Abstract 18345: Accumulation of Islet Amyloid Polypeptide Oligomers in the Heart in Type-2 Diabetes Alters Ca Cycling in Myocytes
Islet amyloid polypeptide (IAPP) toxic oligomers form within the secretory pathway of pancreatic β-cells and represent the primary toxic species of amyloids in type-2 diabetes mellitus. These toxic entities can also be released in the blood. We showed recently that IAPP toxic oligomers are abundantly present in blood and failing hearts from pre-diabetic and diabetic humans, suggesting a possible contribution to heart dysfunction in diabetes. Here, we tested the hypothesis that accumulation of IAPP oligomers in the heart alters Ca handling in cardiac myocytes, accelerating the occurrence of heart failure in diabetes. We measured Ca transients in rats transgenic for amyloidogenic human IAPP (HIP rats) that demonstrate accumulation of IAPP toxic oligomers in the heart and rats bearing only non-amyloidogenic rat IAPP (UCD-T2DM rats), an IAPP variant that does not form toxic oligomers. At low stimulation frequency (0.5 Hz), Ca transient amplitude was significantly larger (4.7±0.5 vs. 3.5±0.3) in cardiac myocytes from pre-diabetic HIP rats vs. age-matched control rats. In contrast, pre-diabetic UCD-T2DM rats showed unaltered Ca transients. In pre-diabetic HIP rats, Ca transient amplitude decreased by 20% with increasing the stimulation frequency from 0.5 Hz to 2 Hz. This might be due to deficiencies in Ca extrusion and/or alterations in the action potential in pre-diabetic HIP rats. Indeed, we found that Ca transient decay is slower in pre-diabetic HIP rats vs. control (0.71±0.07 s vs. 0.55±0.04 s). Increased cellular Ca load is involved in hypertrophic signaling. 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, indicating that cardiac hypertrophy already starts in pre-diabetes. In conclusion, our data suggest that IAPP oligomer is a biomarker of diabetic heart failure that manifests starting from early pre-diabetes. IAPP oligomers represent an effective target for diagnostic purposes and therapeutic strategies.
- © 2010 by American Heart Association, Inc.