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Plasma Dipeptidyl Peptidase-4 Activity, a Novel Biomarker or Even a Possible Therapeutic Target for Depression in Type 2 Diabetic Patients: Results from a Cross-Sectional Study in China

DPP4 inhibitors have already been widely used as novel antidiabetic drugs in clinical practice; however, no study has ever evaluated the association between DPP4 activity and depression in type 2 diabetes. Consequently, in this study, we focus first on the evaluation of the association between plasma DPP4 activities and depression in type 2 diabetes. Second, we focus on the mechanisms and clinical implications for such an association. The present study included cross-sectional data from a total of 1,458 type 2 diabetic patients aged between 40 and 82 years. Exclusion criteria were: (1) subjects who had taken drugs that could affect DPP4 activity or depression symptoms for more than 3 months or at any time within 12 months before the enrollment; (2) subjects with presence of any of the diseases including acute inflammatory diseases, autoimmune disease, malignancy, hypothyroidism, newly diagnosed type 2 diabetes (diabetes duration <1 year), heart, respiratory, liver, and kidney failure; (3) subjects with incomplete data. The study has been approved by the Ethics Committee at the Affiliated Hospital of Guilin Medical University; all participants gave their written informed consent. This study was registered in the Chinese clinical trial registry (ChiCTR-EPC-14005273). On the survey date, all enrolled patients underwent routine medical history inquiries, physical examinations, and laboratory measurements. After an overnight fast of ≥ 10 h, venous blood samples were collected to measure hemoglobin (Hb) A 1c , interleukin (IL)-6, C-reactive protein (CRP), nitrotyrosine, 8-isoprostaglandin (PG) F 2a , NPY and DPP4 activity. Depression symptoms were assessed with the Patient Health Questionnaire-9 (PHQ-9), and the final diagnosis of depression was confirmed by a multidisciplinary team comprising psychiatrists and neuropsychologists. Patients with higher DPP4 activities tended to have higher levels of HbA 1c , IL-6, CRP, nitrotyrosine, 8-iso-PGF 2a , and PHQ-9 scores (all p < 0.05). The odds ratios (ORs) for increased HbA 1c , IL-6, CRP, nitrotyrosine, 8-iso-PGF 2a , and PHQ-9 score were higher with increasing DPP4 quartiles after adjustment for confounders. NPY was not found decreased with increasing DPP4 quartiles, neither in the crude model nor in the adjusted model. Among the 1,458 type 2 diabetic patients included in this study, 271 patients (18.6%) had depression symptoms. The prevalences Findings of epidemiological studies have shown an overall 2-fold increased prevalence of depression in patients with type 2 diabetes compared with the general population worldwide. Consequently, identifying biological markers and potential therapeutic targets for depression intervention seems crucial to effectively manage comorbid depression in patients with diabetes and improve health outcomes. Moreover, the best treatment for depression in diabetes would be an approach that simultaneously improved depressive symptoms and glycemic control [1] . Previous studies have already highlighted the pathogenetic role of hyperglycemia, inflammation, and oxidative stress in the development of depression [2, 3] . In addition, previous findings also lent support to the pathogenetic role of decreased neuropeptide Y (NPY) in depression [4] . Dipeptidyl peptidase-4 (DPP4) is a widely expressed multifunctional exopeptidase that exists as a membrane-anchored cell surface protein or in a soluble form in the plasma. In addition to its catalytic function in the degradation of NPY, it has also been identified as a novel adipokine playing important roles in the development of hyperglycemia, inflammation, and oxidative stress [5, 6] , all of which have been suggested to be involved in the pathogenesis of depression. More importantly, in our previous longitudinal study [5] , DPP4 activity was found to be higher in type 2 diabetic patients than in those with normal glucose tolerance. According to these findings above, we speculate that DPP4 activity may be positively correlated with depression symptoms in type 2 diabetes. Received: May 29, 2016 Accepted after revision: January 5, 2017 Published online: June 24, 2017