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Abstract Background Diabetes is associated with inner ear dysfunction. Furthermore, C57BL/6J mice fed high fat diet (HFD), a model for insulin resistance and diabetes, develop endolymphatic hydrops (EH). Aim Evaluate if betahistine, spironolactone (aldosterone antagonist) and empagliflozin (sodium –glucose cotransporter2 inhibitor) can prevent EH induced by HFD and explore potential mechanisms. Methods C57BL/6J mice fed HFD were treated with respective drug. The size of the endolymphatic fluid compartment was measured using contrast enhanced MRI. Secondarily, mice treated with cilostamide, a phosphodiesterase3 inhibitor, to induce EH and HEI-OC1 auditory cells were used to study potential cellular mechanisms of betahistine. Results HFD-induced EH was prevented by betahistine but not by spironolactone and empagliflozin. Betahistine induced phosphorylation of protein kinaseA substrates but did not prevent cilostamide-induced EH. Conclusions Betahistine prevents the development of EH in mice fed HFD, most likely not involving pathways downstream of phosphodiesterase3, an enzyme with implications for dysfunction in diabetes. The finding that spironolactone did not prevent HFD-induced EH suggests different mechanisms for EH induction/treatment since spironolactone prevents EH induced by vasopressin, as previously observed. Significance This further demonstrates that independent mechanisms can cause hydropic inner ear diseases which suggests different therapeutic approaches and emphazises the need for personalized medicine.