病的一种新的治疗策略。
