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Ye XW, Zhang HX, Li Q, Li CS, Zhao CJ, Xia LJ, Ren HM, Wang XX, Yang C, Wang YJ, Jiang SL, Xu XF, Li XR. Scientometric analysis and historical review of diabetic encephalopathy research: Trends and hotspots (2004-2023). World J Diabetes 2025; 16:91200. [DOI: 10.4239/wjd.v16.i5.91200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 12/18/2024] [Accepted: 02/20/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Diabetic encephalopathy (DE) is a common and serious complication of diabetes that can cause death in many patients and significantly affects the lives of individuals and society. Multiple studies investigating the pathogenesis of DE have been reported. However, few studies have focused on scientometric analysis of DE.
AIM To analyze literature on DE using scientometrics to provide a comprehensive picture of research directions and progress in this field.
METHODS We reviewed studies on DE or cognitive impairment published between 2004 and 2023. The latter were used to identify the most frequent keywords in the keyword analysis and explore the hotspots and trends of DE.
RESULTS Scientometric analysis revealed 1308 research papers on DE, a number that increased annually over the past 20 years, and that the primary topics explored were domain distribution, knowledge structure, evolution, and emergence of research topics related to DE. The inducing factors, comorbidities, pathogenesis, treatment, and animal models of DE help clarify its occurrence, development, and treatment. An increasing number of studies on DE may be a result of the recent increase in patients with diabetes, unhealthy lifestyles, and unhealthy eating habits, which have aggravated the incidence of this disease.
CONCLUSION We identified the main inducing factors and comorbidities of DE, though other complex factors undoubtedly increase social and economic burdens. These findings provide vital references for future studies.
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Affiliation(s)
- Xian-Wen Ye
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, Jiangxi Province, China
| | - Hai-Xia Zhang
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Qian Li
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Chun-Shuai Li
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, Jiangxi Province, China
| | - Chong-Jun Zhao
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Liang-Jing Xia
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Hong-Min Ren
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xu-Xing Wang
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Chao Yang
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yu-Jie Wang
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Shui-Lan Jiang
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xin-Fang Xu
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xiang-Ri Li
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
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Tang C, Hao J, Tao F, Feng Q, Song Y, Zeng B. Association of Metformin use with risk of dementia in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab 2025; 27:1992-2001. [PMID: 39780315 DOI: 10.1111/dom.16192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 12/17/2024] [Accepted: 12/28/2024] [Indexed: 01/11/2025]
Abstract
AIM There is ongoing debate concerning the association of metformin with the risk of dementia in type 2 diabetes mellitus (T2DM). This study was conducted to evaluate the impact of metformin therapy on dementia in patients with T2DM. MATERIALS AND METHODS PubMed, Embase, Cochrane Library, Web of Science and the ClinicalTrials.gov website were searched until 9 April 2024. Cohort studies investigating the effects of metformin therapy compared with other antidiabetic drugs or no therapy in T2DM were included. The hazard ratio (HR) and the 95% confidence interval (CI) were computed using the random effects model. RESULTS Twenty cohort studies (24 individual comparisons) involving 3 463 100 participants were identified. A meta-analysis revealed that people with T2DM who take metformin are linked to a lower incidence of all-cause dementia compared to non-user (n = 17, HR = 0.76, 95% CI = 0.65-0.91, p = 0.002, I2 = 98.9%) and sulfonylureas (n = 5, HR = 0.88, 95% CI = 0.85-0.90, p < 0.001, I2 = 9.7%), but not to thiazolidinedione (n = 2, HR = 0.53, 95% CI = 0.08-3.41, p = 0.503, I2 = 92.7%). Additionally, metformin showed favourable effects in non-specified T2DM (n = 19, HR = 0.75, 95% CI = 0.64-0.89), but not in newly diagnosed T2DM (n = 5, HR = 1.01, 95% CI = 0.81-1.27). CONCLUSION Metformin might correlate with a lower dementia incidence in people with T2DM. However, it is crucial to interpret these results with caution considering the high heterogeneity.
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Affiliation(s)
- Chunbian Tang
- Medical School of Tianjin University, Tianjin, China
- Department of General Medicine, Peking University Binhai Hospital (Tianjin Fifth Central Hospital), Tianjin, China
| | - Jiayi Hao
- Medical School of Tianjin University, Tianjin, China
| | - Fengran Tao
- Office of the President, Peking University Binhai Hospital (Tianjin Fifth Central Hospital), Tianjin, China
| | - Qingguo Feng
- Medical School of Tianjin University, Tianjin, China
- Department of Emergency, Peking University Binhai Hospital (Tianjin Fifth Central Hospital), Tianjin, China
| | - Ying Song
- Medical School of Tianjin University, Tianjin, China
- Department of General Medicine, Peking University Binhai Hospital (Tianjin Fifth Central Hospital), Tianjin, China
- Office of the President, Peking University Binhai Hospital (Tianjin Fifth Central Hospital), Tianjin, China
| | - Baoqi Zeng
- Department of Emergency, Peking University Binhai Hospital (Tianjin Fifth Central Hospital), Tianjin, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
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Hui EK, Mukadam N, Kohl G, Livingston G. Effect of diabetes medications on the risk of developing dementia, mild cognitive impairment, or cognitive decline: A systematic review and meta-analysis. J Alzheimers Dis 2025; 104:627-648. [PMID: 40017057 DOI: 10.1177/13872877251319054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Background: Diabetes is a risk factor for dementia, but we do not know whether specific diabetes medications ameliorate this risk. Objective: To systematically review and meta-analyze such medication's effect on the risk of developing dementia, mild cognitive impairment (MCI), or cognitive decline. Methods: We searched three databases until 21 November 2023. We included randomized controlled trials (RCT), cohort, and case-control studies assessing association between antidiabetic medication and future dementia, MCI, or cognitive decline. We meta-analyzed studies separately for individual drug classes and their comparators (no medication, placebo, or another drug). We appraised study quality using the Newcastle-Ottawa Scale and Physiotherapy Evidence Database Scale. Results: 42 studies fulfilled inclusion criteria. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) versus placebo reduced dementia risk by 53% in three RCTs (n = 15,820, RR = 0.47[0.25, 0.86]) and 27% in three case-control studies (n = 312,856, RR = 0.73[0.54, 0.99], I2 = 96%). Repaglinide was superior to glibenclamide by 0.8 points on the Mini-Mental State Examination scale in another RCT. Meta-analysis of seven longitudinal studies showed glitazones (n = 1,081,519, RR = 0.78[0.76, 0.81], I2 = 0%) were associated with reduced dementia risk. Metformin (n = 999,349, RR = 0.94[0.79, 1.13], I2 = 98.4%), sulfonylureas (RR = 0.98[0.78, 1.22], I2 = 83.3%), dipeptidyl peptidase-IV inhibitors (DPP-1V) (n = 192,802, RR = 0.86[0.65, 1.15], I2 = 92.9%) and insulin (n = 571,274, RR = 1.09[0.95, 1.25], I2 = 94.8%) were not. Most studies were observational and limited by confounding by indication. Conclusions: In people with diabetes, RCTs consistently showed GLP-RAs reduce future dementia risk. Glitazones consistently showed protective effects, without heterogeneity, suggesting potential generalizability of these results. Metformin, sulfonylureas, insulin, and DPP-1V studies had inconsistent findings. If information is available future studies should consider dosage, severity, and duration.
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Affiliation(s)
- Esther K Hui
- Division of Psychiatry, University College London, London, UK
| | - Naaheed Mukadam
- Division of Psychiatry, University College London, London, UK
| | - Gianna Kohl
- Division of Psychology and Language Sciences, University College London, London, UK
| | - Gill Livingston
- Division of Psychiatry, University College London, London, UK
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Kruczkowska W, Gałęziewska J, Buczek P, Płuciennik E, Kciuk M, Śliwińska A. Overview of Metformin and Neurodegeneration: A Comprehensive Review. Pharmaceuticals (Basel) 2025; 18:486. [PMID: 40283923 PMCID: PMC12030719 DOI: 10.3390/ph18040486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 03/13/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025] Open
Abstract
This comprehensive review examines the therapeutic potential of metformin, a well-established diabetes medication, in treating neurodegenerative disorders. Originally used as a first-line treatment for type 2 diabetes, recent studies have begun investigating metformin's effects beyond metabolic disorders, particularly its neuroprotective capabilities against conditions like Parkinson's disease, Alzheimer's disease, Huntington's disease, and multiple sclerosis. Key findings demonstrate that metformin's neuroprotective effects operate through multiple pathways: AMPK activation enhancing cellular energy metabolism and autophagy; upregulation of antioxidant defenses; suppression of inflammation; inhibition of protein aggregation; and improvement of mitochondrial function. These mechanisms collectively address common pathological features in neurodegeneration and neuroinflammation, including oxidative stress, protein accumulation, and mitochondrial dysfunction. Clinical and preclinical evidence supporting metformin's association with improved cognitive performance, reduced risk of dementia, and modulation of pathological hallmarks of neurodegenerative diseases is critically evaluated. While metformin shows promise as a therapeutic agent, this review emphasizes the need for further investigation to fully understand its mechanisms and optimal therapeutic applications in neurodegenerative diseases.
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Affiliation(s)
- Weronika Kruczkowska
- Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; (W.K.); (J.G.); (P.B.); (E.P.)
| | - Julia Gałęziewska
- Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; (W.K.); (J.G.); (P.B.); (E.P.)
| | - Paulina Buczek
- Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; (W.K.); (J.G.); (P.B.); (E.P.)
| | - Elżbieta Płuciennik
- Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; (W.K.); (J.G.); (P.B.); (E.P.)
| | - Mateusz Kciuk
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland;
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
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Wu Y, Liu Y, Jiao Z, Chen X, Li H, Zhou Y, Liu G. Association between the weight-adjusted waist index and age-related macular degeneration in US adults aged≥40 years: the NHANES 2005-2008. Front Med (Lausanne) 2025; 12:1552978. [PMID: 40115778 PMCID: PMC11922941 DOI: 10.3389/fmed.2025.1552978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Accepted: 02/24/2025] [Indexed: 03/23/2025] Open
Abstract
Objective The association between the weight-adjusted waist index (WWI) and age-related macular degeneration (AMD) in US adults aged 40 years and older is unknown. The goal of this study was to ascertain a possible association between the two. Methods Data were obtained from the National Health and Nutrition Examination Survey (NHANES) in the US from 2005 to 2008. The WWI was calculated by dividing waist circumference (WC) by the square root of body weight (kg). AMD was diagnosed based on distinctive features observed in the fundus, using a standard classification system. Weighted logistic regression analyses were conducted to investigate the association between the WWI and AMD. Spline smoothing and threshold effects were applied to explore non-linear correlations. Subgroup analyses were performed to identify underlying covariates affecting this relationship. In addition, receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive power of the WWI for AMD. Results A total of 5,132 participants were enrolled in this study. The results showed a significant positive association between the WWI and risk of AMD (OR = 1.76 (1.52, 2.04); p < 0.0001). When the WWI was categorized into tertiles, the highest group exhibited a stronger association compared to the lowest tertile (OR = 2.90 (2.18, 3.86); p < 0.0001) in model 1. The subgroup analyses and interaction tests indicated that the relationship between the WWI and AMD was stable across various populations. The spline smoothing and threshold effects showed a positive non-linear correlation between the WWI and AMD incidence. Furthermore, compared to body mass index (BMI), WC, and weight, the WWI showed better predictability for AMD, as shown by the ROC analysis. Conclusion There exists a positive non-linear association between the WWI and AMD in US adults aged 40 years and older. The WWI-related obesity management is necessary for the prevention and treatment of AMD.
