| Hyperamylinemia contributes to cardiac dysfunction in obesity and diabetes: a study in humans and rats. | |
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MedLine Citation:
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PMID: 22275486 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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(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. |
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Authors:
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Sanda Despa; Kenneth B Margulies; Le Chen; Anne A Knowlton; Peter J Havel; Heinrich Taegtmeyer; Donald M Bers; Florin Despa |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2012-01-24 |
Journal Detail:
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Title: Circulation research Volume: 110 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-02-20 Completed Date: 2012-04-09 Revised Date: 2012-05-24 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 598-608 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, University of California-Davis, 451 Health Sciences Drive, Davis, CA 95616, USA. fdespa@ucdavis.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged Animals Blotting, Western Calcium Signaling Cardiomegaly / etiology, metabolism, physiopathology Diabetes Mellitus, Type 2 / complications*, metabolism Diabetic Cardiomyopathies / etiology*, metabolism, physiopathology, ultrasonography Disease Models, Animal Female Heart Failure / etiology*, metabolism, physiopathology, ultrasonography Histone Deacetylases / metabolism Humans Immunohistochemistry Islet Amyloid Polypeptide / genetics, metabolism* Male Middle Aged Myocardium / metabolism*, pathology NFATC Transcription Factors / metabolism Obesity / complications*, metabolism Prediabetic State / complications*, metabolism Rats Rats, Sprague-Dawley Rats, Transgenic Ventricular Dysfunction, Left / etiology, metabolism, physiopathology Ventricular Function, Left Ventricular Pressure Ventricular Remodeling Young Adult |
| Grant Support | |
ID/Acronym/Agency:
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AT003645/AT/NCCAM NIH HHS; DK087307/DK/NIDDK NIH HHS; HL075675/HL/NHLBI NIH HHS; HL091333/HL/NHLBI NIH HHS; HL107256/HL/NHLBI NIH HHS; P01 HL080101-05/HL/NHLBI NIH HHS; R01 HL061483-10/HL/NHLBI NIH HHS; R01 HL109501-01/HL/NHLBI NIH HHS; R01 HL109501-02/HL/NHLBI NIH HHS; R01-AG017022/AG/NIA NIH HHS; R01-HL061483/HL/NHLBI NIH HHS; R01-HL073162/HL/NHLBI NIH HHS; R01-HL077281/HL/NHLBI NIH HHS; R01-HL079071/HL/NHLBI NIH HHS; R01-HL089847/HL/NHLBI NIH HHS; R01-HL109501/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Islet Amyloid Polypeptide; 0/NFATC Transcription Factors; EC 3.5.1.98/Histone Deacetylases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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