AUTHOR=Huang Rong , Tian Sai , Han Jing , Cai Rongrong , Lin Hongyan , Guo Dan , Wang Jiaqi , Wang Shaohua 

TITLE=Increased Ratio of Global O-GlcNAcylation to Tau Phosphorylation at Thr212 Site Is Associated With Better Memory Function in Patients With Type 2 Diabetes

JOURNAL=Frontiers in Physiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2019.00110

DOI=10.3389/fphys.2019.00110

ISSN=1664-042X

ABSTRACT=<p><bold>Objective:</bold> Aberrant <italic>O</italic>-GlcNAc modification has been implicated in type 2 diabetes mellitus (T2DM) and the pathogenesis of neurodegenerative diseases via competition with tau phosphorylation. We aimed to investigate the association between global <italic>O</italic>-GlcNAcylation, tau phosphorylation levels and mild cognitive impairment (MCI) in the whole blood of patients with T2DM.</p><p><bold>Methods:</bold> Sociodemographic, clinical characteristics and cognitive performances of the enrolled T2DM subjects were extensively assessed. Global <italic>O</italic>-GlcNAcylation and tau phosphorylation levels in the whole blood were also determined using Western blot.</p><p><bold>Results:</bold> Forty-eight T2DM subjects, including 24 with MCI and 24 with normal cognition, were enrolled in this study. Compared with cognitively normal controls, T2DM with MCI subjects displayed decreased global <italic>O</italic>-GlcNAcylation level, but increased tau phosphorylation levels (all <italic>p</italic> &lt; 0.05). To reflect the combined effect, the ratios of global <italic>O</italic>-GlcNAcylation to tau phosphorylation levels, including specific sites, such as Ser396, Ser404, Thr212, and Thr231, were all significantly decreased in MCI subjects (all <italic>p</italic> &lt; 0.05). Further multivariable logistic regression analysis revealed that high glycated hemoglobin A1c was an independent risk factor, whereas increased <italic>O</italic>-GlcNAc/p-T212 was an independent protective factor for MCI in patients with T2DM (odds ratio [OR] = 2.452, 95% confidence interval [CI] 1.061–5.668, <italic>p</italic> = 0.036; OR = 0.028, 95%CI 0.002–0.388, <italic>p</italic> = 0.008, respectively). With regard to each cognitive domain, <italic>O</italic>-GlcNAc/p-T212 was positively correlated with the score of Auditory Verbal Learning Test-delayed recall (<italic>r</italic> = 0.377, <italic>p</italic> = 0.010).</p><p><bold>Conclusion:</bold> Our study suggests that increased ratio of global <italic>O</italic>-GlcNAcylation to tau phosphorylation at Thr212 site in the whole blood is associated with decreased risk of MCI, especially with better memory function in T2DM subjects.</p><p><bold>Clinical Trial Registration:</bold><ext-link ext-link-type="uri" xlink:href="http://www.ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">www.ClinicalTrials.gov</ext-link>, identifier ChiCTR-OCC-15006060.</p>