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Affiliation(s)
- Yuting Wu
- Department of Ophthalmology, Affiliated People's Hospital (Fujian Provincial People's Hospital), Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Eye Institute of Integrated Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Yuxin Liu
- Department of Ophthalmology, Affiliated People's Hospital (Fujian Provincial People's Hospital), Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Eye Institute of Integrated Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Ziman Jiao
- Department of Ophthalmology, Affiliated People's Hospital (Fujian Provincial People's Hospital), Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Eye Institute of Integrated Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Xin Chen
- Department of Ophthalmology, Affiliated People's Hospital (Fujian Provincial People's Hospital), Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Eye Institute of Integrated Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Haiyu Li
- Department of Ophthalmology, Affiliated People's Hospital (Fujian Provincial People's Hospital), Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Eye Institute of Integrated Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Yunhao Zhou
- Department of Bioengineering, College of Biological Science and Biotechnology, Fuzhou University, Fuzhou, China
| | - Guanghui Liu
- Department of Ophthalmology, Affiliated People's Hospital (Fujian Provincial People's Hospital), Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Eye Institute of Integrated Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
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Sawalha K, Gautam N, Sivakumar K, Paydak H, Mehta JL. Metformin: Its salutary effects beyond diabetes mellitus. J Investig Med 2025:10815589251327511. [PMID: 40033492 DOI: 10.1177/10815589251327511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Metformin, an oral hypoglycemic agent, is commonly used in patients with type II diabetes mellitus. Studies have shown its use is associated with a reduction in major cardiovascular events (MACE) in patients with type 2 diabetes such as hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death. There is also a suggestion that metformin may have effects beyond those relating to lowering of blood sugar. The goal of this review is to assess the effects of metformin in coronary artery disease (CAD), but more importantly, its effects on disease states other than CAD.
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Affiliation(s)
- Khalid Sawalha
- Division of Cardiovascular Disease, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Nitesh Gautam
- Division of Cardiovascular Disease, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Kalaivani Sivakumar
- Division of Cardiovascular Disease, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Hakan Paydak
- Division of Cardiovascular Disease, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Jawaher L Mehta
- Division of Cardiovascular Disease, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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Abdullah Z, Cui Y, Platt RW, Renoux C, Azoulay L, Xia C, Yu OHY. Association between use of sodium-glucose co-transporter-2 inhibitor and the risk of incident dementia: a population-based cohort study. BMJ Open Diabetes Res Care 2025; 13:e004541. [PMID: 39842866 PMCID: PMC11751778 DOI: 10.1136/bmjdrc-2024-004541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 12/22/2024] [Indexed: 01/24/2025] Open
Abstract
OBJECTIVES To assess the association between sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use and the risk of incident dementia compared with dipeptidyl peptidase-4 inhibitors (DPP-4i) use among individuals with type 2 diabetes. DESIGN A population-based retrospective cohort study. SETTING The Clinical Practice Research Datalink (CPRD) Aurum database from the UK. PARTICIPANTS Individuals with type 2 diabetes, aged 40 years or older, newly prescribed SGLT-2i or DPP-4i on or after 2013-2021, registered in the CPRD Aurum database. MAIN OUTCOME MEASURE The primary outcome was incident dementia, and the secondary outcome was incident mild cognitive impairment (MCI). Cox proportional hazard models were used to estimate the HR and corresponding 95% CI for the primary and secondary outcomes. Propensity score fine stratification weights were used to adjust for confounding. RESULTS Among a cohort of 118 006 individuals, the incident rate (IR) of dementia was 0.56/1000 person-years over a median follow-up period of 1.54 years among SGLT-2i users compared with 2.67/1000 person-years in DPP-4i users, over a median follow-up period of 1.79 years. The adjusted HR for SGLT-2i use compared with DPP-4i use for dementia was 0.78 (95% CI 0.55 to 1.12), while for MCI was 0.86 (95% CI 0.80 to 0.92). The age-specific stratified analysis demonstrated the adjusted HR for SGLT-2i use compared with DPP-4i use for the risk of incident dementia among elderly, aged ≥65 years, was 0.50 (95% CI 0.31 to 0.80). CONCLUSION Primary findings did not yield conclusive evidence to infer an association between SGLT-2i use and the risk of incident dementia.
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Affiliation(s)
- Zarin Abdullah
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada
- Lady Davis Institute for Medical Research Centre for Clinical Epidemiology, Montreal, Québec, Canada
| | - Ying Cui
- Lady Davis Institute for Medical Research Centre for Clinical Epidemiology, Montreal, Québec, Canada
| | - Robert W Platt
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Québec, Canada
| | - Christel Renoux
- Lady Davis Institute for Medical Research Centre for Clinical Epidemiology, Montreal, Québec, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada
| | - Laurent Azoulay
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada
- Lady Davis Institute for Medical Research Centre for Clinical Epidemiology, Montreal, Québec, Canada
| | - Chenjie Xia
- Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada
| | - Oriana Hoi Yun Yu
- Lady Davis Institute for Medical Research Centre for Clinical Epidemiology, Montreal, Québec, Canada
- Department of Medicine, McGill University, Montreal, Québec, Canada
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Schwartz SS, Herman ME, Tun MTH, Barone E, Butterfield DA. The double life of glucose metabolism: brain health, glycemic homeostasis, and your patients with type 2 diabetes. BMC Med 2024; 22:582. [PMID: 39696300 DOI: 10.1186/s12916-024-03763-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 11/11/2024] [Indexed: 12/20/2024] Open
Abstract
The maintenance of cognitive function is essential for quality of life and health outcomes in later years. Cognitive impairment, however, remains an undervalued long-term complication of type 2 diabetes by patients and providers alike. The burden of sustained hyperglycemia includes not only cognitive deficits but also the onset and progression of dementia-related conditions, including Alzheimer's disease (AD). Recent research has shown that the brain maintains an independent glucose "microsystem"-evolved to ensure the availability of fuel for brain neurons without interruption by transient hypoglycemia. When this milieu is perturbed, brain hyperglycemia, brain glucotoxicity, and brain insulin resistance can ensue and interfere with insulin signaling, a key pathway to cognitive function and neuronal integrity. This newly understood brain homeostatic system operates semi-autonomously from the systemic glucoregulatory apparatus. Large-scale clinical studies have shown that systemic dysglycemia is also strongly associated with poorer cognitive outcomes, which can be mitigated through appropriate clinical management of plasma glucose levels. Moreover, these studies demonstrated that glucose-lowering agents are not equally effective at preventing cognitive dysfunction. Glucagon-like peptide-1 (GLP-1) receptor analogs and sodium glucose cotransporter 2 inhibitors (SGLT2is) appear to afford the greatest protection; metformin and dipeptidyl peptidase 4 inhibitors (DPP-4is) also significantly improved cognitive outcomes. Sulfonylureas (SUs) and exogenous insulin, on the other hand, do not provide the same protection and may actually worsen cognitive outcomes. In the creation of a treatment plan, comorbid cognitive conditions should be considered. These efficacious treatments create a new gold standard of managing hyperglycemia-one which is consistent with the "complication-centric prescribing" mandates issued in type 2 diabetes treatment guidelines. The increasing longevity enjoyed by our populace places the onus on clinical care to play the "long game" in using targeted treatments for glucose control in patients with, or at risk for, cognitive decline to maintain cognitive wellness later in life. This article reviews critical emerging data for scientists and trialists and translates new enhancements in patient care for practitioners.
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Affiliation(s)
- Stanley S Schwartz
- University of Pennsylvania School of Medicine, 771 County Line Road, Villanova, PA, 19085, USA
| | - Mary E Herman
- Social Alchemy: Building Physician Competency Across the Globe, 5 Ave Sur #36, Antigua, Sacatepéquez, Guatemala.
| | - May Thet Hmu Tun
- Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY, 11219, USA
| | - Eugenio Barone
- Sapienza University of Rome, Via Degli Equi 42, Scala A, Int. 5, 00185, Rome, Italy
| | - D Allan Butterfield
- Sanders-Brown Center On Aging, Department of Chemistry, University of Kentucky, 249 Chemistry-Physics Building, Lexington, KY, 40506-0055, USA
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Zhou Y, Xue F. Revolutionary drug repositioning: the preventive and therapeutic potential of metformin and other antidiabetic drugs in age-related macular degeneration. Front Pharmacol 2024; 15:1507860. [PMID: 39720591 PMCID: PMC11666363 DOI: 10.3389/fphar.2024.1507860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 11/26/2024] [Indexed: 12/26/2024] Open
Abstract
Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly worldwide. Anti-vascular endothelial growth factor (anti-VEGF) injections remain the first-line therapy for AMD. However, their high cost and the need for frequent administration pose challenges to long-term adherence, highlighting the need for accessible and cost-effective preventive strategies. Emerging evidence suggests that traditional antidiabetic drugs, such as metformin, sulfonylureas, and thiazolidinediones, may offer neuroprotective benefits, opening new avenues for AMD prevention. Among these, metformin has emerged as the most promising candidate, demonstrating significant potential in reducing AMD risk, even at low cumulative doses, primarily through AMP-activated protein kinase (AMPK) activation. Sulfonylureas, although effective in stimulating insulin secretion, carry risks such as hypoglycemia, hyperinsulinemia, and a possible association with increased cancer risk. Similarly, thiazolidinediones, while improving insulin sensitivity, are associated with adverse effects, including cardiovascular risks and macular edema, limiting their broader application in AMD prevention. This paper explores the preventive potential and underlying mechanisms of these antidiabetic drugs in AMD and discusses the role of artificial intelligence in optimizing individualized prevention strategies. By advancing precision medicine, these approaches may improve public health outcomes and reduce the burden of aging-related vision loss.
