Observational Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Jan 16, 2024; 12(2): 302-313
Published online Jan 16, 2024. doi: 10.12998/wjcc.v12.i2.302
Inverse relationship between platelet Akt activity and hippocampal atrophy: A pilot case-control study in patients with diabetes mellitus
Haruhiko Tokuda, Takamitsu Hori, Daisuke Mizutani, Tomoyuki Hioki, Kumi Kojima, Takashi Onuma, Yukiko Enomoto, Tomoaki Doi, Rie Matsushima-Nishiwaki, Shinji Ogura, Hiroki Iida, Toru Iwama, Takashi Sakurai, Osamu Kozawa
Haruhiko Tokuda, Takamitsu Hori, Daisuke Mizutani, Tomoyuki Hioki, Kumi Kojima, Tomoaki Doi, Rie Matsushima-Nishiwaki, Osamu Kozawa, Department of Metabolic Research, Research Institute, National Center for Geriatrics and Gerontology, Obu 474-8511, Japan
Haruhiko Tokuda, Department of Clinical Laboratory, National Center for Geriatrics and Gerontology, Obu 474-8511, Japan
Haruhiko Tokuda, Takamitsu Hori, Daisuke Mizutani, Tomoyuki Hioki, Rie Matsushima-Nishiwaki, Osamu Kozawa, Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Takamitsu Hori, Daisuke Mizutani, Yukiko Enomoto, Toru Iwama, Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Tomoyuki Hioki, Department of Dermatology, Central Japan International Medical Center, Minokamo 505-8510, Japan
Takashi Onuma, Hiroki Iida, Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Tomoaki Doi, Department of Emergency Medicine, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan
Tomoaki Doi, Shinji Ogura, Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Takashi Sakurai, Research Institute, National Center for Geriatrics and Gerontology, Obu 474-8511, Japan
Author contributions: Tokuda H contributed to project administration, funding acquisition, and patient recruitment; Tokuda H and Kozawa O contributed to conceptualisation, methodology, resources, and data curation; Tokuda H, Hori T, and Mizutani D conducted investigation; Hori T, Mizutani D, Hioki T, and Kojima K performed formal analysis; Hioki T, and Kojima K performed visualization; Tokuda H, Kozawa O, and Sakurai T performed validation; Tokuda H, Hori T, Mizutani D, Hioki T, Onuma T, and Kozawa O contributed to the writing and the editing of the manuscript; Enomoto Y, Doi T, Matsushima-Nishiwaki R, Ogura S, Iida H, and Iwama T contributed to supervision; All the authors have read and agreed to the published version of the manuscript.
Supported by Research Funding for Longevity Science from The National Center for Geriatrics and Gerontology, Japan, No. 19-21; and No. 22-19.
Institutional review board statement: This study was reviewed and approved by the Committee of Conduct of Human Research at the Gifu University Graduate School of Medicine (approval code: 2019-105) and the Institutional Review Board of the National Center for Geriatrics and Gerontology (approval code: 1237).
Informed consent statement: All study participants provided informed written consent before study enrolment.
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Haruhiko Tokuda, MD, PhD, Professor, Department of Metabolic Research, Research Institute, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu 474-8511, Japan. tokuda@ncgg.go.jp
Received: October 20, 2023
Peer-review started: October 20, 2023
First decision: November 28, 2023
Revised: December 15, 2023
Accepted: December 21, 2023
Article in press: December 21, 2023
Published online: January 16, 2024
Processing time: 82 Days and 20.8 Hours
Abstract
BACKGROUND

Akt plays diverse roles in humans. It is involved in the pathogenesis of type 2 diabetes mellitus (T2DM), which is caused by insulin resistance. Akt also plays a vital role in human platelet activation. Furthermore, the hippocampus is closely associated with memory and learning, and a decrease in hippocampal volume is reportedly associated with an insulin-resistant phenotype in T2DM patients without dementia.

AIM

To investigate the relationship between Akt phosphorylation in unstimulated platelets and the hippocampal volume in T2DM patients.

METHODS

Platelet-rich plasma (PRP) was prepared from the venous blood of patients with T2DM or age-matched controls. The pellet lysate of the centrifuged PRP was subjected to western blotting to analyse the phosphorylation of Akt, p38 mitogen-activated protein (MAP) kinase and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Phosphorylation levels were quantified by densitometric analysis. Hippocampal volume was analysed using a voxel-based specific regional analysis system for Alzheimer’s disease on magnetic resonance imaging, which proposes the Z-score as a parameter that reflects hippocampal volume.

RESULTS

The levels of phosphorylated Akt corrected with phosphorylated p38 MAP kinase were inversely correlated with the Z-scores in the T2DM subjects, whereas the levels of phosphorylated Akt corrected with GAPDH were not. However, this relationship was not observed in the control patients.

CONCLUSION

These results suggest that an inverse relationship may exist between platelet Akt activation and hippocampal atrophy in T2DM patients. Our findings provide insight into the molecular mechanisms underlying T2DM hippocampal atrophy.

Keywords: Akt; Platelet; Hippocampal atrophy; Magnetic resonance imaging; Diabetes mellitus

Core Tip: Type 2 diabetes mellitus (T2DM) is caused by insulin resistance, and Akt is involved in this process. Akt also plays an important role in human platelet activation. The hippocampus, associated with memory and learning, can decrease in volume in patients with an insulin-resistant phenotype. We investigated the relationship between Akt phosphorylation in unstimulated platelets and hippocampal volume-reflecting Z-score in T2DM patients. The levels of phosphorylated Akt corrected for phosphorylated p38 mitogen-activated protein kinase were inversely correlated with Z-scores in T2DM patients. These results suggest an inverse relationship between Akt activation in platelets and hippocampal atrophy in patients with T2DM.