The role of mitochondrial dysfunction in diabetes-associated cognitive dysfunction: A bibliometric analysis

Abstract

Background

Diabetes, a prevalent chronic disorder, is frequently complicated by diabetes-associated cognitive dysfunction (DACD). The impact of diabetes on specific cerebral regions accelerates the progression from mild cognitive impairment to Alzheimer's disease. Research has indicated that mitochondrial dysfunction is a pivotal factor in DACD, yet its underlying mechanisms remain elusive.

Objective

Our research aims to elucidate the research trends in this field over the past fifteen years by employing bibliometric analysis.

Methods

A systematic search and aggregation of literatures related to mitochondrial dysfunction in DACD published within the Web of Science Core Collection from 2010 to 2024 were performed. Subsequently, a bibliometric analysis was conducted employing four bibliometric software: HistCite, R-bibliometrix, VOSviewer, and CiteSpace.

Results

A total of 309 papers were identified for analysis. The most prolific country, institution, and authors were China, University of Coimbra, Moreira PI, and Li YS, respectively. The USA, Texas Tech University, and Reddy PH were the key country, institution, and author, respectively. Among references to articles in this field, Diabetes has the most cumulative citations. According to the analysis of co-citations, oxidative stress was the largest cluster. The primary keywords were “Alzheimer's disease” and “oxidative stress”. In recent years, the keyword “mitophagy” has received a lot of attention.

Conclusions

Oxidative stress represents a principal research topic within this field. Mitophagy offers a potential therapeutic avenue for DACD and may emerge as a novel focus of future investigations.

Keywords

Alzheimer's disease bibliometric analysis diabetes-associated cognitive dysfunction mitochondrial dysfunction mitophagy oxidative stress

Introduction

Diabetes is a globally prevalent chronic progressive disease. World Health Organization data indicates that 382 million people worldwide suffer from diabetes, and this number will reach 642 million by 2040.¹ Approximately 37% of individuals aged 65 and above suffer from diabetes-associated cognitive dysfunction (DACD), exhibiting symptoms such as memory decline and executive dysfunction.² Furthermore, diabetes mellitus has been implicated in inducing significant alterations in brain structure, potentially exacerbating the progression from mild cognitive impairment to Alzheimer's disease (AD).³ Previous research indicates that chronic hyperglycemia-induced oxidative stress, mitochondrial dysfunction, inflammatory responses, insulin signaling pathway disruptions, impaired blood-brain barrier function, and vascular changes exert concerted effects on the brain, ultimately culminating in cognitive dysfunction.⁴ However, the pathophysiological mechanisms underlying DACD have not been fully elucidated, garnering considerable research attention in this field.

A number of studies indicate mitochondrial dysfunction may play a critical role in DACD.⁵ The brain's cognitive abilities depend on the communication between neurons at synapses, which results in a significant energy demand.⁶ Mitochondria, known as the cell's powerhouses, are crucial for preserving neuronal integrity and responsiveness.⁷ Additionally, mitochondria maintain cellular viability by regulation of reactive oxygen species (ROS) production, intracellular calcium buffering, and apoptosis.^8–10 Under conditions of hyperglycemia, there is an augmentation in ROS production by mitochondria, leading to impairment of mitochondrial DNA and proteins, which consequently affects the energy supply and other crucial functions of the mitochondria. Furthermore, insulin resistance leads to a disturbance in the signaling pathway of insulin/insulin-like growth factor 1 (IGF-1), thereby impacting the biogenesis, functionality, and dynamic equilibrium of mitochondria.¹¹ The interplay of these factors collectively influences brain structure and function, culminating in a decrement of cognitive capacity. However, the underlying mechanisms of mitochondrial dysfunction in DACD are still not completely understood.

To more effectively address these issues and delineate future research directions, we have employed bibliometric analysis to uncover the present landscape of study within a specific domain. Bibliometrics, a discipline that leverages mathematical and statistical approaches to analyze literature data, enables the assessment and visualization of contributions from countries, institutions, authors, journals, and articles, as well as the interconnections among them.¹² Furthermore, due to its robust predictive capabilities for research trends, bibliometric analysis has been extensively applied across numerous domains of medical research.¹³ Therefore, we have collected articles from the past 15 years in this field to conduct a bibliometric analysis, thereby constructing a map of research forces and a knowledge map for this domain. Additionally, we have summarized current research focuses and the most promising directions for future research to assist scholars in exploring the intricate mechanisms and preventative and therapeutic strategies for DACD.

Methods

Data extraction

Literature about mitochondrial dysfunction in DACD in the last 15 years (2010–2024) was downloaded from the Web of Science Core Collection (WoSCC) on June 23, 2024. We constructed the search strategy by combining terms from the MeSH thesaurus and search strings previously used in other bibliometric studies on this topic. The retrieval strategy was TS = (“cognitive dysfunction” OR “cognitive impairment*” OR “neurocognitive disorder*” OR “cognitive decline”) AND TS = (diabetes* OR “hyperglycemia”) AND TS = (“mitochondrial dysfunction”). A total of 341 papers were obtained through this step. Subsequently, 21 documents were excluded, including proceeding papers (n = 9), editorial materials (n = 5), book chapters (n = 4), and meeting articles (n = 3). Furthermore, we manually screened for papers closely related to our research field. The criteria for manual screening were as follows: the title, abstract, or keywords of the paper should contain vocabulary related to the search string, and the research content should involve the mechanisms, influencing factors, or potential therapeutic approaches between mitochondrial dysfunction and DACD. Two researchers (WC and HSY) conducted the screening and recorded the data. Before the screening, the researchers involved were trained to ensure that they understood the research objectives and screening criteria. Each member conducted the screening independently, and then the results were collated. Inconsistent cases were compared and resolved through discussion or by consulting experts (WZH) in the field. Finally, only 309 papers were included in the subsequent analysis. Figure 1 presents the PRISMA flow diagram illustrating the process of literature search and selection.

