Hyperglycemia-induced aberrant glucose metabolism is a causative factor of neurodegeneration and cognitive impairment in diabetes mellitus (DM) patients. The pyruvate dehydrogenase kinase (PDK)–lactic acid axis is regarded as a critical link between metabolic reprogramming and the pathogenic process of neurological disorders. However, its role in diabetic neuropathy remains unclear. Here, we found that PDK1 and phosphorylation of pyruvate dehydrogenase (PDH) were obviously increased in high glucose (HG)-stimulated primary neurons and Neuro-2a cell line. Acetyl-coA, a central metabolic intermediate, might enhance PDK1 expression via histone H3K9 acetylation modification in HG condition. The epigenetic regulation of PDK1 expression provided an available negative feedback pattern in response to HG environment-triggered mitochondrial metabolic overload. However, neuronal PDK1 was decreased in the hippocampus of streptozotocin (STZ)-induced diabetic mice. Our data showed that the expression of PDK1 also depended on the hypoxia-inducible factor-1 (HIF-1) transcriptional activation under the HG condition. However, HIF-1 was significantly reduced in the hippocampus of diabetic mice, which might explain the opposite expression of PDK1 in vivo. Importantly, overexpression of PDK1 reduced HG-induced reactive oxygen species (ROS) generation and neuronal apoptosis. Enhancing PDK1 expression in the hippocampus ameliorated STZ-induced cognitive impairment and neuronal degeneration in mice. Together, our study demonstrated that both acetyl-coA-induced histone acetylation and HIF-1 are necessary to direct PDK1 expression, and enhancing PDK1 may have a protective effect on cognitive recovery in diabetic mice.