Effects of kv1.3 inhibition in type 2 diabetes-induced cardiac electrical remodeling

Type 2 diabetes (T2D), characterized by insulin resistance and hyperglycemia, is accompanied by a low-grade inflammatory status. Certain pro-inflammatory cytokines, such as TNF-α and IL-1β, are highly expressed in T2D and play a critical role in insulin resistance. On the other hand, T2D shows a cardiac electrical remodeling, reflected as a prolongation of the QT interval of the ECG, which correlates with a higher risk of ventricular arrhythmia and sudden death. Besides, TNF-α and IL-1β, secreted by lymphocytes and macrophages, also cause cardiac electrical remodeling and increase arrhythmogenesis in cardiomyocytes. Thus, a treatment that modulates the inflammatory status could normalize hyperglycemia, by reducing insulin resistance. Moreover, the reduction of proinflammatory cytokines could also improve the cardiac electrical remodeling and reduce the risk of ventricular arrhythmia. In this sense, it is known that Kv1.3 channel expression in macrophages and T-lymphocytes modulates their activation and the inhibition of this channel improves insulin resistance and decreases TNF-α levels in obesity models. Therefore, we have studied the effects of the PAP-1, a Kv1.3 channel blocker, in the T2D and its associated cardiac electrical remodeling by using a T2D animal model that combines insulin resistance with β-cell damage.