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Yang Y, Zhang X, Zhang Y, Zhao J, Jia J, Liu H, Song S. Metformin treatment improves depressive symptoms associated with type 2 diabetes: A 24-week longitudinal study. J Affect Disord 2024; 365:80-86. [PMID: 39147157 DOI: 10.1016/j.jad.2024.08.071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 06/23/2024] [Accepted: 08/12/2024] [Indexed: 08/17/2024]
Abstract
OBJECTIVE Metformin is a medication that is widely used for lowering blood sugar in patients with type 2 diabetes. Metformin was shown to have significant antidepressant effects; however, it is not clear whether metformin treatment improves outcomes in patients with type 2 diabetes who have concomitant depressive symptoms. METHODS A total of 475 patients with type 2 diabetes mellitus with depressive symptoms were included in this study and divided into metformin and nonmetformin groups according to whether they were taking metformin. The DASS-21 was used to assess patients' depression and anxiety scores before and after a 24-week intervention. In addition, general information about whether the patients had developed complications from diabetes and whether they had been diagnosed with other diseases was assessed. RESULTS (1) After 24 weeks, anxiety and depression scores were significantly lower in the metformin group than in the nonmetformin group. (2) The prevalence of depressive symptoms was significantly greater in female type 2 diabetic patients than in male patients (OR = 2.039, 95 % CI = 1.160-3.568). (3) People with type 2 diabetes who develop complications from diabetes (OR = 1.794, 95 % CI = 1.015-3.171) and those diagnosed with other conditions are more likely to experience depressive symptoms. CONCLUSION Metformin has an ameliorative effect on type 2 diabetes. However, women, those with diabetes complications, and those with type 2 diabetes who are also diagnosed with other conditions are more likely to experience depressive symptoms.
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Affiliation(s)
- Yating Yang
- The Second People's Hospital of Huizhou, Huizhou 512200, Guangdong, China
| | - Xi Zhang
- Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei 238000, China; School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei, 238000, China; Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Hefei 23800, China
| | - Yun Zhang
- Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei 238000, China; School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei, 238000, China; Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Hefei 23800, China
| | - Jianyong Zhao
- Department of Endocrinology, Chaohu Hospital of Anhui Medical University, Hefei 238000, China
| | - Jingfang Jia
- Department of Endocrinology, Chaohu Hospital of Anhui Medical University, Hefei 238000, China
| | - Huanzhong Liu
- Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei 238000, China; Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Hefei 23800, China.
| | - Suqi Song
- Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei 238000, China; Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Hefei 23800, China.
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11
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Zhang S, Wang F, Xie L, Xu J, Song X, Tao J, Chen J, Ma D, Yu X, Shi X, Yang Y. Sodium-glucose cotransporter 2 inhibition through henagliflozin ameliorates cognitive impairment in patients with type 2 diabetes. J Diabetes Investig 2024; 15:1596-1603. [PMID: 39254788 PMCID: PMC11527823 DOI: 10.1111/jdi.14306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/12/2024] [Accepted: 08/22/2024] [Indexed: 09/11/2024] Open
Abstract
AIMS/INTRODUCTION To assess whether the sodium-glucose cotransporter 2 inhibitor, henagliflozin, improves cognitive impairment in patients with type 2 diabetes. MATERIALS AND METHODS We carried out a prospective study on 290 patients with type 2 diabetes and cognitive impairment. Montreal Cognitive Assessment scores and plasma phosphorylated tau181 levels were used to assess cognition. The association between henagliflozin use and changes in cognition was examined using multivariable logistic regression analysis. RESULTS Montreal Cognitive Assessment scores at enrollment and after 6 months were 21 (interquartile range [IQR]19-23) versus 22 (IQR 20-25; P < 0.0001) in all patients, 21 (IQR 19-23) versus 24 (IQR 22-26; P < 0.0001) in the henagliflozin group and 21 (IQR 19-22) versus 21 (IQR 19-23; P > 0.05) in the non-sodium-glucose cotransporter 2 inhibitor group. Logistic regression analysis showed that henagliflozin treatment was associated with Montreal Cognitive Assessment score improvement independent of potential confounders (odds ratio [OR] 3.670, 95% confidence interval [CI] 2.224-6.056, P < 0.0001). Additionally, plasma phosphorylated tau181 levels significantly decreased at 6-month follow up in all patients (OR 11.5, 95% CI 9.9-13.7 vs OR 10.1, 95% CI 7.8-12.9, P < 0.0001) and in the henagliflozin group (OR 11.5, 95% CI 10.3-13.0 vs OR 9.2, 95% CI 7.1-10.7, P < 0.0001), but not in the non-sodium-glucose cotransporter 2 inhibitor group. Henagliflozin treatment was independently associated with decreased phosphorylated tau181 levels (OR 3.670, 95% CI 1.598-4.213, P < 0.0001). CONCLUSIONS Henagliflozin treatment was independently associated with improvements in Montreal Cognitive Assessment scores and plasma phosphorylated tau181 levels, indicating significant beneficial effects on cognitive impairment in patients with type 2 diabetes.
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Affiliation(s)
- Shujun Zhang
- Department of Endocrinology, Tongji Medical College, Tongji HospitalHuazhong University of Science and TechnologyWuhanHubei ProvinceChina
- Branch of National Clinical Research Center for Metabolic DiseaseWuhanHubei ProvinceChina
| | - Fen Wang
- Department of Endocrinology, Tongji Medical College, Tongji HospitalHuazhong University of Science and TechnologyWuhanHubei ProvinceChina
- Branch of National Clinical Research Center for Metabolic DiseaseWuhanHubei ProvinceChina
| | - Lei Xie
- Department of Endocrinology, Tongji Medical College, Tongji HospitalHuazhong University of Science and TechnologyWuhanHubei ProvinceChina
- Branch of National Clinical Research Center for Metabolic DiseaseWuhanHubei ProvinceChina
| | - Jialu Xu
- Department of Endocrinology, Tongji Medical College, Tongji HospitalHuazhong University of Science and TechnologyWuhanHubei ProvinceChina
- Branch of National Clinical Research Center for Metabolic DiseaseWuhanHubei ProvinceChina
| | - Xiaoqing Song
- Department of Endocrinology, Tongji Medical College, Tongji HospitalHuazhong University of Science and TechnologyWuhanHubei ProvinceChina
- Branch of National Clinical Research Center for Metabolic DiseaseWuhanHubei ProvinceChina
| | - Jing Tao
- Department of Endocrinology, Tongji Medical College, Tongji HospitalHuazhong University of Science and TechnologyWuhanHubei ProvinceChina
- Branch of National Clinical Research Center for Metabolic DiseaseWuhanHubei ProvinceChina
| | - Juan Chen
- Department of Neurosurgery, Tongji Medical College, Tongji HospitalHuazhong University of Science and TechnologyWuhanHubei ProvinceChina
| | - Delin Ma
- Department of Endocrinology, Tongji Medical College, Tongji HospitalHuazhong University of Science and TechnologyWuhanHubei ProvinceChina
- Branch of National Clinical Research Center for Metabolic DiseaseWuhanHubei ProvinceChina
| | - Xuefeng Yu
- Department of Endocrinology, Tongji Medical College, Tongji HospitalHuazhong University of Science and TechnologyWuhanHubei ProvinceChina
- Branch of National Clinical Research Center for Metabolic DiseaseWuhanHubei ProvinceChina
| | - Xiaoli Shi
- Department of Endocrinology, Tongji Medical College, Tongji HospitalHuazhong University of Science and TechnologyWuhanHubei ProvinceChina
- Branch of National Clinical Research Center for Metabolic DiseaseWuhanHubei ProvinceChina
| | - Yan Yang
- Department of Endocrinology, Tongji Medical College, Tongji HospitalHuazhong University of Science and TechnologyWuhanHubei ProvinceChina
- Branch of National Clinical Research Center for Metabolic DiseaseWuhanHubei ProvinceChina
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12
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Hroudová J, Fišar Z. Alzheimer's disease approaches - Focusing on pathology, biomarkers and clinical trial candidates. Prog Neuropsychopharmacol Biol Psychiatry 2024; 134:111069. [PMID: 38917881 DOI: 10.1016/j.pnpbp.2024.111069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 06/19/2024] [Accepted: 06/19/2024] [Indexed: 06/27/2024]
Abstract
The strategy for the development of new drugs for Alzheimer's disease (AD) recognizes that an effective therapy requires early therapeutic intervention and a multifactorial approach that considers the individual initiators of AD development. Current knowledge of AD includes the understanding of pathophysiology, risk factors, biomarkers, and the evolving patterns of biomarker abnormalities. This knowledge is essential in identifying potential molecular targets for new drug development. This review summarizes promising AD drug candidates, many of which are currently in phase 2 or 3 clinical trials. New agents are classified according to the Common Alzheimer's Disease Research Ontology (CADRO). The main targets of new drugs for AD are processes related to amyloid beta and tau neurotoxicity, neurotransmission, inflammation, metabolism and bioenergetics, synaptic plasticity, and oxidative stress. These interventions are aimed at preventing disease onset and slowing or eliminating disease progression. The efficacy of pharmacotherapy may be enhanced by combining these drugs with other treatments, antioxidants, and dietary supplements. Ongoing research into AD pathophysiology, risk factors, biomarkers, and the dynamics of biomarker abnormalities may contribute to the understanding of AD and offer hope for effective therapeutic strategies in the near future.
