Amylin and diabetic cardiomyopathy – amylin-induced sarcolemmal Ca2+ leak is independent of diabetic remodeling of myocardium

• Published in: Biochimica et biophysica acta 2018-05, Vol.1864 (5), p.1923-1930
• Main Authors: Liu, Miao, Hoskins, Amanda, Verma, Nirmal, Bers, Donald M., Despa, Sanda, Despa, Florin
• Format: Article
• Language: English
• Subjects: Amylin; Calcium; Diabetic cardiomyopathy; Hyperamylinemia; Prediabetes; Type-2 diabetes
• ISSN: 0925-4439; 0006-3002; 1879-260X; 1878-2434
• DOI: 10.1016/j.bbadis.2017.10.024

Amylin is a pancreatic β-cell hormone co-secreted with insulin, plays a role in normal glucose homeostasis, and forms amyloid in the pancreatic islets of individuals with type-2 diabetes. Aggregated amylin is also found in blood and extra-pancreatic tissues, including myocardium. Myocardial amylin accumulation is associated with myocyte Ca2+ dysregulation in diabetic rats expressing human amylin. Whether deposition of amylin in the heart is a consequence of or a contributor to diabetic cardiomyopathy remains unknown. We used amylin knockout (AKO) mice intravenously infused with either human amylin (i.e, the aggregated form) or non-amyloidogenic (i.e., monomeric) rodent amylin to test the hypothesis that aggregated amylin accumulates in the heart in the absence of diabetes. AKO mice infused with human amylin, but not rodent amylin, showed amylin deposits in the myocardium. Cardiac amylin level was larger in males compared to females. Sarcolemmal Ca2+ leak and Ca2+ transients were increased in myocytes isolated from males infused with human amylin while no significant changes occurred in either females injected with human amylin or in rat amylin-infused mice. In isolated cardiac myocytes, the amylin receptor antagonist AC-187 did not effectively block the interaction of amylin with the sarcolemma. In conclusion, circulating aggregated amylin accumulates preferentially in male vs. female hearts and its effects on myocyte Ca2+ cycling do not require diabetic remodeling of the myocardium. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers. •Basal amylin has no effect on myocyte Ca2+ cycling.•Aggregated amylin provokes myocyte Ca2+ dysregulation by enhancing sarcolemmal Ca2+ leak.•Myocyte uptake of amylin does not entail pre-existing diabetic remodeling of myocardium.•Circulating aggregated amylin, but not monomeric amylin, accumulates in myocardium.•Cardiac amylin accumulation is larger in male compared to female mice.