The Classically Cardioprotective Agent Diazoxide Elicits Arrhythmias in Type 2 Diabetes Mellitus

Background Type 2 diabetes mellitus (T2DM) is associated with an enhanced propensity for ventricular tachyarrhythmias (VTs) under conditions of metabolic demand. Activation of mitochondrial adenosine triphosphate-sensitive potassium (K_ATP) channels by low-dose diazoxide (DZX) improves hypoglycemia-related complications, metabolic function, and triglyceride and free fatty acid levels and reverses weight gain in T2DM. Objectives In this study, we hypothesized that DZX prevents ischemia-mediated arrhythmias in T2DM via its putative cardioprotective and antidiabetic property. Methods Zucker obese diabetic fatty (ZO) rats (n = 43) with T2DM were studied. Controls consisted of Zucker lean (ZL; n = 13) and normal Sprague-Dawley (SprD; n = 30) rats. High-resolution optical action potential mapping was performed before and during challenge with no-flow ischemia for 12 min. Results Electrophysiological properties were relatively stable in T2DM hearts at baseline. In contrast, ischemia uncovered major differences between groups, because action potential duration (APD) in T2DM failed to undergo progressive adaptation to ischemic challenge. DZX promoted the incidence of arrhythmias, because all DZX-treated T2DM hearts exhibited ischemia-induced VTs that persisted on reperfusion. In contrast, untreated T2DM and controls did not exhibit VT during ischemia. Unlike DZX, pinacidil promoted ischemia-mediated arrhythmias in both control and T2DM hearts. Rapid and spatially heterogeneous shortening of APD preceded the onset of arrhythmias in T2DM. DZX-mediated proarrhythmia in T2DM was not related to changes in the messenger ribonucleic acid expression of Kir6.1, Kir6.2, SUR1A, SUR1B, SUR2A, SUR2B, or ROMK (renal outer medullary potassium channel). Conclusions Ischemia uncovers a paradoxical resistance of T2DM hearts to APD adaptation. DZX reverses this property, resulting in rapid and heterogeneous APD shortening. This promotes reentrant VT during ischemia. DZX should be avoided in diabetic patients at risk of ischemic events.