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Affiliation(s)
- Jana Hroudová
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic.
| | - Zdeněk Fišar
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic
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13
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Aderinto N, Olatunji G, Kokori E, Fawehinmi P, Moradeyo A, Igwe S, Ojabo R, Alabi BO, Okafor EC, Ologbe D, Olafimihan A, Olawade DB. Metformin mitigates dementia risk among individuals with type 2 diabetes. Clin Diabetes Endocrinol 2024; 10:10. [PMID: 38725077 PMCID: PMC11084076 DOI: 10.1186/s40842-024-00168-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 01/18/2024] [Indexed: 05/12/2024] Open
Abstract
This mini-narrative review explores the relationship between diabetes and dementia, focusing on the potential mitigating role of metformin in reducing cognitive decline among individuals with type 2 diabetes. The interplay of factors such as glycemic control, diabetic complications, and lifestyle influences characterises diabetes-related dementia. This review emphasises the significance of comprehensive diabetes management in addressing the heightened risk of dementia in this population. Methodologically, the review synthesises evidence from 23 studies retrieved through searches on PubMed, Embase, Google Scholar, and Scopus. Current evidence suggests a predominantly positive association between metformin use and a reduced risk of dementia in individuals with diabetes. However, the review shows the complex nature of these outcomes, revealing variations in results in some studies. These discrepancies show the importance of exploring dose-response relationships, long-term effects, and demographic diversity to unravel the complexities of metformin's impact on cognitive health. Limitations in the existing body of research, including methodological disparities and confounding variables, necessitate refined approaches in future studies. Large-scale prospective longitudinal studies and randomised controlled trials focusing specifically on cognitive effects are recommended. Propensity score matching and exploration of molecular mechanisms can enhance the validity of findings in clinical practice. From a clinical perspective, metformin can serve as a potential adjunctive therapy for individuals with diabetes at risk of cognitive decline.
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Affiliation(s)
- Nicholas Aderinto
- Department of Medicine and Surgery, Ladoke Akintola University of Technology, Ogbomoso, Nigeria.
| | - Gbolahan Olatunji
- Department of Medicine and Surgery, University of Ilorin, Ilorin, Nigeria
| | - Emmanuel Kokori
- Department of Medicine and Surgery, University of Ilorin, Ilorin, Nigeria
| | - Praise Fawehinmi
- Southern Illinois University Edwardsville, Edwardsville, IL, USA
| | - Abdulrahmon Moradeyo
- Department of Medicine and Surgery, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Stephen Igwe
- Department of Medicine and Surgery, University of Ilorin, Ilorin, Nigeria
| | | | | | | | | | | | - David B Olawade
- Department of Allied and Public Health, School of Health, Sport and Bioscience, University of East London, London, UK
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14
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Loan A, Syal C, Lui M, He L, Wang J. Promising use of metformin in treating neurological disorders: biomarker-guided therapies. Neural Regen Res 2024; 19:1045-1055. [PMID: 37862207 PMCID: PMC10749596 DOI: 10.4103/1673-5374.385286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/25/2023] [Accepted: 07/29/2023] [Indexed: 10/22/2023] Open
Abstract
Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases (Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), cerebrovascular conditions (stroke), and neurodevelopmental disorders (autism spectrum disorder). Although they affect millions of individuals around the world, only a limited number of effective treatment options are available today. Since most neurological disorders express mitochondria-related metabolic perturbations, metformin, a biguanide type II antidiabetic drug, has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism. However, controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders. Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging, lifestyle, genetics, and environment, it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders. These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment, ultimately developing targeted therapy. In this review, we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.
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Affiliation(s)
- Allison Loan
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biology, Faculty of Science, University of Ottawa, Ottawa, ON, Canada
| | - Charvi Syal
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Margarita Lui
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Ling He
- Department of Pediatrics and Medicine, Johns Hopkins Medical School, Baltimore, MD, USA
| | - Jing Wang
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
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15
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Morgan AE, Mc Auley MT. Vascular dementia: From pathobiology to emerging perspectives. Ageing Res Rev 2024; 96:102278. [PMID: 38513772 DOI: 10.1016/j.arr.2024.102278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/16/2024] [Accepted: 03/17/2024] [Indexed: 03/23/2024]
Abstract
Vascular dementia (VaD) is the second most common type of dementia. VaD is synonymous with ageing, and its symptoms place a significant burden on the health and wellbeing of older people. Despite the identification of a substantial number of risk factors for VaD, the pathological mechanisms underpinning this disease remain to be fully elucidated. Consequently, a biogerontological imperative exists to highlight the modifiable lifestyle factors which can mitigate against the risk of developing VaD. This review will critically examine some of the factors which have been revealed to modulate VaD risk. The survey commences by providing an overview of the putative mechanisms which are associated with the pathobiology of VaD. Next, the factors which influence the risk of developing VaD are examined. Finally, emerging treatment avenues including epigenetics, the gut microbiome, and pro-longevity pharmaceuticals are discussed. By drawing this key evidence together, it is our hope that it can be used to inform future experimental investigations in this field.
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Affiliation(s)
- Amy Elizabeth Morgan
- School of Health and Sports Sciences, Hope Park, Liverpool Hope University, Liverpool L16 9JD, United Kingdom.
| | - Mark Tomás Mc Auley
- School of Science, Engineering and Environment, University of Salford Manchester, Salford M5 4NT, United Kingdom
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16
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Rosell-Díaz M, Fernández-Real JM. Metformin, Cognitive Function, and Changes in the Gut Microbiome. Endocr Rev 2024; 45:210-226. [PMID: 37603460 PMCID: PMC10911951 DOI: 10.1210/endrev/bnad029] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 08/03/2023] [Accepted: 08/16/2023] [Indexed: 08/23/2023]
Abstract
The decline in cognitive function and the prevalence of neurodegenerative disorders are among the most serious threats to health in old age. The prevalence of dementia has reached 50 million people worldwide and has become a major public health problem. The causes of age-related cognitive impairment are multiple, complex, and difficult to determine. However, type 2 diabetes (T2D) is linked to an enhanced risk of cognitive impairment and dementia. Human studies have shown that patients with T2D exhibit dysbiosis of the gut microbiota. This dysbiosis may contribute to the development of insulin resistance and increased plasma lipopolysaccharide concentrations. Metformin medication mimics some of the benefits of calorie restriction and physical activity, such as greater insulin sensitivity and decreased cholesterol levels, and hence may also have a positive impact on aging in humans. According to recent human investigations, metformin might partially restore gut dysbiosis related to T2D. Likewise, some studies showed that metformin reduced the risk of dementia and improved cognition, although not all studies are concordant. Therefore, this review focused on those human studies describing the effects of metformin on the gut microbiome (specifically the changes in taxonomy, function, and circulating metabolomics), the changes in cognitive function, and their possible bidirectional implications.
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Affiliation(s)
- Marisel Rosell-Díaz
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, 17007 Girona, Spain
- Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IdibGi), 17007 Girona, Spain
- CIBERobn Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - José Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, 17007 Girona, Spain
- Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IdibGi), 17007 Girona, Spain
- CIBERobn Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
- Department of Medical Sciences, School of Medicine, University of Girona, 17004 Girona, Spain
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Kuate Defo A, Bakula V, Pisaturo A, Labos C, Wing SS, Daskalopoulou SS. Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta-analysis. Diabetes Obes Metab 2024; 26:441-462. [PMID: 37869901 DOI: 10.1111/dom.15331] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 09/12/2023] [Accepted: 09/29/2023] [Indexed: 10/24/2023]
Abstract
AIMS The objective of this umbrella review and meta-analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. MATERIALS AND METHODS We conducted a systematic umbrella review on diabetes and its treatment, and a meta-analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta-analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 July 2023. We conducted random-effects meta-analyses to obtain risk ratios and 95% confidence intervals estimating the association of metformin, thiazolidinediones, pioglitazone, dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, meglitinides, insulin, sulphonylureas, glucagon-like peptide-1 receptor agonists (GLP1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) with risk of dementia from cohort/case-control studies. The subgroups analysed included country and world region. Risk of bias was assessed with the AMSTAR tool and Newcastle-Ottawa Scale. RESULTS We included 100 reviews and 27 cohort/case-control studies (N = 3 046 661). Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk. CONCLUSIONS Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with reduced risk of dementia. More longitudinal studies aimed at determining their relative benefit in different populations should be conducted.
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Affiliation(s)
- Alvin Kuate Defo
- Vascular Health Unit, Research Institute of the McGill University Health Centre, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Veselko Bakula
- Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | | | - Christopher Labos
- Vascular Health Unit, Research Institute of the McGill University Health Centre, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Simon S Wing
- Division of Endocrinology & Metabolism, Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
| | - Stella S Daskalopoulou
- Vascular Health Unit, Research Institute of the McGill University Health Centre, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
- Division of Internal Medicine, Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
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Kaur DP, Bucholc M, Finn DP, Todd S, Wong-Lin KF, McClean PL. Impact of Different Diagnostic Measures on Drug Class Association with Dementia Progression Risk: A Longitudinal Prospective Cohort Study. J Alzheimers Dis 2024; 100:631-644. [PMID: 38905041 DOI: 10.3233/jad-230456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/23/2024]
Abstract
Background The Clinical Dementia Rating Scale Sum of Boxes (CDRSOB) score is known to be highly indicative of cognitive-functional status and is regularly employed for clinical and research purposes. Objective Our aim is to determine whether CDRSOB is consistent with clinical diagnosis in evaluating drug class associations with risk of progression to mild cognitive impairment (MCI) and dementia. Methods We employed weighted Cox regression analysis on longitudinal NACC data, to identify drug classes associated with disease progression risk, using clinical diagnosis and CDRSOB as the outcome. Results Aspirin (antiplatelet/NSAID), angiotensin II inhibitors (antihypertensive), and Parkinson's disease medications were significantly associated with reduced risk of progression to MCI/dementia and Alzheimer's disease medications were associated with increased MCI-to-Dementia progression risk with both clinical diagnosis and CDRSOB as the outcome. However, certain drug classes/subcategories, like anxiolytics, antiadrenergics, calcium (Ca2+) channel blockers, and diuretics (antihypertensives) were associated with reduced risk of disease progression, and SSRIs (antidepressant) were associated with increased progression risk only with CDRSOB. Additionally, metformin (antidiabetic medication) was associated with reduced MCI-to-Dementia progression risk only with clinical diagnosis as the outcome. Conclusions Although the magnitude and direction of the effect were primarily similar for both diagnostic outcomes, we demonstrate that choice of diagnostic measure can influence the significance of risk/protection attributed to drug classes and consequently the conclusion of findings. A consensus must be reached within the research community with respect to the most accurate diagnostic outcome to identify risk and improve reproducibility.
