Type 2 diabetes (T2D) can result in a number of comorbidities involving various organs including heart, eye, kidney and even the brain. However, little is known about the molecular basis of T2D associated brain disorders. In this study, we performed a comprehensive transcriptomic analysis in a total of 304 T2D samples and 608 matched control samples from thirteen distinct brain regions. We observed prominent difference among transcriptomic profiles of diverse brain regions in T2D. The most striking change was found in caudate with thousands of T2D-associated genes identified, followed by hippocampus, while nearly no transcriptomic change was observed in other brain regions. Functional analysis of T2D-associated genes revealed impaired synaptic functions and an association with neurodegenerative diseases. Co-expression analysis of caudate transcriptomic profiles unveiled a core regional specific module that was disorganized in T2D. Sub-modules consisting of regional markers were enriched in T2D risk single nucleotide polymorphisms (SNPs) and implied a causal link with T2D. Hub genes of this module include NSF and ADD2, the former of which has been associated with T2D and neurogenerative diseases. Thus, our work provides useful information for further studies in T2D associated brain disorders.