Hyperamylinemia contributes to cardiac dysfunction in obesity and diabetes: A study in humans and rats

Sanda Despa, Kenneth B. Margulies, Le Chen, Anne A Knowlton, Peter J Havel, Heinrich Taegtmeyer, Donald M Bers, Florin Despa

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

RATIONALE: 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. OBJECTIVE: 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. METHODS AND RESULTS: 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 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. CONCLUSIONS: 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.

Original languageEnglish (US)
Pages (from-to)598-608
Number of pages11
JournalCirculation Research
Volume110
Issue number4
DOIs
StatePublished - Feb 17 2012

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Keywords

  • calcium
  • diabetic cardiomyopathy
  • HIP rat
  • hyperamylinemia
  • hyperinsulinemia
  • UCD-T2DM rat

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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