title: Hyperamylinemia contributes to cardiac dysfunction in obesity and diabetes: a study in humans and rats.
abstract: BACKGROUND
  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.
  
  
  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(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.
  
  
  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.
authors.affiliation: Department of Pharmacology, University of California-Davis, 451 Health Sciences Drive, Davis, CA 95616, USA. fdespa@ucdavis.edu
authors.forename: Sanda
authors.initials: S
authors.lastname: Despa
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.forename: Le
authors.initials: L
authors.lastname: Chen
authors.forename: Anne A
authors.initials: AA
authors.lastname: Knowlton
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Havel
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Florin
authors.initials: F
authors.lastname: Despa
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000000981:diagnostic imaging / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D011236:Prediabetic State / Q000150:complications* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D020257:Ventricular Remodeling; D055815:Young Adult
chemical_list: D058228:Islet Amyloid Polypeptide; D050778:NFATC Transcription Factors; D006655:Histone Deacetylases