Details

Autor(en) / Beteiligte

• Gao, Yang
• Yu, Haitao
• Liu, Yanchao
• Xu, Zhipeng
• He, Benrong
• Liu, Honghai
• Wang, Yuying
• Zhang, Yao
• Liang, Yi
• Yang, Ying
• Zheng, Jie
• Wang, Jian‐Zhi

Titel

GSK‐3β activation mediates apolipoprotein E4‐associated cognitive impairment in type 2 diabetes mellitus: A multicenter, cross‐sectional study

Ist Teil von

• Journal of diabetes, 2024-01, Vol.16 (1), p.e13470-n/a

Ort / Verlag

Melbourne: Wiley Publishing Asia Pty Ltd

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Wiley Online Library All Journals

Beschreibungen/Notizen

• Aim Both the activation of glycogen synthase kinase‐3β (GSK‐3β) and the presence of ApoE ε4 genotype have been found to respectively correlate with cognitive decline in patients with type 2 diabetes mellitus (T2DM), who further show a high incidence of developing Alzheimer's disease. However, the relationship between ApoE ε4 and GSK‐3β in the cognitive impairment of T2DM patients remains unclear. Methods ApoE genotypes and platelet GSK‐3β level were measured in 1139 T2DM patients recruited from five medical centers in Wuhan, China. Cognitive functions were assessed by Mini‐Mental State Examination (MMSE). The association and the relationships among apolipoprotein E (ApoE) genotypes, GSK‐3β activity and cognitive function were analyzed by regression and mediating effect analyses, respectively. Results T2DM patients with ApoE ε4 but not ApoE ε2 haplotype showed poorer cognitive function and elevated platelet GSK‐3β activity, when using ApoE ε3 as reference. The elevation of GSK‐3β activity was positively correlated the diabetes duration, as well as plasma glycated hemoglobin (HbA1c) and glucose levels. Moreover, correlation and regression analysis also revealed significant pairwise correlations among GSK‐3β activity, ApoE gene polymorphism and cognitive function. Lastly, using Baron and Kenny modeling, we unveiled a mediative role of GSK‐3β activity between ApoE ε4 and cognitive impairment. Conclusion We reported here that the upregulation of GSK‐3β activity mediates the exacerbation of cognitive impairment by ApoE ε4‐enhanced cognitive impairment in T2DM patients, suggesting GSK‐3β inhibitors as promising drugs for preserving cognitive function in T2DM patients, especially to those with ApoE ε4 genotype. Highlights The association of ApoE polymorphism with cognitive impairment in type 2 diabetes mellitus (T2DM) was inconclusive. Moreover, it is not reported whether and how glycogen synthase kinase‐3β (GSK‐3β), a crucial kinase in insulin resistance and Alzheimer disease‐like pathologies, play a role in linking ApoE ε4 and cognitive impairment. We revealed that ApoE ε4, but not ApoE ε2, was a risk factor of cognitive impairment in Chinese Han population. GSK‐3β activation acts as a mediator between ApoE ε4 and cognitive impairment. These data reveal a novel role ApoE ε4 and GSK‐3β in T2DM‐associated cognitive deficits. Targeting GSK‐3β, such as inhibitor, could be a constructive strategy in preserving the cognitive function in T2DM patients but need further proof.