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Introduction: Type 2 diabetes mellitus (T2DM) patients with depression have a higher risk of complications and mortality than T2DM without depression. However, the exact neuropathophysiological mechanism remains unclear. Consequently, the current study aimed to investigate the alteration of cortical and subcortical spontaneous neural activity in T2DM patients with and without depression. Methods: The demographic data, clinical variables, neuropsychological tests, and functional and anatomical magnetic resonance imaging of depressed T2DM (n=47) of non-depressed T2DM (n=59) and healthy controls (n=41) were collected and evaluated. The correlation analysis, stepwise multiple linear regression, and receiver operating characteristic curve were performed for further analysis. Results: Abnormal neural activities in the bilateral posterior cingulate cortex (PCC) and hippocampus were observed in depressed and non-depressed T2DM and the right putamen of the depressed T2DM. Interestingly, the subcortical degree centrality (DC) of the right hippocampus and putamen were higher in depressed than non-depressed T2DM. Furthermore, the cortical amplitude of low-frequency fluctuation (ALFF) in PCC, subcortical DC in the putamen of depressed T2DM, and hippocampus of non-depressed T2DM was correlated with cognitive scores. In contrast, the cortical fractional ALFF in PCC of non-depressed T2DM was correlated with depression scores. Conclusions: The abnormalities of spontaneous cortical activity in PCC and subcortical activity in the hippocampus might represent the neurobiological feature of cerebral dysfunction in T2DM. Notably, the altered subcortical activity in the right putamen might mainly associate with negative emotion in T2DM, which could be a promising biomarker for recognizing early cerebral dysfunction in depressed T2DM.

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