As an example, FoxO1 decreases glucose oxidation in the heart via promoting transcription of Pdk4, thereby increasing expression of PDH (pyruvate dehydrogenase) kinase 4, which phosphorylates and inactivates PDH, the rate-limiting enzyme of glucose oxidation.36 Moreover, pharmacological inhibition of FoxO1 fails to alleviate diastolic dysfunction in diabetic mice with a cardiac-specific deficiency of PDH,14 illustrating that increases in PDH activity and glucose oxidation contribute to how FoxO1 inhibition improves cardiac function in T2D. This evidence concerns the gene PDK4 and type 2 diabetes mellitus.