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Introduction Type 2 diabetes (T2D) can cause diabetic cardiomyopathy (dbCM) characterised by functional and metabolic impairment. In T2D, Na +/K+-ATPase activity is impaired due to insulin resistance, hyperglycemia and hyperlipidaemia leading to intracellular sodium (Nai) overload and calcium dysregulation. Elevated Nai is a reversible modulator of myocardial mitochondrial metabolism.Thus, alleviating factors that drive Na+/K+-ATPase dysregulation in T2D could be an attractive therapeutic approach to ameliorate metabolic derangement and cardiac dysfunction in dbCM. Diltiazem, a calcium channel blocker, reduces cardiac calcium overload and restores intracellular insulin signalling and sensitivity. Therefore, we investigated whether diltiazem treatment can alleviate the dbCM phenotype, including Nai overload, in a mouse model of type 2 diabetes.Methods Diabetic db/db mice were treated with diltiazem (10mg/kg/day, n=14) in drinking water for 4-weeks prior to termination at 20-weeks of age. Cardiometabolic phenotype was assessed by echocardiography, Langendorff-perfused heart 23Na and 31P NMR spectroscopy, LC-MS/MS and biochemical analysis of plasma.Results 20-week db/db mice are obese, hyperglycaemic, insulin resistant and hyperlipidaemic. Development of dbCM is evident by diastolic dysfunction, alterations in left ventricle geometry, changes in cardiac metabolomic profile and elevated myocardial Nai (TQF 23Na spectra: lean 0.88±0.04, db/db 1.11±0.03 arb units, p<0.05). Compared to untreated db/db mice, diltiazem treatment alleviated hyperlipidaemia, hyperinsulinaemia, and restored cardiac function (E/A ratio: lean 1.45±0.03, db/db 1.73±0.06, diltiazem 1.43±0.08, p<0.05). Furthermore, diltiazem treatment improved metabolomic profile of db/db hearts, however elevated myocardial Nai was unaffected.Conclusion We show that diltiazem treatment alleviates the development of dbCM and metabolic derangement in T2D mouse model, independent of lowering elevated myocardial Nai.