Intrinsically Disordered Islet Amyloid Polypeptide Is a Pathogenic Link Between Type-2 diabetes and Heart Disease

Abstract

Islet amyloid polypetide (IAPP) is an intrinsically disordered protein co-expressed and secreted with insulin by pancreatic β-cells. IAPP is produced at increased rates in patients with pre-diabetes, leading to proteotoxicity and extracellular amyloid deposition, a hallmark of type-2 diabetes. We found high IAPP levels in blood and failing hearts from pre-diabetic and diabetic humans, showing that IAPP accumulates in the heart and may contribute to heart dysfunction. Here, we tested the hypothesis that accumulation of IAPP in the heart alters Ca handling in cardiac myocytes, accelerating the occurrence of heart failure. We measured Ca transients in rats transgenic for human IAPP (HIP rats) and in wild-type RIP rats that bear only the non-diabetogenic IAPP isoform. Ca transient amplitude was significantly larger in cardiac myocytes from pre-diabetic HIP rats vs. age-matched control rats. In contrast, pre-diabetic RIP rats showed unaltered Ca transients. We also found increased Ca transients in myocytes incubated with exogenous human IAPP but not with rodent IAPP. Increased cellular Ca load is involved in hypertrophic signaling and pathological remodeling of the heart. We measured the level of brain natriuretic peptide (BNP), a molecular marker of hypertrophy, in heart protein homogenates from HIP rats using western blots. BNP expression was already elevated (by 70±21%) in hearts from pre-diabetic rats vs. age-matched control littermates and further increased with diabetes development. These data show that cardiac Ca dysregulation and hypertrophy correlates with toxic deposition of IAPP in the heart. In conclusion, our data suggest that accumulation of IAPP oligomers contribute significantly to the pathogenesis of diabetic heart failure. IAPP represents an effective target for diagnostic purposes and therapeutic strategies.