Figure 1.

PRISMA flowchart for literature search and selection.

Statistical analysis

VOSviewer (version 1.6.20), CiteSpace (version 6.3.R1), HistCite (version 2.1), R-bibliometrix, and Scimago Graphica (version 1.0.45) were used for bibliometric analysis.

HistCite is an influential citation analysis tool developed to process the literature index information from the Web of Science.¹⁴ HistCite can swiftly process the bibliographic data imported from the WoSCC and automatically extract data for each article to facilitate article screening and ranking. Researchers can freely select data such as publication year, author, institution, journal, and citation to conduct data analysis of articles in the field. This efficient computational capability enables researchers to obtain a large amount of accurate citation data for literature in a short period. In this study, HistCite was employed to calculate the total global citation score (TGCS) and total local citation score (TLCS) for yearly publications, top countries, institutions, authors, and journals.¹⁵ TGCS represents the total number of citations in the Web of Science, while TLCS represents the number of citations in the database for a specific research field (finally determined 309 publications).

VOSviewer is a Java-based software for visualizing scientific knowledge networks.¹⁶ VOSviewer is a powerful tool for visualizing scientific knowledge networks. It can present complex scientific knowledge networks in an intuitive graphical format, helping researchers quickly identify key nodes and relationships in a research field. In the current study, it was deployed to construct collaboration networks between countries, institutions, and authors. The node colors indicate different time or clusters, node size represents the number of publications, and line thickness indicates the strength of cooperation.

Scimago Graphica can present the global network of national collaborations in a more intuitive geographical map or chord diagram, enabling researchers to understand the geographical distribution and intensity of international academic cooperation from a macro perspective.¹⁷ The size of each node indicates the number of publications, while the color of the node or line indicates the strength of the cooperation.

The R-bibliometrix package is a powerful bibliometric analysis tool developed in R. It not only helps researchers quickly obtain an overview of a research field but also, in combination with R's visualization tools, can generate high-quality visualizations to intuitively present analysis results.¹⁸ It was deployed to calculate the annual increase rate in publications, the publications of top authors over time, G and H index of top authors, which are vital indicators for the evaluation of the academic contributions of researchers.

CiteSpace is a core software with significant advantages in bibliometric analysis. It simplifies complex bibliographic data through visualization, enabling researchers to quickly identify hotspots and emerging trends in a research field.¹⁹ CiteSpace performs clustering analysis and co-occurrence analysis of keywords through the analysis of co-citation information, intuitively presenting the relationships between different topics and their evolution over time. Additionally, CiteSpace can identify literature or keywords with a significant increase in citations during a specific period through its citation burst function, helping researchers quickly capture research hotspots. It offers features such as dual-map overlay, co-citation analysis of journals, examination of co-citation networks, cluster analysis, timeline views of references, co-occurrence analysis of keywords, and the identification of citation bursts for both references and keywords. The size of the node indicates the total co-citation or occurrence frequency of the elements, and the various colors represent different clusters or years. Lines between nodes indicate co-citations or co-occurrences. Centrality is a metric used to measure the element's signiﬁcance. It indicates the number of times that the shortest paths between any two nodes in the network pass through a particular node. Nodes with high centrality are usually located between two large clusters or sub-networks, acting as a “mediator” or “bridge.” When the value of element centrality is greater than 0.1, a purple outer ring is added. Citation bursts represent a large change in citations over time. If an element node has a strong burst, the color of the node is red or pink. Modularity Q and mean silhouette value are two metrics to assess cluster quality. Generally, if modularity Q > 0.3, the cluster structure is signiﬁcant. And the cluster is considered persuasive if the mean silhouette value > 0.7.

Results

Quantitative distribution of publications and citation

Annual paper output is a key indicator reflecting the pace of knowledge progression and the evolving trends within a field.²⁰ From 2010 to 2024, a total of 309 documents associated with the role of mitochondrial dysfunction in DACD were obtained, including 173 articles and 136 reviews. The annual publications generally showed an upward trend, with the most growth from 2021 to 2022 and the highest number of 52 publications in 2023 (Figure 2A). Despite fluctuations in the volume of research publications within this field over the past 15 years, a distinct overall trend of growth is observed. By the date of the search, the total number of citations for these publications amounted to 10,188. (mean, 32.97). The year 2017 marked the peak in citations for TGCS, reaching 2,020, indicating a significant enhancement in the level of research during this period. In general, the dynamic changes in publications and citations indicated a rapid progression of interest in this field.

Figure 2.

Analysis of publication outputs and citations. (A) Annual publications and cumulative publications; (B) Global citations and local citations. TGCS, total global citation score. TLCS, total local citation score.

