Hyperamylinemia Contributes to Cardiac Dysfunction in Obesity and Diabetes

Abstract

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 non-failing 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, non-diabetic humans. Small amylin oligomers were even elevated in non-failing 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 Ca2+ dysregulation, pathological myocyte remodeling, and diastolic dysfunction, starting from pre-diabetes. In contrast, pre-diabetic rats expressing the same level of wild-type rat amylin, a non-amyloidogenic 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.

Pharmacological inhibition of soluble epoxide hydrolase provides cardioprotection in hyperglycemic rats

“…Combined with reduced Ca 2ϩ transient amplitude, this suggests that, in diabetic UCD-T2DM rats, systolic dysfunction occurs in the absence of diastolic dysfunction. This is somewhat surprising since in several other diabetic rodent models, including our T2DM rat model expressing human amylin (19), diastolic dysfunction precedes systolic dysfunction (19,40,45,9). We found reduced SERCA expression in both treated and untreated diabetic UCD-T2DM rats.…”

“…[Ca 2ϩ ] i is central to cardiac myocyte contractility and viability (6). [Ca 2ϩ ] i dysregulation plays an important role in the pathophysiology of heart disease (6), including diabetic cardiomyopathy (19,32,40,45). Thus, we examined Ca 2ϩ cycling in cardiac myocytes from age-matched treated and untreated UCD-T2DM rats and age-matched, healthy control rats.…”

“…As an indicator of myocyte function, we measured Ca 2ϩ cycling. Intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) is central to cardiac myocyte contractility and viability, and dysregulation of [Ca 2ϩ ] i plays an important role in the pathophysiology of heart disease (6), including diabetic cardiac disease (19,32,40,45).…”

RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity

“…Aggregation of h-IAPP into amyloid fibrils involves 3 observable stages: Preamyloid oligomers (or prefibrillar intermediates) formed in the lag phase (LP) (first phase) assemble into amyloid fibrils in the growth phase (GP) (second phase), leading to an equilibrium between amyloid fibrils and residual soluble peptide in the saturation phase (SP) (third phase) (Supplemental Figure 1, A and B; supplemental material available online with this article; https:// doi.org/10.1172/JCI85210DS1). Toxic h-IAPP aggregates cause pancreatic β cell and islet dysfunction and death, contributing to T2D, islet transplant failure, and, ultimately, cardiovascular and microvascular complications (19)(20)(21)(22)(23).…”

Prion-Like Protein Aggregates and Type 2 Diabetes

“…In fact, longitudinal studies in nonhuman primates suggest that IAPP accumulation in the pancreas begins well before the appearance of any impairment in glucose metabolism (Guardado-Mendoza et al 2009). Moreover, a recent report indicates that diseased hearts from obese, prediabetic individuals exhibit oligomeric IAPP, suggesting that the process of IAPP accumulation may begin decades before the onset of overt T2D (Despa et al 2012). Increased risk of developing impairment in glucose metabolism and diabetes has also been noted in individuals who have received chronic blood transfusion (Chern et al 2001;Shamshirsaz et al 2003).…”