Emerging evidence suggests that type 2 diabetes mellitus (T2DM) is associated with the pathogenesis of intervertebral disc degeneration (IDD). However, it is still unclear how T2DM contributes to IDD. Herein, we observed the accumulation of blood glucose and degenerative lumbar discs in mice fed a high-fat diet. Detection of differentially expressed genes in degenerative lumbar discs revealed that ADAMTS4 (A Disintegrin and Metalloproteinase with Thrombospondin motifs) and ADAMTS5 genes were significantly increased. In vitro analyses demonstrated that Runt-Related Transcription Factor 2 (Runx2) recruited both PPARgamma Coactivator 1alpha (PGC-1α) and CREB-Binding Protein (CBP) to transactivate the expression of ADAMTS4/5. Glucose stimulation could dose-dependently induce the accumulation of PGC-1α and promoted the binding of the CBP-PGC-1α-Runx2 complex to the promoters of ADAMTS4/5. Depletion of CBP-PGC-1α-Runx2 complex members and treatment with either PGC-1α inhibitor SR-18292 or CBP inhibitor EML425 in vitro could dramatically inhibit the glucose-induced expression of ADAMTS4/5. Administration of SR-18292 and EML425 in diabetic mice could prevent the degeneration of lumbar discs. Collectively, our results revealed a molecular mechanism by which the hyperglycemia-dependent CBP-PGC-1α-Runx2 complex was required for the transactivation of ADAMTS4/5. The blockage of this complex in diabetic mice may help prevent IDD.