Distribution of countries/regions

The bibliometric analysis delineated a geographical distribution in the scholarship on mitochondrial dysfunction research in DACD. In total, 56 countries have published papers about mitochondrial dysfunction in DACD. China emerges as the preeminent contributor, amassing 88 publications, which translates to a substantial 28.48% of the global output (Figure 3A, B and Table 1). The United States follow with a significant 76 publications, constituting 24.60%. It is noteworthy that while the United States does not lead in publication volume, it has the highest TGCS (3806), signifying the superior quality of its research within this domain. Further, a co-authorship network among countries with more than two publications was constructed (Figure 3C, D). The United States has the highest total link strength (43), reflecting the most intense collaborative relationships with other nations, followed by China (22), Italy (19), and Australia (19). In conclusion, the findings mentioned indicate that The United States, China, Italy, and Australia make great contributions to this research field.

Figure 3.

Analysis of countries/regions. (A) Visual cluster analysis of cooperation among countries; (B) Density map of cooperation among countries; (C) World map of the intensity of cooperation between countries; (D) Circle diagram of international collaboration between countries.

Table 1.

The top 10 countries with the most publications.

Rank	Country	Publications	TGCS	TLCS	Total Link Strength
1	China	88 (28.48%)	1663	63	22
2	USA	76 (24.60%)	3806	86	43
3	Italy	23 (7.44%)	712	8	19
4	India	21 (6.70%)	347	6	14
5	South Korea	16 (5.18%)	354	4	7
6	Australia	14 (4.53%)	718	12	19
7	Portugal	12 (3.88%)	367	24	2
8	Spain	12 (3.88%)	653	1	14
9	Japan	10 (3.24%)	364	7	4
10	Mexico	10 (3.24%)	328	7	12

Distribution of institutions

Sum totaling 550 institutions conducted research on the mitochondrial dysfunction in DACD. Table 2 illustrates that among the top 13 institutions with the highest publication output are the University of Coimbra, Xi An Jiao Tong University, Fujian Medical University, and Texas Tech University with 12, 10, 8, and 8, respectively. Within the top 13 institutions, five are Chinese institutions, highlighting the considerable presence of China in this scientific domain. Additionally, Texas Tech University has the highest TGCS (612), followed by the University of Coimbra (367) and Xi An Jiao Tong University (270). Additionally, we constructed a co-authorship network for institutions with more than two publications. The co-authorship network demonstrates that collaboration between domestic institutions is relatively close, while international cooperation is not strong enough (Figure 4A, B). Therefore, fostering international collaboration among relevant institutions is crucial for propelling the future development of this field.

Figure 4.

Analysis of institutions. (A) Visual cluster analysis of cooperation among institutions; (B) Density map of cooperation among institutions.

Table 2.

The top 13 institutions that published the highest number of publications.

Rank	Institution	Country	Publications	TGCS	TLCS
1	University of Coimbra	Portugal	12 (3.88%)	367	24
2	Xi An Jiao Tong University	China	10 (3.24%)	270	11
3	Fujian Medical University	China	8 (2.59%)	85	12
4	Texas Tech University	USA	8 (2.59%)	612	18
5	Gyeongsang National University	South Korea	6 (1.94%)	37	0
6	Chinese Academy of Sciences	China	5 (1.62%)	209	0
7	University of Barcelona	Spain	5 (1.62%)	149	1
8	University of Kansas	USA	5 (1.62%)	215	28
9	Sapienza University of Rome	Italy	4 (1.29%)	230	3
10	Shanghai Jiao Tong University	China	4 (1.29%)	83	0
11	Sichuan University	China	4 (1.29%)	124	15
12	Universidad Autónoma de Chile	Chile	4 (1.29%)	149	3
13	University of Kentucky	USA	4 (1.29%)	258	16

Analysis of authorship

To pinpoint the leading authorities in this research field over the past 15 years, a ranking of 1660 authors has been compiled based on their publication counts (Table 3). The authors with the highest publication output are Moreira PI (9) from Portugal and Li YS (9) from China. However, the author with the highest TGCS is Reddy PH (669) from the United States. Subsequently, we constructed a collaboration network for authors with more than three publications (Figure 5A). Individual authors have formed their respective research groups and are actively collaborating in this field. It is noteworthy that there has been no interaction between these groups. Advancing this scientific discipline requires a concerted push towards bolstering teamwork and fostering better inter-team dialogue in the future.

Figure 5.

Analysis of authors. (A) Cooperation network of authors; (B) The top authors’ production over time; (C) Author local impact by H-index; (D) Author local impact by G-index.

Table 3.

The top 10 productive authors.

Rank	Author	Publications	Country	Institution	TGCS	TLCS
1	Moreira PI	9	Portugal	University of Coimbra	283	21
2	Li YS	9	China	Xi An Jiao Tong University	126	11
3	Wang Q	8	China	Xi An Jiao Tong University	96	11
4	Reddy PH	7	USA	Oregon Health & Science University	669	18
5	Carvalho C	7	Portugal	University of Coimbra	217	20
6	Cardoso S	6	Portugal	University of Coimbra	225	18
7	Chen Z	6	China	Fujian Medical University	75	12
8	Liu LB	6	China	Fujian Medical University	75	12
9	Santos MS	5	Portugal	University of Coimbra	216	19
10	Duarte AI	5	Portugal	University of Coimbra	203	15

A timeline depicting the publication history of the authors was drawn (Figure 5B). In the ranking of the most productive authors, Reddy PH has been contributing to this research area for no less than 12 years, beginning in 2013. It is worth noting that Li YS and Wang Q have published many valuable articles in recent four years in this field. Subsequently, the G and H index were calculated for all authors. Moreira PI not only has a substantial output but also has made a significant impact on the field. The comprehensive analysis indicates that Reddy PH, Li YS, and Moreira PI are prominent figures in this research area.

