The Comorbidity of Depression and Diabetes Is Involved in the Decidual Protein Induced by Progesterone 1 (Depp1) Dysfunction in the Medial Prefrontal Cortex

Background: There is a high rate of depressive symptoms such as irritability, anhedonia, fatigue, and hypersomnia in patients with type 2 diabetes mellitus (T2DM). However, the causes and underlying mechanisms of the comorbidity of depression and diabetes remain unknown. Methods: For the first time, we identified Decidual protein induced by progesterone 1 (Depp1), also known as DEPP autophagy regulator 1, as a hub gene in both depression and T2DM models. Depp1 levels were increased in the mPFC but not in other brain regions, such as the hippocampus or nucleus accumbens, according to Western blot and PCR assays. Results: Glucose dysregulation and synaptic loss occur in both depression and T2DM. The typical hyperglycemia in T2DM was observed in two models of depression, namely, chronic social defeat stress (CSDS) and chronic restraint stress (CRS). Hyperglycemia, which occurred in T2DM, was observed, and metabolomics data clearly showed the perturbation of glucose levels and glucose metabolism in the medial prefrontal cortex (mPFC). Decreased protein levels of BDNF and PSD95 suggested significant synaptic loss in depressed and diabetic mice. Conclusion: These findings suggest that the comorbidity of depression and diabetes is involved in the dysfunction of Depp1 in the mPFC.