Enhancing glucose oxidation In Vitro restores depressed transient outward K⁺ current (I_to) in ventricular myocytes from diabetic rats

The aim of this study was to examine the effects of increasing glucose oxidation on cardiac K⁺ channel function in experimental diabetes mellitus induced by streptozotocin. I_to and inward rectifier (I_kl) K⁺ currents were recorded by the whole cell voltage-clamp technique in ventricular myocytes isolated from the hearts of 2- to 4-wk diabetic and age-matched control rats. Under basal recording conditions, I_to density and kinetics of inactivation (τ₂) at +60 mV were ∼30% and ∼50% less in diabetics (n=23) than in control (n=22, P < 0.01), whereas I_kl was not altered. We separately tested two structurally different compounds that increase glucose oxidation: insulin and dichloroacetate (DCA). These agents had no effect on I_kl in either group of cells. However, each completely normalized I_to channel activity in myocytes from diabetic rats. Mean I_to density and τ₂ al +60 mV after 4 h treatment arc summarized as follows: INSULIN DCA Untreated 0.01μM 0.1μM C+0.1μM Untreated 0.15mM 1.5mM C+1.5mM (n=12) (n=7) (n=16) (n=8) (n=12) (n=6) (n=9) (n=8) I₁ (pA/pK)18.5±1.4 23.2±4.7 26.3±2.1* 26.4±4.1* 18.5±1.4 22.3±3.9 26.1±2.1* 27.6±4.7* τ₂ (ms) 111±15 153±59 213±50* 228±35* 110±16 214±56 236±54* 238±35* * p<0.05 vs. untreated diabetics. C = control myocytes. n = number of myocytes. The time course of normalization of I_to density in diabetic myocytes was also examined at hourly intervals After exposure to insulin or DCA, mean I_to density started to increase at 1-2 h, and was totally normalized after 2-3 h. Moreover, 3-bromopyruvate, an inhibitor of glucose oxidation, significantly reduced maximum I_to density in normal myocytes after 6-8 h exposure (25.6±3.3 pA/pF for untreated vs. 16.3±1.5 pA/pF at 1μM, and 12.1±2.0 pA/pF at 10 μM, n=12, p<0.05). These findings suggest that depressed glucose metabolism in the diabetic heart may be a key factor underlying the suppression of I_to channel activity, which may contribute to the contractile derangements and propensity for arrhythmias associated with diabetic cardiomyopathy.