Abstract 13874: Elevated [Na + ] i in Cardiac Myocytes from Diabetic Rats Due to Enhanced Na + - Glucose Cotransport

Abstract

Intracellular Na + concentration ([Na + ] i ) is a key regulator of cardiac Ca 2+ cycling, contractility and metabolism. [Na + ] i is elevated in myocytes from failing hearts, leading to arrhythmias and oxidative stress. We hypothesized that myocyte [Na + ] i is also increased in type-2 diabetes (T2D) due to enhanced activity of the Na + -glucose cotransporter (SGLT). To test this hypothesis, we used myocardial tissue from humans with T2D and an animal model of late-onset T2D (HIP rats). We found increased SGLT expression in failing hearts from patients with T2D compared to non-diabetic individuals (by 55±16%) and in HIP rat hearts ( vs . age-matched wild-type, WT, littermates; by 59±17%). [Na + ] i , measured with the fluorescent indicator SBFI, is increased in myocytes from diabetic HIP rats, both at rest (14.7±0.9 mM compared to 11.4±0.7 mM in WT) and during electrical stimulation at 2 Hz (17.3±0.8 mM vs . 15.0±0.7 mM in WT). However, the Na + /K + -pump function (measured as the rate of pump-mediated [Na + ] i decline in intact myocytes) is not significantly altered in diabetic HIP rats. This result suggests that higher [Na + ] i is due to an increased Na + entry in HIP rat myocytes. Indeed, Na + influx, assessed as the rate of [Na + ] i rise upon Na + /K + -pump inhibition with 10 mM ouabain, was significantly larger in myocytes from diabetic HIP vs . WT rats (1.74±0.13 mM/min vs . 1.27±0.07 mM/min). SGLT inhibition with 250 μM phlorizin significantly reduced Na + influx in myocytes from diabetic HIP rats (to 1.08±0.20 mM/min), while it had no effect in the WT (1.14±0.21 mM/min). Phlorizin also significantly decreased glucose uptake in HIP rat myocytes (by 50±10 %) but not in WT, indicating an increased reliance on SGLT for glucose uptake in T2D hearts. In agreement with this result, the insulin-sensitive glucose uptake was greatly reduced in HIP rat myocytes vs . WT. These data suggest that SGLT is upregulated in diabetic hearts to compensate for reduced insulin-mediated glucose uptake. In summary, we found that [Na + ] i is elevated in myocytes from diabetic HIP rats due to an increased Na + entry via the Na + -glucose cotransporter. Higher [Na + ] i may contribute to arrhythmogenesis and oxidative stress in diabetic hearts.