High-fat diet is a key contributor to type 2 diabetes. Typically, people adhering to a high-fat diet are obese and resistant to insulin. In the heart, lipid accumulation leads to cardiac insulin resistance and ultimately contractile dysfunction. CD36 has been identified as the main fatty acid transporter in the heart.  In this thesis we discovered that as part of the CD36 translocation machinery, v-ATPase, the proton pump, is a key player in regulation of CD36 translocation. More specifically, v-ATPase becomes inhibited during lipid oversupply, which then directly leads to insulin resistance and contractile dysfunction. High glucose infusion could induce the re-assembly of v-ATPase. Novel therapeutic strategies that would selectively upregulate glucose uptake would be suited to re-activate v-ATPase, thereby combat insulin resistance in the lipid-overloaded diabetic heart.