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Affiliation(s)
- Daman Preet Kaur
- Personalised Medicine Centre, School of Medicine, Ulster University, Altnagelvin Hospital, Derry/Londonderry, Northern Ireland, UK
| | - Magda Bucholc
- Intelligent Systems Research Centre, School of Computing, Engineering and Intelligent Systems, Ulster University, Derry/Londonderry, Northern Ireland, UK
| | - David P Finn
- Pharmacology and Therapeutics, School of Medicine, Galway Neuroscience Centre, University of Ireland, Galway, Ireland
| | - Stephen Todd
- Altnagelvin Area Hospital, Western Health and Social Care Trust, Derry/Londonderry, Northern Ireland, UK
| | - Kong Fatt Wong-Lin
- Intelligent Systems Research Centre, School of Computing, Engineering and Intelligent Systems, Ulster University, Derry/Londonderry, Northern Ireland, UK
| | - Paula L McClean
- Personalised Medicine Centre, School of Medicine, Ulster University, Altnagelvin Hospital, Derry/Londonderry, Northern Ireland, UK
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Tahmi M, Benitez R, Luchsinger JA. Metformin as a Potential Prevention Strategy for Alzheimer's Disease and Alzheimer's Disease Related Dementias. J Alzheimers Dis 2024; 101:S345-S356. [PMID: 39422959 DOI: 10.3233/jad-240495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Background Metformin is a safe and effective medication for type 2 diabetes (T2D) that has been proposed to decrease the risk of aging related disorders including Alzheimer's disease (AD) and Alzheimer's disease related disorders(ADRD). Objective This review seeks to summarize findings from studies examining the association of metformin with AD/ADRD related outcomes. Methods This is a narrative review of human studies, including observational studies and clinical trials, examining the association of metformin with cognitive and brain outcomes. We used PubMed as the main database for our literature search with a focus on English language human studies including observational studies and clinical trials. We prioritized studies published from 2013 until February 15, 2024. Results Observational human studies are conflicting, but those with better study designs suggest that metformin use in persons with T2D is associated with a lower risk of dementia. However, these observational studies are limited by the use of administrative data to ascertain metformin use and/or cognitive outcomes. There are few clinical trials in persons without T2D that have small sample sizes and short durations but suggest that metformin could prevent AD/ADRD. There are ongoing studies including large clinical trials with long duration that are testing the effect of metformin on AD/ADRD outcomes in persons without T2D at risk for dementia. Conclusions Clinical trial results are needed to establish the effect of metformin on the risk of AD and ADRD.
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Affiliation(s)
- Mouna Tahmi
- Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, NY, USA
| | - Richard Benitez
- Departments of Medicine, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - José A Luchsinger
- Departments of Medicine, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Department of Epidemiology, Joseph P. Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA
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Wu CY, Wang C, Saskin R, Shah BR, Kapral MK, Lanctôt KL, Herrmann N, Cogo-Moreira H, MacIntosh BJ, Edwards JD, Swardfager W. No association between metformin initiation and incident dementia in older adults newly diagnosed with diabetes. J Intern Med 2024; 295:68-78. [PMID: 37747779 DOI: 10.1111/joim.13723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
BACKGROUND Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity. OBJECTIVES To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias. METHODS Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models. RESULTS Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years). CONCLUSION Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported.
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Affiliation(s)
- Che-Yuan Wu
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | | | | | - Baiju R Shah
- ICES, Toronto, Ontario, Canada
- Divisions of Endocrinology and Obstetric Medicine, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Moira K Kapral
- ICES, Toronto, Ontario, Canada
- Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada
- Division of General Internal Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Krista L Lanctôt
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
- KITE University Health Network Toronto Rehabilitation Institute, Toronto, Ontario, Canada
| | - Nathan Herrmann
- Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Hugo Cogo-Moreira
- Faculty of Education, ICT, and Learning, Østfold University College, Halden, Norway
| | - Bradley J MacIntosh
- Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- Department of Radiology and Nuclear Medicine, Computational Radiology & Artificial Intelligence (CRAI), Oslo University Hospital, Oslo, Norway
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Jodi D Edwards
- University of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- ICES, Ottawa, Ontario, Canada
| | - Walter Swardfager
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- KITE University Health Network Toronto Rehabilitation Institute, Toronto, Ontario, Canada
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21
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de la Monte SM. Conquering Insulin Network Dysfunctions in Alzheimer's Disease: Where Are We Today? J Alzheimers Dis 2024; 101:S317-S343. [PMID: 39422949 PMCID: PMC11807374 DOI: 10.3233/jad-240069] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Functional impairments in the brain's insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver of the Alzheimer's disease (AD) neurodegeneration cascade. AD-associated insulin-deficient and insulin-resistant states mimic those of diabetes mellitus and affect all cell types in the brain. Besides accounting for abundant amyloid-β and hyperphosphorylated tau lesions in AD, insulin/IGF pathway dysfunctions cause cortical atrophy, loss of synaptic plasticity, white matter myelin/oligodendrocyte degeneration, astrocyte and microglial neuroinflammation and oxidative stress, deficits in energy metabolism, mitochondrial dysfunction, and microvascular disease. These same neuropathological processes have been linked to cognitive impairment in type 2 diabetes mellitus, Parkinson's disease, and vascular dementia. Strategies to address metabolic mediators of cognitive impairment have been borrowed from diabetes and other insulin-resistant diseases and leveraged on preclinical AD model data. The repurposing of diabetes drugs led to clinical trials with intranasal insulin, followed by insulin sensitizers including metformin and peroxisome-proliferator-activated receptor agonists, and then incretin mimetics primarily targeting GLP-1 receptors. In addition, other glucose-lowering agents have been tested for their efficacy in preventing cognitive declines. The strengths and limitations of these approaches are discussed. The main conclusion of this review is that we have now arrived at a stage in which it is time to address long-term deficits in trophic factor availability and receptor responsiveness, signaling abnormalities that extend beyond insulin and include IGFs and interconnected pathways, and the need for multi-pronged rather than single-pronged therapeutic targeting to remediate AD and other forms of neurodegeneration.
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Affiliation(s)
- Suzanne M. de la Monte
- Departments of Pathology and Laboratory Medicine, Medicine, Neurology and Neurosurgery, Rhode Island Hospital, Lifespan Academic Institutions, and the Warren Alpert Medical School of Brown University, Providence, RI, USA
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22
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Tian S, Jiang J, Wang J, Zhang Z, Miao Y, Ji X, Bi Y. Comparison on cognitive outcomes of antidiabetic agents for type 2 diabetes: A systematic review and network meta-analysis. Diabetes Metab Res Rev 2023; 39:e3673. [PMID: 37302139 DOI: 10.1002/dmrr.3673] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 03/02/2023] [Accepted: 04/25/2023] [Indexed: 06/13/2023]
Abstract
We aimed to summarise current evidence on different antidiabetic drugs to delay cognitive impairment, including mild cognitive impairment, dementia, Alzheimer's disease (AD) and vascular dementia, among subjects with type 2 diabetes mellitus (T2DM). Medline, Cochrane and Embase databases were searched from inception to 31 July 2022. Two investigators independently reviewed and screened trials comparing antidiabetic drugs with no antidiabetic drugs, placebo, or other active antidiabetic drugs on cognitive outcomes in T2DM. Data were analysed using meta-analysis and network meta-analysis. Twenty-seven studies met the inclusion criteria, including 3 randomised controlled trials, 19 cohort studies and 5 case-control studies. Compared with non-user, SGLT-2i (OR 0.41 [95% CI 0.22-0.76]), GLP-1RA (OR 0.34 [95% CI 0.14-0.85]), thiazolidinedione (OR 0.60 [95% CI 0.51-0.69]), and DPP-4i (OR 0.78 [95% CI 0.61-0.99]) users had a decreased risk of dementia, whereas sulfonylurea (OR 1.43 [95% CI 1.11-1.82]) increased dementia risk. Network meta-analysis showed that SGLT-2i was most likely to rank best (SUCRA = 94.4%), GLP-1 RA second best (SUCRA = 92.7%), thiazolidinedione third best (SUCRA = 74.7%) and DPP-4i fourth best (SUCRA = 54.9%), while sulfonylurea second worst (SUCRA = 20.0%) for decreasing dementia outcomes, by synthesising evidence from direct and indirect comparisons of multiple intervention. Evidence suggests the effects of SGLT-2i ≈ GLP-1 RAs > thiazolidinedione > DPP-4i for delaying cognitive impairment, dementia and AD outcomes, whereas sulfonylurea was associated with the highest risk. These findings provide evidence for evaluating the optional treatment for clinical practice. PROSPERO REGISTRATION: Registration no. CRD42022347280.
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Affiliation(s)
- Sai Tian
- Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
| | - Jiaxuan Jiang
- Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
| | - Jin Wang
- Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
| | - Zhou Zhang
- Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
| | - Yingwen Miao
- Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
| | - Xinlu Ji
- Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
| | - Yan Bi
- Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
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Shi X, Li L, Liu Z, Wang F, Huang H. Exploring the mechanism of metformin action in Alzheimer's disease and type 2 diabetes based on network pharmacology, molecular docking, and molecular dynamic simulation. Ther Adv Endocrinol Metab 2023; 14:20420188231187493. [PMID: 37780174 PMCID: PMC10540612 DOI: 10.1177/20420188231187493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 05/19/2023] [Indexed: 10/03/2023] Open
Abstract
Background Metformin, which has been shown to be highly effective in treating type 2 diabetes (T2D), is also believed to be valuable for Alzheimer's disease (AD). Computer simulation techniques have emerged as an innovative approach to explore mechanisms. Objective To study the potential mechanism of metformin action in AD and T2D. Methods The chemical structure of metformin was obtained from PubChem. The targets of metformin were obtained from PubChem, Pharm Mapper, Batman, SwissTargetPrediction, DrugBank, and PubMed. The pathogenic genes of AD and T2D were retrieved from the GeneCards, OMIM, TTD, Drugbank, PharmGKB, and DisGeNET. The intersection of metformin with the targets of AD and T2D is represented by a Venn diagram. The protein-protein interaction (PPI) and core targets networks of intersected targets were constructed by Cytoscape 3.7.1. The enrichment information of GO and Kyoto Encyclopedia of Gene and Genomics (KEGG) pathways obtained by the Metascape was made into a bar chart and a bubble diagram. AutoDockTools, Pymol, and Chem3D were used for the molecular docking. Gromacs software was used to perform molecular dynamics (MD) simulation of the best binding target protein. Results A total of 115 key targets of metformin for AD and T2D were obtained. GO analysis showed that biological process mainly involved response to hormones and the regulation of ion transport. Cellular component was enriched in the cell body and axon. Molecular function mainly involved kinase binding and signal receptor regulator activity. The KEGG pathway was mainly enriched in pathways of cancer, neurodegeneration, and endocrine resistance. Core targets mainly included TP53, TNF, VEGFA, HIF1A, IL1B, IGF1, ESR1, SIRT1, CAT, and CXCL8. The molecular docking results showed best binding of metformin to CAT. MD simulation further indicated that the CAT-metformin complex could bind well and converge relatively stable at 30 ns. Conclusion Metformin exerts its effects on regulating oxidative stress, gluconeogenesis and inflammation, which may be the mechanism of action of metformin to improve the common pathological features of T2D and AD.
