Increased Plasma Dipeptidyl Peptidase-4 Activities Predict Mild Cognitive Impairment in Elderly Type 2 Diabetic Patients: Findings from the GDMD Cohort Study in China

Abstract

Background: Dipeptidyl peptidase-4(DPP4) is a newly identified adipokine that has been proved to promote hyperglycemia, insulin resistance, oxidative stress and inflammation, all of which have been involved in the pathogenesis of mild cognitive impairment (MCI). Hence, we examined whether increased DPP4 activity was associated with prospective risk of MCI and determined whether this association was mediated by these four risk factors in elderly type 2 diabetic patients. Methods: Baseline plasma DPP4 activity, HOMA of insulin resistance (HOMA-IR), oxidative stress parameters, inflammatory markers and long-term glycemic control were ascertained in a cohort of elderly type 2 diabetic patients aged>60 years (n = 2,066), along with questionnaire findings, biochemical measurements and MCI diagnoses. Prospective associations of baseline DPP4 activity and MCI events and its possible mediators were determined by Cox regression and mediation analyses. Findings: Over a median follow-up of 4.8 years, 367 patients (17.8 %) were diagnosed with MCI. Higher baseline DPP4 activity, IL-6, CRP, nitrotyrosine and 8-iso-PGF2a were independent predictors of MCI after adjustment (P<0.001). Furthermore, IL-6, CRP, nitrotyrosine and 8-iso-PGF2a all had statistically significant mediating effects on DPP4 activity-associated MCI incidence (P<0.05). We did not find a positive association between baseline HOMA-IR, average HbA1c and MCI incidence. Interpretation: Our results suggest that increased plasma DPP4 activity is an independent risk factor for incident MCI, and this association appears to be partially mediated by oxidative stress and inflammation, not insulin resistance or long-term glycemic control, both of which might not be able to predict MCI as well. Trial Registration: Registered on the Chinese clinical trial registry (ChiCTR-EPC-14005273). Funding Statement: This study was supported by grants from National Natural Science Foundation of China (Grant NO. 81770829 and NO. 81560144), Scientific Research and Technology Development Projects of Science and Technology Department of Guangxi province (Grant NO.1598012-13), Natural Science Foundation of Guangxi Province (Grant NO. 2015GXNSFBA139119) and High-Level Medical Talents Training Program of Guangxi Province (G201903002). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The GDMD Study was approved by the institutional medical ethical committee at Affiliated Hospital of Guilin Medical University. All participants gave written informed consent before data collection.