Abstract 13963: Hyperamylinemia, a Potential Therapeutic Target in Diabetic Cardiorenal Syndrome
Background: Recent studies show that hyperamylinemia, which is common in humans with prediabetic insulin resistance, promotes accumulation of oligomeric amylin not only in pancreatic islets, but also in kidneys and heart. The oligomerized amylin is a potent source of oxidative stress and inflammation.
Hypothesis: Controlling hyperamylinemia may improve cardiac and renal function in type-2 diabetes (T2D).
Methods: To test this hypothesis, we used a rat model of T2D overexpressing human amylin in the pancreas (HIP rat). Cardiac function (M-mode echocardiography), intra-arterial blood pressure and kidney function (metabolic cage) were assessed in diabetic HIP vs. age-matched control rats. To reduce amylin deposition, we pharmacologically elevated the endogenous blood levels of eicosanoids, molecules with anti-aggregation properties, by blocking the soluble epoxide hydrolase.
Results: We found that amylin begins to accumulate in the cardiovascular system in the pre-diabetic state (i.e. non-fasted blood glucose level in the 150-200 mg/dl domain). Oligomerized amylin was identified in the blood vessel wall, glomeruli and cardiac myocytes suggesting that hyperamylinemia may directly affect cardiac and renal function. Compared to wild-type littermates, HIP rats develop cardiac hypertrophy (~75% increase in heart to body weight ratio; P<0.01), systolic dysfunction (fractional shortening of 36.9±2.0% vs. 44.7±1.6% in wild-type; P<0.05), hypertension (mean arterial blood pressure was increased by ~20%; P<0.05) and typical signs nephropathy, including increased diuresis (by ~500/%; P<0.001), natriuresis (by ~120%; P<0.001), creatinine clearance (by~70%; P<0.01) and microalbuminuria (by 300%; P<0.001). Treatment doubled the blood level of eicosanoids, which drastically reduced incorporation of aggregated amylin in heart and kidneys. Animals in the treated group showed reduced cardiac hypertrophy and hypertension. The protective mechanisms included the mitigation of amylin-induced oxidative stress and inflammation.
Conclusions: Accumulation of oligomerized amylin affects cardiac and renal function in T2D. This pathological process is reduced by elevating the blood levels of anti-aggregation eicosanoids.
Author Disclosures: S. Srodulski: None. A. Loria: None. S. Despa: None. F. Despa: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.