Core journals

We set the parameter K = 5 in CiteSpace to construct the co-citation network of journals. As shown in Figure 6A and Table 4, the analysis of journal co-citations indicated that Diabetes (222 citations) is the most cited journal followed by Proceedings of the National Academy of Sciences of the United States of America (220 citations) and PLoS One (212 citations). Among the top 10 journals by citation frequency, Nature has the highest IF of 50.5012. Sixty percent of the top 10 most co-cited journals are classified within Q1, while the rest belong to Q2. The journal with the highest centrality is Journal of Biological Chemistry (0.40), followed by Neurology (0.33) and Biochimica et Biophysica Acta-Molecular Basis of Disease (0.32), suggesting that these journals have exerted a substantial impact on this field.

Figure 6.

Analysis of journals. (A) Visualization of co-cited journals; (B) The dual-map overlay of journals. (Left side represents areas covered by citing journals, right side represents areas covered by cited journals).

Table 4.

The top 10 journals by co-citation and centrality.

Rank	Journal	Co-citations	JCR Partitions	Impact Factor (2023)	Journal	Centrality	JCR Partitions	Impact Factor (2023)
1	Diabetes	222	Q1	6.2001	Journal of Biological Chemistry	0.40	Q2	4
2	Proceedings of the National Academy of Sciences of the United States of America	220	Q1	9.4006	Neurology	0.33	Q1	7.7002
3	PLoS One	212	Q1	2.8997	Biochimica et Biophysica Acta-Molecular Basis of Disease	0.32	Q2	4.1998
4	Journal of Alzheimer's Disease	207	Q2	3.4	Diabetes	0.29	Q1	6.2001
5	Journal of Biological Chemistry	191	Q2	4	Brain Research	0.25	Q3	2.7001
6	Journal of Neuroscience	181	Q1	23.213	Molecular Neurobiology	0.24	Q1	4.6
7	Journal of Neurochemistry	179	Q2	4.1998	Journal of Neurochemistry	0.18	Q2	4.1998
8	Nature	178	Q1	50.5012	New England Journal of Medicine	0.17	Q1	96.1978
9	Neurobiology of Aging	175	Q2	3.7001	Science	0.16	Q1	44.7011
10	Diabetes Care	170	Q1	14.8	Cell	0.15	Q1	45.4993

Employing the dual-map overlay function of CiteSpace, the scholarly landscape across Scientific journals was constructed. The tags indicate the subjects addressed by the journal, and the tinted trails signify the connections established through citations. The citing journals mainly belong to the fields of molecular, biology, and immunology. The cited journals primarily pertain to the domains of molecular, biology, and genetics (Figure 6B).

Analysis of cited and co-cited references

Examining the cited literature offers insights into the intellectual framework of an academic discipline, identifying foundational works and pivotal contributions. According to Table 5, the cited reference with the highest citation counts is Talbot K (2004). This research directly establishes brain insulin resistance as an early and prevalent characteristic of AD, associated with IGF-1 resistance and IRS-1 dysfunction, yet it promotes cognitive dysfunction independent of classical AD pathology.²¹ Numerous researches have revealed a significant association between IGF-1 and IRS-1 with mitochondrial dysfunction.^22–24 Therefore, Talbot K's article provides a new perspective for studying the relationship between mitochondrial dysfunction and DACD. Referring to Table 6, the study with the highest co-citation frequency was published by Arnold SE et al. in 2018, who defined the concept of “brain insulin resistance” and reviewed evidence of intrinsic brain insulin resistance in AD and related dementias.²⁵ This article reveals a significant link between brain insulin resistance in T2DM and AD, potentially propelling the development of preventive and symptomatic treatment strategies.

Table 5.

The top 10 cited references.

Rank	First Author	Year	Journal	Citations	Title
1	Talbot K	2012	The Journal of Clinical Investigation	48	Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline
2	Steen E	2005	Journal of Alzheimer's Disease	39	Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease—is this type 3 diabetes?
3	Ott A	1999	Neurology	35	Diabetes mellitus and the risk of dementia
4	Arnold SE	2018	Nature Reviews Neurology	31	Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums
5	Biessels GJ	2018	Nature Reviews Endocrinology	30	Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications
6	Bomfim TR	2012	The Journal of Clinical Investigation	30	An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease–associated Aβ oligomers
7	Craft S	2012	Archives of Neurology	30	intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment
8	Biessels GJ	2006	Lancet Neurology	29	Risk of dementia in diabetes mellitus: a systematic review
9	de la Monte Suzanne M	2008	Journal of Diabetes Science and Technology	28	Alzheimer's disease is type 3 diabetes-evidence reviewed
10	De Felice FG	2014	Diabetes	25	Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease

Table 6.

The top 10 co-cited references.