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Affiliation(s)
- Xin Shi
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | - Lingling Li
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | - Zhiyao Liu
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | - Fangqi Wang
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | - Hailiang Huang
- Shandong University of Traditional Chinese Medicine, 4655 Guyunhu Street, Changqing District, Jinan City, Shandong Province, China
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Tseng CH. Effect of Metformin on Lower Urinary Tract Symptoms in Male Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Study in Taiwan. World J Mens Health 2023; 41:680-691. [PMID: 36593711 PMCID: PMC10307653 DOI: 10.5534/wjmh.220133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/24/2022] [Accepted: 09/20/2022] [Indexed: 01/04/2023] Open
Abstract
PURPOSE This study investigated the risk of lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) associated with metformin use. MATERIALS AND METHODS We used the database of Taiwan's National Health Insurance to create 9,833 pairs of ever users and never users of metformin matched on propensity score. They were males with a new diagnosis of type 2 diabetes during 1999-2005. The incidence of LUTS/BPH was calculated from January 1, 2006 until December 31, 2011. We estimated hazard ratios by Cox regression weighted on propensity score. RESULTS There were 515 incident cases in ever users after a median follow-up of 5.4 years (incidence rate: 11.24 per 1,000 person-years) and 682 cases in never users after 5.2 years (15.92 per 1,000 person-years). The hazard ratio (HR) that compared ever to never users was 0.69 (95% confidence interval [CI], 0.62-0.78). The HRs that compared ever users categorized into quartiles of cumulative duration (<19.33, 19.33-41.56, 41.57-67.17, and >67.17 mo) to never users were 1.02 (0.84-1.23), 1.01 (0.86-1.20), 0.57 (0.47-0.69), and 0.40 (0.32-0.49), respectively. For the quartiles of cumulative dose of <582.00, 582.00-1,361.00, 1,361.01-2,449.00, and >2,449.00 g, the respective HRs were 1.03 (0.85-1.24), 0.96 (0.81-1.13), 0.60 (0.49-0.72), and 0.40 (0.32-0.50). The lower risk was significant in all quartiles of defined daily dose. However, a larger daily dose was associated with a greater risk reduction. There were no significant interactions between metformin and other antidiabetic drugs. Patients who used rosiglitazone and/or pioglitazone without metformin had a significantly higher risk (HR, 1.33; 95% CI, 1.09-1.63) and a combination with metformin attenuated such an adverse impact (HR, 0.78; 95% CI, 0.66-0.91). CONCLUSIONS A significantly lower risk of LUTS/BPH is observed in males with type 2 diabetes who use metformin.
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Affiliation(s)
- Chin-Hsiao Tseng
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan.
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Lin HC, Chung CH, Chen LC, Wang JY, Chen CC, Huang KY, Tsai MH, Chien WC, Lin HA. Pioglitazone use increases risk of Alzheimer's disease in patients with type 2 diabetes receiving insulin. Sci Rep 2023; 13:6625. [PMID: 37095270 PMCID: PMC10126143 DOI: 10.1038/s41598-023-33674-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 04/17/2023] [Indexed: 04/26/2023] Open
Abstract
Pioglitazone is an insulin resistance inhibitor widely used as monotherapy or combined with metformin or insulin in treating type 2 diabetes mellitus (T2DM). This study further investigated the relationship between pioglitazone use and the risk of developing Alzheimer's disease (AD) in patients newly diagnosed with T2DM, and examined the potential impact of insulin use on this association. Data were extracted from the National Health Insurance Research Database (NHIRD) of Taiwan. Our data exhibited that the risk of developing AD in the pioglitazone group was 1.584-fold (aHR = 1.584, 95% CI 1.203-1.967, p < 0.05) higher than that in the non-pioglitazone controls. Compared to patients without both insulin and pioglitazone, higher cumulative risk of developing AD was found in patients receiving both insulin and pioglitazone (aHR = 2.004, 95% CI = 1.702-2.498), pioglitazone alone (aHR = 1.596, 95% CI = 1.398-1.803), and insulin alone (aHR = 1.365, 95% CI = 1.125-1.572), respectively (all p < 0.05). A similar observation also found in the evaluation the use of diabetic drugs with a cumulative defined daily dose (cDDD). No interaction between pioglitazone and major risk factors (comorbidities) of AD was observed. In conclusion, alternative drug therapies may be an effective strategy for reducing risk of developing AD in T2DM patients.
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Affiliation(s)
- Hsin-Chung Lin
- Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei City, 11490, Taiwan
- Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei City, 11490, Taiwan
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei City, 11490, Taiwan
- Taiwanese Injury Prevention and Safety Promotion Association, Taipei City, 11490, Taiwan
| | - Lih-Chyang Chen
- Department of Medicine, Mackay Medical College, New Taipei City, 252, Taiwan
| | - Jui-Yang Wang
- Department of Family Medicine, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei City, 10581, Taiwan
| | - Chien-Chou Chen
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei City, 10581, Taiwan
| | - Kuo-Yang Huang
- Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei City, 11490, Taiwan
| | - Ming-Hang Tsai
- Department of Medicine, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei City, 10581, Taiwan
| | - Wu-Chien Chien
- School of Public Health, National Defense Medical Center, Taipei City, 11490, Taiwan.
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei City, 11490, Taiwan.
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei City, 11490, Taiwan.
| | - Hsin-An Lin
- Division of Infection, Department of Medicine, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, No. 131, Jiankang Rd., Songshan District, Taipei City, 10581, Taiwan.
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Chegão A, Vicente Miranda H. Unveiling new secrets in Parkinson's disease: The glycatome. Behav Brain Res 2023; 442:114309. [PMID: 36706808 DOI: 10.1016/j.bbr.2023.114309] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/04/2023] [Accepted: 01/19/2023] [Indexed: 01/25/2023]
Abstract
We are witnessing a considerable increase in the incidence of Parkinson's disease (PD), which may be due to the general ageing of the population. While there is a plethora of therapeutic strategies for this disease, they still fail to arrest disease progression as they do not target and prevent the neurodegenerative process. The identification of disease-causing mutations allowed researchers to better dissect the underlying causes of this disease, highlighting, for example, the pathogenic role of alpha-synuclein. However, most PD cases are sporadic, which is making it hard to unveil the major causative mechanisms of this disease. In the recent years, epidemiological evidence suggest that type-2 diabetes mellitus (T2DM) individuals have higher risk and worst outcomes of PD, allowing to raise the hypothesis that some dysregulated processes in T2DM may contribute or even trigger the neurodegenerative process in PD. One major consequence of T2DM is the unprogrammed reaction between sugars, increased in T2DM, and proteins, a reaction named glycation. Pre-clinical reports show that alpha-synuclein is a target of glycation, and glycation potentiates its pathogenicity which contributes for the neurodegenerative process. Moreover, it triggers, anticipates, or aggravates several PD-like motor and non-motor complications. A given profile of proteins are differently glycated in diseased conditions, altering the brain proteome and leading to brain dysfunction and neurodegeneration. Herein we coin the term Glycatome as the profile of glycated proteins. In this review we report on the mechanisms underlying the association between T2DM and PD, with particular focus on the impact of protein glycation.
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Affiliation(s)
- Ana Chegão
- iNOVA4Health, NOVA Medical School, NMS, Universidade NOVA de Lisboa, Lisboa, Portugal
| | - Hugo Vicente Miranda
- iNOVA4Health, NOVA Medical School, NMS, Universidade NOVA de Lisboa, Lisboa, Portugal.
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Zhao H, Zhuo L, Sun Y, Shen P, Lin H, Zhan S. Thiazolidinedione use is associated with reduced risk of dementia in patients with type 2 diabetes mellitus: A retrospective cohort study. J Diabetes 2023; 15:97-109. [PMID: 36660897 PMCID: PMC9934955 DOI: 10.1111/1753-0407.13352] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 11/27/2022] [Accepted: 12/21/2022] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) and dementia cause heavy health burden in mainland China, where few studies have investigated the association between glucose-lowering agents and dementia risk. We aimed to assess the association between use of thiazolidinediones (TZDs) and dementia incidence in a mainland Chinese population with T2DM. METHODS A retrospective cohort of T2DM patients who were new users of TZDs or alpha glucosidase inhibitors (AGIs) was assembled using the Yinzhou Regional Health Care Database. A Cox model with inverse probability of treatment weighting (IPTW) for controlling potential founding was applied to estimate the hazard ratio (HR) of the association between use of TZDs and dementia risk. RESULTS A total of 49 823 new users of AGIs and 12 752 new users of TZDs were included in the final cohort. In the primary analysis, the incidence of dementia was 195.7 and 78.2 per 100 000 person-years in users of AGIs and TZDs respectively. TZD use was associated with a reduced risk of incident dementia after adjusting for potential confounding using IPTW, with a HR of 0.51 (95% CI, 0.38-0.67). The results in various subgroup analyses and sensitivity analyses were consistent with the findings of the primary analysis. CONCLUSIONS Use of TZDs is associated with a decreased risk of dementia incidence in a mainland Chinese population with T2DM.
