PMID- 37700547
OWN - NLM
STAT- MEDLINE
DCOM- 20240207
LR  - 20240207
IS  - 1753-0407 (Electronic)
IS  - 1753-0393 (Print)
IS  - 1753-0407 (Linking)
VI  - 16
IP  - 1
DP  - 2024 Jan
TI  - GSK-3beta activation mediates apolipoprotein E4-associated cognitive impairment in 
      type 2 diabetes mellitus: A multicenter, cross-sectional study.
PG  - e13470
LID - 10.1111/1753-0407.13470 [doi]
LID - e13470
AB  - AIM: Both the activation of glycogen synthase kinase-3beta (GSK-3beta) and the presence 
      of ApoE epsilon4 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 epsilon4 and GSK-3beta in the cognitive impairment of T2DM patients remains unclear. 
      METHODS: ApoE genotypes and platelet GSK-3beta 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-3beta activity and 
      cognitive function were analyzed by regression and mediating effect analyses, 
      respectively. RESULTS: T2DM patients with ApoE epsilon4 but not ApoE epsilon2 haplotype 
      showed poorer cognitive function and elevated platelet GSK-3beta activity, when 
      using ApoE epsilon3 as reference. The elevation of GSK-3beta 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-3beta activity, ApoE gene polymorphism 
      and cognitive function. Lastly, using Baron and Kenny modeling, we unveiled a 
      mediative role of GSK-3beta activity between ApoE epsilon4 and cognitive impairment. 
      CONCLUSION: We reported here that the upregulation of GSK-3beta activity mediates 
      the exacerbation of cognitive impairment by ApoE epsilon4-enhanced cognitive impairment 
      in T2DM patients, suggesting GSK-3beta inhibitors as promising drugs for preserving 
      cognitive function in T2DM patients, especially to those with ApoE epsilon4 genotype.
CI  - (c) 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai 
      Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.
FAU - Gao, Yang
AU  - Gao Y
AUID- ORCID: 0000-0003-1707-9053
AD  - Department of Pathophysiology, School of Basic Medicine, Ministry of Education 
      Key Laboratory for Neurological Disorders, Hubei Key Laboratory for Neurological 
      Disorders, Tongji Medical College, Huazhong University of Science and Technology, 
      Wuhan, China.
AD  - Department of Radiology, Wuhan Brain Hospital, Wuhan, China.
FAU - Yu, Haitao
AU  - Yu H
AD  - Department of Fundamental Medicine, Wuxi School of Medicine, Jiangnan University, 
      Wuxi, China.
FAU - Liu, Yanchao
AU  - Liu Y
AD  - Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Xu, Zhipeng
AU  - Xu Z
AD  - Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - He, Benrong
AU  - He B
AD  - Department of Pathophysiology, School of Basic Medicine, Ministry of Education 
      Key Laboratory for Neurological Disorders, Hubei Key Laboratory for Neurological 
      Disorders, Tongji Medical College, Huazhong University of Science and Technology, 
      Wuhan, China.
FAU - Liu, Honghai
AU  - Liu H
AD  - School of Medicine and Health Management, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Wang, Yuying
AU  - Wang Y
AD  - Department of Pathophysiology, School of Basic Medicine, Ministry of Education 
      Key Laboratory for Neurological Disorders, Hubei Key Laboratory for Neurological 
      Disorders, Tongji Medical College, Huazhong University of Science and Technology, 
      Wuhan, China.
FAU - Zhang, Yao
AU  - Zhang Y
AD  - Li-Yuan Hospital, Tongji Medical College, Huazhong University of Science and 
      Technology, Wuhan, China.
FAU - Liang, Yi
AU  - Liang Y
AD  - Department of Radiology, Wuhan Brain Hospital, Wuhan, China.
FAU - Yang, Ying
AU  - Yang Y
AD  - Department of Pathophysiology, School of Basic Medicine, Ministry of Education 
      Key Laboratory for Neurological Disorders, Hubei Key Laboratory for Neurological 
      Disorders, Tongji Medical College, Huazhong University of Science and Technology, 
      Wuhan, China.
FAU - Zheng, Jie
AU  - Zheng J
AD  - Neuroscience Research Institute and Department of Neurobiology, School of Basic 
      Medical Sciences, Peking University; Key Laboratory for Neuroscience, Ministry of 
      Education/National Health Commission, Peking University, Beijing, China.
FAU - Wang, Jian-Zhi
AU  - Wang JZ
AUID- ORCID: 0000-0003-3569-9715
AD  - Department of Pathophysiology, School of Basic Medicine, Ministry of Education 
      Key Laboratory for Neurological Disorders, Hubei Key Laboratory for Neurological 
      Disorders, Tongji Medical College, Huazhong University of Science and Technology, 
      Wuhan, China.
AD  - Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
LA  - eng
GR  - 018B030336001/Guangdong Provincial Key S&T Program/
GR  - 2016YFC1305800/National Key R&D Program of China/
GR  - 2018ACA142/National Key R&D Program of China/
GR  - 31730035/Natural Science Foundation of China/
GR  - 81721005/Natural Science Foundation of China/
GR  - 81901107/Natural Science Foundation of China/
GR  - 91949205/Natural Science Foundation of China/
GR  - WX20Q04/Wuhan Health Science Foundation/
GR  - YCJJ202203019/Fundamental Research Funds for the Central Universities/
GR  - WJ2021M041/Hubei Province scientific research project/
PT  - Journal Article
PT  - Multicenter Study
DEP - 20230912
PL  - Australia
TA  - J Diabetes
JT  - Journal of diabetes
JID - 101504326
RN  - 0 (Apolipoprotein E4)
RN  - 0 (Apolipoproteins E)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - 0 (ApoE protein, human)
RN  - EC 2.7.11.1 (GSK3B protein, human)
SB  - IM
MH  - Humans
MH  - Alleles
MH  - Apolipoprotein E4/genetics
MH  - Apolipoproteins E/genetics
MH  - *Cognitive Dysfunction/genetics
MH  - Cross-Sectional Studies
MH  - *Diabetes Mellitus, Type 2/complications/genetics
MH  - Genotype
MH  - Glycogen Synthase Kinase 3 beta/genetics
PMC - PMC10809305
OTO - NOTNLM
OT  - ApoE
OT  - gene polymorphism
OT  - glycogen synthase kinase-3beta
OT  - mediation analyses
OT  - mild cognitive impairment
OT  - type 2 diabetes mellitus
COIS- The authors have no conflict of interest to declare.
EDAT- 2023/09/13 06:42
MHDA- 2024/01/30 12:44
PMCR- 2023/09/12
CRDT- 2023/09/13 02:03
PHST- 2023/07/17 00:00 [revised]
PHST- 2023/05/05 00:00 [received]
PHST- 2023/08/16 00:00 [accepted]
PHST- 2024/01/30 12:44 [medline]
PHST- 2023/09/13 06:42 [pubmed]
PHST- 2023/09/13 02:03 [entrez]
PHST- 2023/09/12 00:00 [pmc-release]
AID - JDB13470 [pii]
AID - 10.1111/1753-0407.13470 [doi]
PST - ppublish
SO  - J Diabetes. 2024 Jan;16(1):e13470. doi: 10.1111/1753-0407.13470. Epub 2023 Sep 
      12.