Rank	First Author	Year	Journal	Co-citations	Title
1	Arnold SE	2018	Nature Reviews Neurology	28	Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums
2	Biessels GJ	2018	Nature Reviews Endocrinology	23	Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications
3	Kandimalla R	2017	Biochimica et Biophysica Acta-Molecular Basis of Disease	16	Is Alzheimer's disease a type 3 diabetes? A critical appraisal
4	Ou ZR	2018	Brain Behavior and Immunity	15	Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice
5	Koenig AM	2017	Alzheimer Disease & Associated Disorders	11	Effects of the insulin sensitizer metformin in Alzheimer disease: Pilot data from a randomized placebo-controlled crossover study
6	Xue M	2019	Ageing Research Reviews	10	Diabetes mellitus and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 144 prospective studies
7	Craft S	2017	Journal of Alzheimer's Disease	10	Effects of regular and long-acting insulin on cognition and Alzheimer's disease biomarkers: a pilot clinical trial
8	Bomfim TR	2012	Journal of Clinical Investigation	9	An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease-associated Aβ oligomers
9	Crane PK	2013	New England Journal of Medicine	9	Glucose levels and risk of dementia
10	Butterfield DA	2014	Biochimica et Biophysica Acta-Molecular Basis of Disease	9	Elevated risk of type 2 diabetes for development of Alzheimer disease: A key role for oxidative stress in brain

Furthermore, it is imperative to consider the impact of time on citations: papers published earlier are generally cited more frequently than those published later.¹⁵ Consequently, we set the parameter K = 5 in CiteSpace to construct the co-citation network of the references (Figure 7A) and then conducted cluster analysis on the co-cited references (Figure 7B). The modularity Q was 0.8814 and weighed mean Silhouette was 0.9244, indicating the high quality of the cluster. Cluster labels were derived and ascribed utilizing the logarithmic likelihood ratio algorithm. The clustering analysis yielded a total of 6 clusters, which are “#1 oxidative stress”, “#5 dopaminergic neuron”, “#6 mitophagy”, “#7 insulin resistance”, “#8 astrocytic psph”, and “#9 synaptic injury”. Among the 6 clusters, “cluster #1 oxidative stress” is the largest. Besides, the timeline view of clusters was constructed to further demonstrate the research hotspots evolving at different periods (Figure 7C). Obviously, mitophagy and oxidative stress have recently garnered the attention of researchers. Finally, the citation burst was conducted based on the most co-cited references with the strongest citations (Figure 7D). The reference with the highest citation burst was published by Biessels GJ, et al. This survey collated the diverse mechanisms through which T2DM contributes to cognitive impairment and dementia, with special emphasis on the role of systemic mitochondrial dysfunction as a significant pathophysiological mechanism leading to the worsening of health conditions and cognitive dysfunction.²⁶

Figure 7.

Analysis of co-cited references. (A) The co-cited references citation network; (B) Cluster analysis of co-cited references; (C) Timeline distribution of the 6 clusters; (D) Top 23 references with the strongest citation bursts.

Analysis of keywords

Analysis of keywords allows for a rapid and direct exploration of prevalent research areas and emerging trends. We set the parameter K = 5 in CiteSpace to construct the co-occurrence network of keywords. The keywords with the highest frequency are “Alzheimer's disease”, “oxidative stress”, “mitochondrial dysfunction”, “insulin resistance” and “cognitive impairment” (Figure 8A). Keyword citation burst detection can illuminate emerging scholarly trends and novel subjects in a particular field. The emergent keywords in recent years mainly include “hippocampus”, “degrading enzyme”, “older adults”, “mitophagy” and “memory impairment” (Figure 8B). These results suggest that oxidative stress and mitophagy may have played a crucial role in the mitochondrial dysfunction that leads to DACD. Additionally, mitophagy has garnered widespread attention in recent studies. In addition, we have reviewed recent reviews published in this field to verify the reliability and timeliness of our research findings. The literature indicates that oxidative stress and mitochondrial dysfunction are common pathological features of T2DM and neurodegenerative diseases (such as AD and Parkinson's disease). Moreover, mitophagy plays a crucial role in maintaining mitochondrial quality and homeostasis by clearing damaged mitochondria through ubiquitin-mediated pathways.²⁷

Figure 8.

Analysis of keywords. (A) Network map of keywords; (B) Top 19 keywords with the strongest citation bursts.

Discussion

In our research, we employed bibliometric techniques to analyze the literature related to mitochondrial dysfunction research in DACD. Our findings suggest that annual research output in this research area has shown an overall growth trend spanning the last decade and a half. The average yearly increase in the number of publications was 26.54%. Additionally, the TGCS of literature in this field has been undergoing a notable increase over time. Initially, it hovers around 50 counts per year, but this figure gradually climbs, peaking at 2020 counts in 2017. In recent years, the annual TGCS has been relatively lower. It's important to note that newly published articles generally receive fewer citations than older articles, as they have less time to accumulate them. In conclusion, the field is anticipated to undergo significant development and gradually reach maturity in the future.