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Affiliation(s)
- Houyu Zhao
- Department of Epidemiology and Biostatistics, School of Public HealthPeking UniversityBeijingChina
| | - Lin Zhuo
- Research Center of Clinical EpidemiologyPeking University Third HospitalBeijingChina
| | - Yexiang Sun
- Yinzhou District Center for Disease Control and PreventionNingboChina
| | - Peng Shen
- Yinzhou District Center for Disease Control and PreventionNingboChina
| | - Hongbo Lin
- Yinzhou District Center for Disease Control and PreventionNingboChina
| | - Siyan Zhan
- Department of Epidemiology and Biostatistics, School of Public HealthPeking UniversityBeijingChina
- Research Center of Clinical EpidemiologyPeking University Third HospitalBeijingChina
- Center for Intelligent Public Health, Institute for Artificial IntelligencePeking UniversityBeijingChina
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28
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Tseng CH. Metformin Reduces the Risk of Hearing Loss: A Retrospective Cohort Study. Otolaryngol Head Neck Surg 2023; 168:1389-1400. [PMID: 36939574 DOI: 10.1002/ohn.232] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/22/2022] [Accepted: 11/30/2022] [Indexed: 01/30/2023]
Abstract
OBJECTIVE To compare the risk of hearing loss with regard to metformin exposure. STUDY DESIGN Retrospective cohort. SETTING Taiwan's National Health Insurance database. METHODS We enrolled 292,071 ever users and 18,200 never users of metformin with new-onset diabetes mellitus from 1999 to 2005 and followed them for hearing loss from January 1, 2006, to December 31, 2011. Hazard ratios (HRs) weighted by propensity score were estimated. RESULTS Hearing loss was newly diagnosed in 10,085 ever users and 1072 never users. Their respective incidence rates (per 100,000 person-years) were 738.09 and 1366.83. The HR comparing ever-to-never users was 0.534 (95% confidence interval [CI]: 0.501-0.569]. The HR (95% CI) for the first (<27.07 months), second (27.07-59.13 months), and third (>59.13 months) tertiles of cumulative duration of metformin therapy were 0.912 (0.852-0.975), 0.544 (0.508-0.582), and 0.275 (0.255-0.295), respectively; and were 0.900 (0.841-0.962), 0.531 (0.496-0.569), and 0.293 (0.273-0.315), respectively, for the first (<796.70 g), second (796.70-2020.15 g), and third (>2020.15 g) tertiles of cumulative dose. The magnitude of risk reduction became more remarkable in corresponding to the increasing tertiles of the defined daily dose prescribed. Subtype analyses suggested that the risk reduction was more significant for sensorineural than conductive hearing loss. Findings derived from a propensity score-matched cohort did not substantially change the conclusions, and the risk reduction for mixed hearing loss was not statistically significant in the matched cohort as significantly observed in the unmatched cohort. CONCLUSION The risk of hearing loss is reduced in a dose-response pattern in patients who use metformin.
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Affiliation(s)
- Chin-Hsiao Tseng
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, Division of Endocrinology and Metabolism, National Taiwan University Hospital, Taipei, Taiwan.,National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Taiwan
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Chen PC, Hong CT, Chen WT, Chan L, Chien LN. Metformin Adherence Reduces the Risk of Dementia in Patients With Diabetes: A Population-based Cohort Study. Endocr Pract 2023; 29:247-253. [PMID: 36657564 DOI: 10.1016/j.eprac.2023.01.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 01/07/2023] [Accepted: 01/09/2023] [Indexed: 01/18/2023]
Abstract
OBJECTIVE Metformin is widely used as the first-line drug for type 2 diabetes mellitus and has numerous benefits apart from lowering blood glucose. However, metformin-retained regimen is challenged by newly launching, powerful glucose-lowering antiglycemic agents. This population-based cohort study examined the association between metformin adherence and the risk of dementia and Parkinson's disease (PD). METHODS Diabetic patients with metformin-included combination antiglycemic therapy were identified from the National Health Insurance Research Database and categorized into metformin-adherent and -nonadherent groups according to the medical record of the first year prescription. Patients contraindicated with metformin, severe diabetic complications, and poor drug compliance were excluded. The study outcome was the diagnosis of dementia or PD. RESULTS A total of 31 384 matched pairs were included after using propensity score matching and both groups were followed up for an average of 5 years. Metformin adherence was associated with a significantly lower risk of dementia (adjusted hazard risk ratio = 0.72, P < .001) but not PD (adjusted hazard risk ratio = 0.97, P = .825). Subgroup analysis revealed that the risk of dementia was significantly reduced in metformin-adherent patients, both male and female, aged >65 or ≤ 65 years, and with or without concurrent insulin treatment. This effect was not influenced by concurrent insulin treatment, which may eliminate the bias caused by the severity of diabetes mellitus. CONCLUSION Despite the launching of numerous new oral antiglycemic agents, metformin may provide further benefit on lowering risk of dementia beyond conventional glycemic control according to the real-world evidence.
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Affiliation(s)
- Po-Chih Chen
- Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan
| | - Chien-Tai Hong
- Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan
| | - Wan-Ting Chen
- Health Data Analytics and Statistics Center, Office of Data Science, Taipei Medical University, Taipei City, Taiwan
| | - Lung Chan
- Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan.
| | - Li-Nien Chien
- Health Data Analytics and Statistics Center, Office of Data Science, Taipei Medical University, Taipei City, Taiwan; Graduate Institute of Data Science, College of Management, Taipei Medical University, Taipei, Taiwan; School of Health Care Administration, College of Management, Taipei Medical University, Taipei City, Taiwan; Master of Public Health Program, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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Mitophagy in Alzheimer's disease: Molecular defects and therapeutic approaches. Mol Psychiatry 2023; 28:202-216. [PMID: 35665766 PMCID: PMC9812780 DOI: 10.1038/s41380-022-01631-6] [Citation(s) in RCA: 81] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 05/08/2022] [Accepted: 05/12/2022] [Indexed: 01/09/2023]
Abstract
Mitochondrial dysfunctions are central players in Alzheimer's disease (AD). In addition, impairments in mitophagy, the process of selective mitochondrial degradation by autophagy leading to a gradual accumulation of defective mitochondria, have also been reported to occur in AD. We provide an updated overview of the recent discoveries and advancements on mitophagic molecular dysfunctions in AD-derived fluids and cells as well as in AD brains. We discuss studies using AD cellular and animal models that have unraveled the contribution of relevant AD-related proteins (Tau, Aβ, APP-derived fragments and APOE) in mitophagy failure. In accordance with the important role of impaired mitophagy in AD, we report on various therapeutic strategies aiming at stimulating mitophagy in AD and we summarize the benefits of these potential therapeutic strategies in human clinical trials.
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Tseng CH. Metformin and risk of gingival/periodontal diseases in diabetes patients: A retrospective cohort study. Front Endocrinol (Lausanne) 2022; 13:1036885. [PMID: 36277720 PMCID: PMC9583654 DOI: 10.3389/fendo.2022.1036885] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 09/20/2022] [Indexed: 12/03/2022] Open
Abstract
AIM To compare the risk of gingival and periodontal diseases (GPD) between ever users and never users of metformin in patients with type 2 diabetes mellitus. METHODS The Taiwan's National Health Insurance database was used to enroll 423,949 patients with new onset diabetes mellitus from 1999 to 2005. After excluding ineligible patients, 60,309 ever users and 5578 never users were followed up for the incidence of GPD from January 1, 2006 until December 31, 2011. Propensity score-weighted hazard ratios were estimated by Cox regression. RESULTS GPD was newly diagnosed in 18,528 ever users (incidence: 7746.51 per 100,000 person-years) and 2283 never users (incidence: 12158.59 per 100,000 person-years). The hazard ratio that compared ever users to never users was 0.627 (95% confidence interval: 0.600-0.655). When metformin use was categorized by tertiles of cumulative duration and cumulative dose, the risk significantly reduced in a dose-response pattern when the cumulative duration reached approximately 2 years or the cumulative dose reached 670 grams. Analyses on the tertiles of defined daily dose of metformin showed that the reduction of GPD risk could be seen in all three subgroups but the benefit would be greater when the daily dose increased. CONCLUSION Long-term use of metformin is associated with a significantly reduced risk of GPD.
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Affiliation(s)
- Chin-Hsiao Tseng
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Dentoni G, Castro-Aldrete L, Naia L, Ankarcrona M. The Potential of Small Molecules to Modulate the Mitochondria-Endoplasmic Reticulum Interplay in Alzheimer's Disease. Front Cell Dev Biol 2022; 10:920228. [PMID: 36092728 PMCID: PMC9459385 DOI: 10.3389/fcell.2022.920228] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/08/2022] [Indexed: 11/13/2022] Open
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting a growing number of elderly individuals. No disease-modifying drugs have yet been identified despite over 30 years of research on the topic, showing the need for further research on this multifactorial disease. In addition to the accumulation of amyloid β-peptide (Aβ) and hyperphosphorylated tau (p-tau), several other alterations have been associated with AD such as calcium (Ca2+) signaling, glucose-, fatty acid-, cholesterol-, and phospholipid metabolism, inflammation, and mitochondrial dysfunction. Interestingly, all these processes have been associated with the mitochondria-endoplasmic reticulum (ER) contact site (MERCS) signaling hub. We and others have hypothesized that the dysregulated MERCS function may be one of the main pathogenic pathways driving AD pathology. Due to the variety of biological processes overseen at the MERCS, we believe that they constitute unique therapeutic targets to boost the neuronal function and recover neuronal homeostasis. Thus, developing molecules with the capacity to correct and/or modulate the MERCS interplay can unleash unique therapeutic opportunities for AD. The potential pharmacological intervention using MERCS modulators in different models of AD is currently under investigation. Here, we survey small molecules with the potential to modulate MERCS structures and functions and restore neuronal homeostasis in AD. We will focus on recently reported examples and provide an overview of the current challenges and future perspectives to develop MERCS modulators in the context of translational research.
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Affiliation(s)
| | | | | | - Maria Ankarcrona
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Science and Society (NVS), Karolinska Institutet, Stockholm, Sweden
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Zhang JH, Zhang XY, Sun YQ, Lv RH, Chen M, Li M. Metformin use is associated with a reduced risk of cognitive impairment in adults with diabetes mellitus: A systematic review and meta-analysis. Front Neurosci 2022; 16:984559. [PMID: 36090264 PMCID: PMC9453211 DOI: 10.3389/fnins.2022.984559] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 07/29/2022] [Indexed: 11/23/2022] Open
Abstract
Objective Controversy exists regarding the impact of metformin and whether it prevents or promotes the incidence of cognitive dysfunction. This systematic review and meta-analysis were conducted to identify the effect of metformin therapy on cognitive function in patients with diabetes. Methods Electronic databases (PubMed, EMBASE, PsycINFO, the Cochrane Library, and Web of Science) were systematically searched by two investigators from the date of inception until March 1, 2022. The study followed PRISMA guidelines. Inclusion criteria were defined according to the PECOSmodel. Eligible studies investigated cognitive dysfunction in metformin users compared with non-users in adults with diabetes. Only observational study designs (such as cohort, cross-section, and case-control) were included. Results A systematic search identified 1,839 articles, of which 28 (17 cohort, 8 case-control, and 3 cross-sectional studies) were included in the meta-analysis. Metformin reduced the occurrence of cognitive impairment in patients with diabetes [unadjusted hazard ratio (HR) = 0.67, 95% CI: 0.62–0.73; adjusted hazard ratio (aHR) = 0.92, 95% CI: 0.85–0.99]. In addition, the use of metformin was associated with a decreased risk of dementia (HR = 0.64, 95% CI: 0.59–0.69; aHR = 0.90, 95% CI: 0.84–0.96), while a random-effects meta-analysis indicated no significant effect of metformin on the risk of Alzheimer's disease (AD) (HR = 0.85, 95% CI: 0.60–1.22; aHR = 1.10, 95% CI: 0.95–1.28). Conclusion Metformin therapy decreased the occurrence risk of cognitive decline in patients with diabetes mellitus. Moreover, the use of metformin by adults with diabetes for the prevention of dementia, but not AD, is supported by the available evidence.
