Abstract 1157: Cardiac Consequences of Increased Amylin Secretion in Diabetics
Type-2 diabetes mellitus (T2DM) is linked to a cardiomyopathy, independent of coronary artery disease and hypertension. The molecular origins of this cardiomyopathy remain largely unknown. Our working hypothesis is that an increased blood level of amylin, an amyloidogenic peptide co-secreted with insulin by pancreatic β-cells, favors the formation of preamyloid oligomers (PAOs) in the heart, causing major cardiac dysfunction. The overexpression of amylin (islet amyloid polypeptide; IAPP) occurs in the prediabetic stage and is responsible for the formation of toxic PAOs in pancreatic islets, β-cell death and progression to T2DM. IAPP deposits have been recently found in kidneys in T2DM patients, suggesting that APP amyloids accumulate in other organs, besides the pancreas. Here, we used immunochemistry with anti-IAPP, anti-oligomer (A11) and anti-fibril (OC) antibodies to assess the IAPP level and state (monomers, PAOs, fibrils) in hearts from T2DM humans and rats. The rodent models included rats transgenic for human IAPP (HIP rats) and an obesity-associated T2DM rat (UCD-T2DM rat) expressing the nonamyloidogenic IAPP variant (rIAPP). We found significantly increased levels of IAPP preamyloid oligomers (by 18±3%) and fibrils (by 21±4%) in failing hearts from T2DM humans vs. non-diabetic control. HIP rat hearts had an increased level of IAPP molecular entities (by 88±15%) vs. UCD-T2DM rats. In both rat models, IAPP oligomers and fibrils started accumulating in the heart already in the prediabetic stage. In vivo echo studies indicate HIP rats that just turned diabetic have decreased fractional shortening, 26% vs. 45% in normal rats. This suggests human IAPP (hIAPP), which is overexpressed in these rats, may alter the cardiac contractile function. To investigate the effect of IAPP on Ca cycling and contractility, we incubated isolated rat cardiac myocytes with exogenous IAPP (5 and 50 μM) for 1–2 h. IAPP significantly increased the amplitude of Ca transients. hIAPP had a significantly larger effect than rIAPP (73±19% vs. 23±10% for myocytes contracting at 2 Hz; 50 μM IAPP). Present data demonstrate that hIAPP amyloidogenic species, the entities implicated in the development of T2DM, accumulate in the heart and are causally linked to cardiac dysfunction.
This research has received full or partial funding support from the American Heart Association, Western States Affiliate (California, Nevada & Utah).