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The ASCEPT Prize Lecture presented at Pharmacology 2019 - Developing targeted therapeutic approaches for the diabetic heart in pre-clinical models Speaker: Professor Rebecca Ritchie Baker, Heart and Diabetes Institute, Australia Chair: Professor Carl Kirkpatrick, Monash University, Australia The increasing global prevalence of and our ageing population has given rise to an epidemic of heart failure. Up to one-third of patients in clinical heart, failure trials are diabetic, and diabetes is an independent predictor of poor outcome. Despite the higher rate of heart failure trials are diabetic, and diabetes is an independent predictor of poor outcome. Despite the higher rate of heart failure in these patients, no specific treatment for heart failure exists for diabetic patients, representing an urgent clinical need. This presentation will provide a summary overview of the current clinical management of diabetes-associated cardiomyopathy and explore likely contributing mechanisms to this ‘diabetic cardiomyopathy’ based on insights from pre-clinical models. We and others have implicated elevated oxidative stress and cardiac generation of the reactive oxygen species (ROS) superoxide as likely contributors to this ‘diabetic cardiomyopathy’. More recently, we have identified novel mechanisms for limiting diabetes-associated cardiomyopathy, taking advantage of cardiac-selective gene delivery approaches to specifically target the myocardium. In particular, targeting the cardiomyocyte p110α subunit of phosphoinositide 3-kinase [PI3K(p100α)] attenuates diabetic cardiomyopathy in mice, even with a delayed therapeutic intervention (a clinically-relevant time point). Cardioprotective actions are evident across cardiac remodelling and impaired cardiac function, and are likely secondary to PI3K(p100α)]-mediated suppression of NADPH oxidase. Likewise, targeting glucose-driven β-Nacetylglucosamine (O-GlcNAc) post-translational modification of proteins in the heart is similarly cardioprotective. Two enzymes regulate this post-translational modification: O-GlcNAc transferase (OGT) which facilitates the addition of the O-GlcNAc sugar moiety to Ser/Thr residues of proteins, and O-GlcNAcase (OGA), which facilitates its removal. Utilizing cardiac-targeted recombinant-adeno-associated viral vector approaches to transduce mouse myocardium in vivo, we have now demonstrated, across both gain-of-function and loss-of-function, the key role of OGT:OGA balance on cardiac phenotype in the context of diabetes. Mechanistic insights implicate modification of both cardiac PI3K(p110α)-Akt signalling and cardiac mitochondrial respiration. Ultimately therapies based on innovative approaches for tackling the diabetic heart could pave the way for the development of much-needed pharmacotherapies for diabetic heart failure.