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Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular complications including ischemia reperfusion injury (IR). Activation of mitochondrial KATP channels by Diazoxide (DZX) promotes beta cell rest and suppresses glucose production in patients. We hypothesized that DZX prevents IR arrhythmias in T2DM owing to its dual cardioprotective & antidiabetic property.Methods: Obese Zucker Diabetic Fatty (ZDF) rats (n=17) with established T2DM were studied. Control groups consisted of lean ZDF (n=6) and normal Sprague Dawley (n=10) rats. High resolution optical action potential (AP) mapping was performed in hearts before and after challenge with no flow ischemia for 12min followed by reperfusion.Results: Basal properties including rate dependence of conduction velocity (CV) and AP duration (APD) were not significantly (p=NS) altered in T2DM. Remarkably, ischemia uncovered major differences between groups as APD in T2DM failed to adapt to the ischemic challenge. Unlike APD, CV was reduced in all groups. DZX paradoxically promoted arrhythmias as all DZX (30uM) treated T2DM hearts exhibited ischemia related VT. In contrast, untreated T2DM (0/5) and control (0/9) hearts did not exhibit VT during ischemia. Underlying arrhythmic vulnerability of DZX treated T2DM hearts was a pronounced reduction (by 75% p<0.01) of the cardiac wavelength (WL) caused by accelerated APD shortening in response to ischemia. Upon reperfusion, T2DM and control groups exhibited a high (60% T2DM vs 44% control, p=NS) rate of VT, although the VT cycle length in T2DM was significantly longer (72 vs 44ms, p<0.01) suggesting a more adverse substrate modification by IR injury. Blocking the inner membrane anion channel (IMAC) fully abrogated reperfusion VT in T2DM.Conclusion: Ischemia uncovers a paradoxical resistance of T2DM hearts to APD adaptation. DZX reverses this property resulting in accelerated APD & WL shortening. This promotes reentrant VT during ischemia. Therefore, the anti-diabetic agent DZX should be avoided in T2DM patients at risk of ischemic events. Instead IMAC is an effective antiarrhythmic target for these patients.