The publications and TGCS of the country, institution, and author can reflect their scientific research level and academic influence. By assessing the research outputs from countries, countries, institutions, and authors can assist new researchers in this field in understanding the location of the primary scientific forces driving progress. As one of the leading forces, China has the highest output and six of the top 13 prolific institutions are located in China. Li YS with the most publications is also from China institutions. This phenomenon is underpinned by multifaceted reasons. In recent years, the Chinese government has placed a high priority on scientific research and has introduced a series of policies to promote its development. The government has also established various funding programs, such as the National Natural Science Foundation of China and the National Key Research and Development Program of China, providing ample financial support for researchers. Moreover, China has adopted a variety of strategies for talent cultivation and introduction. On the one hand, by strengthening the cultivation of domestic talents, a large number of high-quality talents have been provided for scientific research. On the other hand, the active introduction of high-level overseas talents has not only enhanced the overall quality of research teams but also brought new ideas and methods to research work. Additionally, this study has found that Chinese institutions have conducted extensive cooperation with institutions from other countries. This cooperation has not only facilitated the exchange of knowledge and technology but also provided researchers with broader perspectives and opportunities for collaboration. Interestingly, while the United States is not lead in publication volume, it has the highest TGCS, which could be explained by several factors. For instance, the United States has long maintained a robust scientific research funding system and a culture of freedom and innovation, which have enabled researchers to produce numerous high-quality research papers. The intensity of international cooperation in the United States is the highest, with its researchers and institutions engaging in extensive and in-depth collaborations with counterparts from other countries. Such cooperation not only facilitates the exchange of knowledge and technology but also forms a powerful research network to further enhance its research level and influence. Additionally, considering the authors’ productivity and their G and H index, it is evident that Moreira PI is a pivotal contributor in this research area. Their research group mainly focused on the pathogenesis of DACD and the therapeutic strategies, such as the role of mitochondria and uncoupling proteins in DACD, and the defensive impact of Exenatide-4 in preventing apoptosis by reducing mitochondrial cytochrome c release.^28,29 In his recent study, it was demonstrated that under high-glucose conditions, defects in mitochondrial transport and autophagy lead to the accumulation of damaged mitochondria, insufficient energy production, and a rise in neuropathological markers associated with AD.³⁰ Moreover, Moreira PI found that vascular system abnormalities closely related to mitochondrial changes and oxidative stress are commonalities between T2DM and AD, which supports the notion that T2DM may predispose to AD-like pathology.³¹ They proposed the concept of “drug repurposing” of antidiabetic drugs for the treatment of neurodegenerative diseases, providing new ideas for subsequent AD treatment.³² The team of Li YS is also an important research group in this field. They have proposed that caveolin-1 plays a significant regulatory role in cognitive decline and its related diseases and may become a potential therapeutic target for cognitive decline.³³ Subsequently, the team has carried out a series of studies targeting caveolin-1. For example, caveolin-1 regulates the mitochondrial fission-mitophagy axis, providing a new target for the treatment of DACD.³⁴ Reddy PH, who has the highest TGCS, and his team have proposed a new concept that human adenovirus 36 can improve DACD by regulating glycemic control and reducing pathological markers of AD.³⁵

The quality and prestige of a journal play a pivotal role in the dissemination of scientific research outcomes. The bibliometrically derived journal metrics provide a reliable reference for researchers in the retrieval of literature and the submission of their work for publication. Our analysis revealed that Diabetes is the journal with the highest number of co-citations. Diabetes published by the American Diabetes Association, covers a wide array of diabetes-related research, with a particular focus on the pathogenesis of DACD. Diabetes is a highly influential academic journal in its field of study, serving as a high-quality reference for scientific research in the domain. Additionally, Nature is the journal with the highest IF among the top 10 journals in co-citation frequency analysis, having published numerous interdisciplinary research findings of significant scientific importance. This suggests that the field of study has a high level of quality.

The analysis of co-cited references and keywords reflects the core discoveries resulting from current scholarly efforts and core themes. Our research findings indicate that the co-citation cluster analysis and keyword analysis have yielded common research subjects, further substantiating that these subjects are the hot topics and frontier areas of study in this field. Based on co-citation cluster analysis and the frequency of keywords, oxidative stress is the topic that researchers in this field are most concerned about. Mitochondrial dysfunction triggers oxidative stress in neurons, which is a key step in causing neuronal damage and cognitive dysfunction in the brain.³⁶ In the brain with insulin resistance, there is observed damage to the structure and function of brain mitochondria, along with substantial ROS production that contributes to oxidative stress.^37,38 Mitochondrial dysfunction results in the overproduction of ROS, which also decreases the functioning of the mitochondrial electron transport chain and the synthesis of ATP.³⁹ Additionally, mitochondrial DNA encodes the respiratory chain complexes and is susceptible to ROS, making it prone to damage caused by oxidative stress and genetic alterations. This further impairs the functioning of the mitochondrial electron transport chain, exacerbating energy failure and oxidative stress.⁴⁰ Excessive oxidative stress can lead to the buildup of amyloid-beta (Aβ) within synaptic mitochondria and the leakage of cytochrome c into the cytoplasm, inducing neuronal apoptosis and ferroptosis, ultimately leading to cognitive dysfunction.^41–43 As shown in Figure 7B, “cluster #1 oxidative stress”, and “cluster #6 mitophagy “partially overlap because the elevated levels of mitophagy serve to impede the generation of ROS by dysfunctional mitochondria, alleviating the oxidative stress within the cell.^44–46

Keyword bursts detected in our bibliometric analysis signify a rapid increase in the frequency of certain keywords within a relatively short period. These bursts are indicative of emerging research areas that are gaining significant attention from the scientific community. The hippocampus is a key brain region implicated in learning and memory impairment. The hippocampus, due to its high energy demands and sensitivity to oxidative stress, is particularly vulnerable to mitochondrial dysfunction, making it a current research hotspot in this field.⁴⁷ Studies have found that inhibiting mitochondrial dysfunction-induced oxidative stress in hippocampal neurons of mice can alleviate diabetes-associated memory impairment.⁴⁸ The emergence of “degrading enzyme” as a keyword suggests a growing interest in the molecular mechanisms underlying mitochondrial degradation and clearance. Understanding the role of specific enzymes in mitophagy and other autophagic processes could provide insights into how to enhance mitochondrial quality control and prevent neuronal damage.⁴⁹ The focus on “older adults” reflects the increasing prevalence of DACD in this population, as well as the growing number of studies focused on the prevention and treatment of DACD in this specific age group.

