Hypersecretion of amylin is common in individuals with prediabetes, causes amylin deposition and proteotoxicity in pancreatic islets, and contributes to the development of type 2 diabetes. Recent studies also identified amylin deposits in failing hearts from patients with obesity or type 2 diabetes and demonstrated that hyperamylinemia accelerates the development of heart dysfunction in rats expressing human amylin in pancreatic β-cells (HIP rats). To further determine the impact of hyperamylinemia on cardiac myocytes, we investigated human myocardium, compared diabetic HIP rats with diabetic rats expressing endogenous (nonamyloidogenic) rat amylin, studied normal mice injected with aggregated human amylin, and developed in vitro cell models. We found that amylin deposition negatively affects cardiac myocytes by inducing sarcolemmal injury, generating reactive aldehydes, forming amylin-based adducts with reactive aldehydes, and increasing synthesis of the proinflammatory cytokine interleukin-1β (IL-1β) independently of hyperglycemia. These results are consistent with the pathological role of amylin deposition in the pancreas, uncover a novel contributing mechanism to cardiac myocyte injury in type 2 diabetes, and suggest a potentially treatable link of type 2 diabetes with diabetic heart disease. Although further studies are necessary, these data also suggest that IL-1β might function as a sensor of myocyte amylin uptake and a potential mediator of myocyte injury.
|Number of pages||12|
|State||Published - Sep 1 2016|
Bibliographical noteFunding Information:
This research was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (grants R01-HL-105993 to K.B.M., R01-HL-109501 to S.D., and R01-HL-118474 to F.D.) and the National Science Foundation Division of Chemical, Bioengineering, Environmental, and Transport Systems (grant CBET 1357600 to F.D.). HPLC analysis was performed in a National Institute of General Medical Sciences-supported protein core (National Heart, Lung, and Blood Institute grant 5P20GM103486 to L.B.H.), while proteomics analysis was performed in the University of Kentucky Proteomics core. The LC-MS/MS equipment was acquired using a National Center for Research Resources High-End Instrumentation grant (S10 RR029127 to H.Z.).
© 2016 by the American Diabetes Association.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism