Differential effects of obesity and diabetes on the action potential waveform and inward currents in rat ventricular myocytes.

Abstract

Obesity is a significant health concern worldwide, increasing the risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease. Studies have found various vascular anomalies, abnormal heart rhythm, and impaired electro-mechanical coupling in patients with diabetes. Research on non-diabetic obese individuals has shown that besides diabetes-related complications, obesity itself raises the risk of developing cardiovascular disease. Recent studies have revealed a decrease in the speed of electrical signal conduction in the heart, along with slight gap junction dysfunction, which is insufficient to explain the observed impediment of impulse conduction. It's still unclear whether this impairment is due to obesity-related fat toxicity or diabetes-related factors. Our study aimed to investigate the ventricular action potential parameters and voltage-gated Na+ (INa) and Ca2+ (I(Ca, L)) currents in Zucker fatty (ZF) rats in comparison to Zucker diabetic fatty (ZDF) rats, a well-established model of obesity and T2DM. Ventricular myocytes were enzymatically isolated from 25-30-week-old Zucker rats. Resting and action potentials were recorded from isolated left ventricular myocytes using a beta-escin perforated patch clamp in current-clamp mode; INa and I(Ca, L) were recorded using whole-cell patch clamp techniques. Ventricular myocytes from ZF rats showed higher excitability and faster upstroke velocity. ZF rats also had a larger density of INa. Conversely, ZDF rats had decreased INa which correlated with a reduced velocity of the action potential upstroke. There were no changes in the density or voltage sensitivity of I(Ca, L) among the three groups of animals. In conclusion, obesity alone and obesity accompanied by DM have distinct effects on the action potential waveform, INa density and excitability of ventricular myocytes in a rat model of T2DM.