Analyzing the timeline of literature clusters and keyword bursts reveals that mitophagy has emerged as a focal point of scientific research in recent years. Mitophagy, a selective autophagic process, targets damaged or surplus mitochondria for degradation, ensuring the balance of mitochondrial quantity and quality within cells through specific labeling, isolation, and elimination. Mitophagy involves the identification of impaired mitochondria, and subsequent tagging by the ubiquitination and PINK1/Parkin signaling pathway, followed by the formation of autophagosomes through LC3 protein aggregation, fusion with lysosomes, and degradation, culminating in the recycling of components to preserve cellular homeostasis.⁵⁰ Excessive mitophagy may precipitate the fragmentation of healthy mitochondria and their subsequent destruction by proteases released from lysosomes, culminating in cellular demise.⁵¹ Particularly in the context of cerebral ischemia-reperfusion (I/R) injury, the overactivation of mitophagy can exacerbate neuronal apoptosis and intensify brain damage.⁵² Meanwhile, insufficient mitophagy leads to the accumulation of impaired mitochondria and an elevation of peroxides, inducing cellular damage.⁵³ Additionally, damaged mitochondria may generate a substantial amount of ROS, which can exacerbate oxidative stress and neuroinflammation, resulting in a decline in cognitive function.⁵⁴ Figure 9 presents a schematic diagram of the impact of mitophagy on nerve cell death resulting from mitochondrial dysfunction.

Figure 9.

Schematic diagram of the impact of mitophagy on nerve cell death resulting from mitochondrial dysfunction. Under normal conditions, mitophagy can suppress oxidative stress and energy failure caused by mitochondrial dysfunction, thereby inhibiting nerve cell death. However, insufficient or excessive mitophagy can promote nerve cell death.

Recent clinical research evidence suggests that dysregulation of mitophagy may play a significant role in DACD. A study employing proteomic analysis has revealed substantial changes in the proteins associated with the mitophagy pathway within peripheral blood platelets of patients exhibiting DACD, with proteins such as OPTN and SQSTM1 being particularly affected.⁵⁵ Additionally, other studies have detected elevated levels of LC3 in brain tissues of patients with type I diabetes mellitus who exhibit neuronal injury, suggesting that the autophagic system may be implicated in brain damage associated with diabetic patients.⁵⁶ AD, associated with brain insulin resistance and cerebral glucose metabolism dysregulation, is referred to as type 3 diabetes.⁵⁷ Evandro F et al. have identified alterations in the morphology of mitochondria within hippocampal neurons of AD patients. Moreover, a significant reduction in the colocalization of mitochondria with lysosomes was observed in hippocampal samples from AD patients compared to those from healthy controls, indicating an impairment in the clearance process of impaired mitochondria.⁵⁸ Conversely, Xuan Ye et al. observed an elevation in the levels of autophagy-related proteins, such as Parkin and LC3-II, in the brains of AD patients compared to control subjects, suggesting an enhancement of mitophagy in AD brains. However, they also detected a significant accumulation of morphologically aberrant mitochondria within neuronal perikarya of AD patient brains, indicating that despite an upregulation of mitophagy, there may be an insufficiency in the capacity to eliminate damaged mitochondria. As of now, there is a relative scarcity of studies investigating the relationship between mitophagy and DACD at the human level, with a corresponding lack of more direct evidence.

Studies conducted at the animal and cellular levels have focused on elucidating the specific mechanisms, thereby providing valuable insights for the treatment of DACD. Research indicates that levels of autophagy-related protein 7 and glycosylated lysosomal-associated membrane protein 1 are significantly diminished in the cortical and hippocampal regions of the brains of 3xTg-AD and T2D mice.⁵⁹ Additionally, researchers detected a marked decrease in the levels of mitophagy-related proteins PINK1 and TERT within the hippocampal tissue of APP transgenic mice in comparison to wild-type mice, which may impair the mitochondrial clearance mechanism, leading to the accumulation of impaired mitochondria and subsequent synaptic damage.⁶⁰ In HT22 cells expressing mAPP, there is a significant decrease in the mRNA levels of mitophagy-related genes PINK1 and TERT, as well as a reduction in mitochondrial length, suggesting that the structural changes in mitochondria may be consequent to compromised mitophagy.⁶¹ Furthermore, Su et al. demonstrated that the high glucose culture of PC12 cells affects the protein levels of PINK1 and Parkin, as well as the fusion process of mitochondria with lysosomes, leading to a reduction in autophagic flux.⁶² Meanwhile, Wang Z et al. demonstrated that in PC12 cells cultured under high-glucose conditions, the promotion of FUNDC1-mediated mitophagy ameliorates mitochondrial dysfunction induced by hyperglycemia.⁴⁴ Subsequently, authors discovered that LncRNA MEG3 alleviates DACD by reducing mitochondrial-derived apoptosis through the promotion of FUNDC1-mediated mitophagy via Rac1-ROS axis. This discovery provides a novel avenue for the treatment of DACD. In addition, Wang H et al. activated mitophagy through the autophagy activator rapamycin, reduced cytochrome c-mediated apoptosis and oxidative stress.⁶³ As a commonly utilized antihyperglycemic agent, metformin can indirectly promote mitophagy by inhibiting the mammalian target of rapamycin, potentially contributing to the therapeutic management of disorders associated with mitochondrial dysfunction, such as DACD.⁶⁴

In summary, the current literature suggests that overactivation of mitophagy in neuron may be associated with DACD, while others propose that it relates to the accumulation of abnormal mitochondria due to insufficient mitophagy. This discrepancy may arise from the challenges in perfectly mimicking hyperglycemic models in vivo, as well as disparities among in vitro models. We hypothesize that the compensatory mechanisms of mitophagy during the initial phase of diabetes, followed by a decompensation in later stages, could also be a potential reason for these contradictory conclusions. Therefore, the specific mechanisms by which mitophagy results in DACD still necessitate further exploration by researchers, which is key to resolving the issue of a dearth of clinical research and the limitations of therapeutic options available for future studies.

Through bibliometric analysis of research in this field, it has been found that mitochondrial dysfunction may be a core element in DACD. Insulin resistance, a hallmark pathological feature of T2DM, impairs mitochondrial energy supply and reduces glucose utilization efficiency, thereby contributing to mitochondrial dysfunction.⁶⁵ Furthermore, insulin resistance promotes amyloid-beta (Aβ) protein production and accumulation through multiple mechanisms.⁶⁶ Aβ deposition directly disrupts mitochondrial function by damaging the electron transport chain and ROS generation.⁶⁷ Concurrently, Aβ aggregation exacerbates insulin resistance via inhibition of insulin signaling pathways, thereby establishing a vicious cycle that amplifies mitochondrial damage.⁶⁸ Mitochondrial dysfunction not only aggravates oxidative stress and inflammatory responses, leading to neuronal injury, but also activates NF-κB signaling pathways and microglial cells, which further promote Aβ aggregation and hyperphosphorylation of tau protein.⁶⁹ Additionally, mitochondrial dysfunction suppresses the autophagic process, resulting in diminished clearance of Aβ and hyperphosphorylated tau proteins, ultimately accelerating neurodegenerative pathology.⁷⁰ It is worth noting that improving mitochondrial function has been proven to effectively alleviate cognitive impairment in diabetes. For example, the use of mitochondrial protectants or drugs that activate mitochondrial biogenesis can significantly improve cognitive function in diabetic mice.⁷¹ In addition, activating PINK1/Parkin-mediated mitophagy can also alleviate cognitive impairment caused by diabetes.⁷² In conclusion, mitochondrial dysfunction can cause neuronal damage, which subsequently leads to the deposition of Aβ protein and the hyperphosphorylation of tau protein, ultimately affecting the cognitive function of patients with diabetes. At the same time, mitochondrial dysfunction is also an important potential therapeutic target.

This is the first study to illustrate the present landscape of research on mitochondrial dysfunction in DACD using bibliometric analysis. However, our study still had some limitations. Initially, due to the constraints of existing bibliometric tools, we confined our analysis to records downloaded from the WoSCC database, which may have led to the omission of data exclusively available in other datasets such as PubMed, Scopus, etc. Subsequently, this research included only articles and reviews, excluding meeting articles, editorial materials, proceeding papers, and book chapters.

Conclusions

In conclusion, this research conducted a comprehensive bibliometric analysis of articles on mitochondrial dysfunction in DACD, highlighting the developments and trends from 2010 to 2024. The global output of literature in this field has grown significantly, with China and the USA leading in terms of publication volume and impact. The University of Coimbra and Texas Tech University have made significant contributions to the research in this field. The works of Moreira PI and Reddy PH have been extensively cited. Diabetes and Nature serve as important sources of background knowledge for research in this domain. Oxidative stress and mitophagy are primary research topics in this field. Notably, mitophagy offers a potential therapeutic avenue for DACD and may emerge as a focal point for future investigations.

Footnotes

Acknowledgements

We really appreciate the editors’ inspiration and continuous support of this research.

ORCID iD

Zhihua Wang

Author contributions

Chen Wang: Methodology; Resources; Visualization; Writing – original draft.

Siyi He: Methodology; Resources; Writing – review & editing.

Lingling Wang: Software; Writing – review & editing.

Yushuang Yin: Supervision; Writing – review & editing.

Wenqi Zhang: Validation; Writing – review & editing.

Guanwen Lin: Project administration; Writing – review & editing.

Duozhi Wu: Formal analysis; Writing – review & editing.

Qin Zhou: Data curation; Writing – review & editing.

Zhihua Wang: Funding acquisition; Writing – review & editing.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Supported by the National Natural Science Foundation of China (82460227), Hainan Province Science and Technology Special Fund (ZDYF2024SHFZ095), and The Youth Fund Program of Hainan Provincial Natural Science Foundation of China (822QN451).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The data supporting the findings of this study are available within the article.

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