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Affiliation(s)
- Jia-Hao Zhang
- Laboratory of Laser Sports Medicine, School of Sports Science, South China Normal University, Guangzhou, China
| | - Xin-Yang Zhang
- Laboratory of Laser Sports Medicine, School of Sports Science, South China Normal University, Guangzhou, China
- *Correspondence: Xin-Yang Zhang
| | - Yan-Qiu Sun
- Department of Rehabilitation Medicine, Guangdong Women and Children Hospital, Guangzhou, China
| | - Ren-Hua Lv
- Department of Rehabilitation Medicine, Xiangtan Central Hospital, Xiangtan, China
| | - Mei Chen
- Laboratory of Laser Sports Medicine, School of Sports Science, South China Normal University, Guangzhou, China
| | - Meng Li
- Laboratory of Laser Sports Medicine, School of Sports Science, South China Normal University, Guangzhou, China
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Dai J, Ports KD, Corrada MM, Odegaard AO, O’Connell J, Jiang L. Metformin and Dementia Risk: A Systematic Review with Respect to Time Related Biases. J Alzheimers Dis Rep 2022; 6:443-459. [PMID: 36186728 PMCID: PMC9484147 DOI: 10.3233/adr-220002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 06/29/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND When studying drug effects using observational data, time-related biases may exist and result in spurious associations. Numerous observational studies have investigated metformin and dementia risk, but have reported inconsistent findings, some of which might be caused by unaddressed time-related biases. Immortal time bias biases the results toward a "protective" effect, whereas time-lag and time-window biases can lead to either a "detrimental" or "protective" effect. OBJECTIVE To conduct a systematic review examining time-related biases in the literature on metformin and dementia. METHODS The electronic databases PubMed, Web of Science, and ProQuest were searched for the terms "Metformin" AND ("dementia" OR "Alzheimer's Disease" OR "cognitive impairment"). These databases were searched from inception through 09/24/2021. Only English language articles and human research were eligible. RESULTS Seventeen studies were identified: thirteen cohort studies, two case-control studies, and two nested case-control studies. Eleven (64.7%) studies reported a reduced risk of dementia associated with metformin use; two (11.8%) suggested metformin increased dementia risk, while four (23.5%) concluded no significant associations. Eight (61.5%) of thirteen cohort studies had immortal time bias or did not clearly address it. Fifteen (88.2%) of seventeen reviewed studies had time-lag bias or did not clearly address it. Two (50.0%) of four case-control studies did not explicitly address time-window bias. The studies that addressed most biases concluded no associations between metformin and dementia risk. CONCLUSION None of the reviewed studies clearly addressed relevant time-related biases, illustrating time-related biases are common in observational studies investigating the impact of anti-diabetic medications on dementia risk.
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Affiliation(s)
- Jiahui Dai
- Department of Epidemiology & Biostatistics, University of California Irvine, Irvine, CA, USA
| | - Kayleen Deanna Ports
- Department of Epidemiology & Biostatistics, University of California Irvine, Irvine, CA, USA
| | - Maria M. Corrada
- Department of Epidemiology & Biostatistics, University of California Irvine, Irvine, CA, USA
- Department of Neurology, University of California Irvine, Irvine, CA, USA
- Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California Irvine, Irvine, CA, USA
| | - Andrew O. Odegaard
- Department of Epidemiology & Biostatistics, University of California Irvine, Irvine, CA, USA
| | - Joan O’Connell
- Centers for American Indian and Alaska Native Health, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Luohua Jiang
- Department of Epidemiology & Biostatistics, University of California Irvine, Irvine, CA, USA
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Ji S, Zhao X, Zhu R, Dong Y, Huang L, Zhang T. Metformin and the risk of dementia based on an analysis of 396,332 participants. Ther Adv Chronic Dis 2022; 13:20406223221109454. [PMID: 35847477 PMCID: PMC9277541 DOI: 10.1177/20406223221109454] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 06/01/2022] [Indexed: 11/17/2022] Open
Abstract
Background: AMPK has attracted widespread interest as a potential therapeutic target for age-related diseases, given its key role in controlling energy homeostasis. Metformin (Met) has historically been used to treat Type 2 diabetes and has been shown to counteract age-related diseases. However, studies regarding the relationship between Met and a variety of age-related classifications of cognitive decline have reported mixed findings. Objective: To assess the potential effect of Met on the onset of dementia and discuss the possible biological mechanisms involved. Methods: This study was registered in the PROSPERO database (CRD420201251468). PubMed, Embase, and Cochrane Library were searched from inception to 25 May 2021, for population-based cohort studies. Effect estimates with 95% confidence intervals (CIs) were pooled using the random-effects model. Meta-regression and subgroup analyses were performed to explore sources of heterogeneity and the stability of the results. Results: Fourteen population-based cohort studies (17 individual comparisons) involving 396,332 participants were identified. Meta-analysis showed that Met exposure was significantly associated with reduced risk of all subtypes of dementias [relative risk (RR) = 0.79, 95% CI = 0.68–0.91; p < 0.001]. Conversely, no significant reduction in risk was observed for those who received Met monotherapy at the onset of vascular dementia (VD), Parkinson’s disease (PD), and Alzheimer’s disease (AD). The effect was more prominent in patients who had long-term Met exposure (⩾4 years) (RR = 0.38, 95% CI = 0.32–0.46; p < 0.001), while no such significant effect was found with short-term Met exposure (1–2 years) (RR = 1.20, 95% CI = 0.87–1.66; p < 0.001). Moreover, no association was observed for Met exposure in participants of European descent (RR = 1.01, 95% CI = 0.66–1.54; p = 0.003) compared with those from other countries. Conclusion: Based on the evidence from population-based cohort studies, our findings suggest that the AMPK activator, Met, is a potential geroprotective agent for dementias, particularly among long-term Met users. Due to the significant heterogeneity among the included studies, we should interpret the results with caution.
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Affiliation(s)
- Shiliang Ji
- Department of pharmacy, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Xingxing Zhao
- Department of Neonatology, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Gusu School, Nanjing Medical University, Suzhou, China
| | - Ruifang Zhu
- Department of pharmacy, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Yongchao Dong
- Department of pharmacy, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Lifeng Huang
- Department of pharmacy, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou 215153, China
| | - Taiquan Zhang
- Department of pharmacy, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou 215153, China
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Luo A, Ning P, Lu H, Huang H, Shen Q, Zhang D, Xu F, Yang L, Xu Y. Association Between Metformin and Alzheimer's Disease: A Systematic Review and Meta-Analysis of Clinical Observational Studies. J Alzheimers Dis 2022; 88:1311-1323. [PMID: 35786654 DOI: 10.3233/jad-220180] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND As one of the widely used drugs for the management of type 2 diabetes mellites (T2DM), metformin is increasingly believed to delay cognitive deterioration and therapeutically for Alzheimer's disease (AD) patients especially those with T2DM. However, studies of the potential neuroprotective effects of metformin in AD patients have reported contradictory results. OBJECTIVE This study aimed to evaluate the association between metformin and the risk of developing AD. METHODS We systematically searched the PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases to identify clinical observational studies on the relationship between AD risk and metformin use published before December 20, 2021. Two investigators independently screened records, extracted data, and assessed the quality of the studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated using random-effect models. RESULTS After screening a total of 1,670 records, we included 10 studies involving 229,110 participants. The meta-analysis showed no significant association between AD incidence and metformin exposure (OR 1.17, 95% CI 0.88-1.56, p = 0.291). However, subgroup analysis showed that among Asians, the risk of AD was significantly higher among metformin users than those who did not (OR 1.71, 95% CI 1.24-2.37, p = 0.001). CONCLUSION The available evidence does not support the idea that metformin reduces risk of AD, and it may, in fact, increase the risk in Asians. Further well-designed randomized controlled trials are required to understand the role played by metformin and other antidiabetic drugs in the prevention of AD and other neurodegenerative diseases.
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Affiliation(s)
- Anling Luo
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, P.R. China
| | - Pingping Ning
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, P.R. China
| | - Haitao Lu
- Department of Neurology, Third People's Hospital of Chengdu, Chengdu, Sichuan Province, P.R. China
| | - Hongyan Huang
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, P.R. China
| | - Qiuyan Shen
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, P.R. China
| | - Dan Zhang
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, P.R. China
| | - Fang Xu
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, P.R. China
| | - Li Yang
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, P.R. China
| | - Yanming Xu
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, P.R. China
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Thomas C, Wurzer L, Malle E, Ristow M, Madreiter-Sokolowski CT. Modulation of Reactive Oxygen Species Homeostasis as a Pleiotropic Effect of Commonly Used Drugs. FRONTIERS IN AGING 2022; 3:905261. [PMID: 35821802 PMCID: PMC9261327 DOI: 10.3389/fragi.2022.905261] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 05/18/2022] [Indexed: 01/17/2023]
Abstract
Age-associated diseases represent a growing burden for global health systems in our aging society. Consequently, we urgently need innovative strategies to counteract these pathological disturbances. Overwhelming generation of reactive oxygen species (ROS) is associated with age-related damage, leading to cellular dysfunction and, ultimately, diseases. However, low-dose ROS act as crucial signaling molecules and inducers of a vaccination-like response to boost antioxidant defense mechanisms, known as mitohormesis. Consequently, modulation of ROS homeostasis by nutrition, exercise, or pharmacological interventions is critical in aging. Numerous nutrients and approved drugs exhibit pleiotropic effects on ROS homeostasis. In the current review, we provide an overview of drugs affecting ROS generation and ROS detoxification and evaluate the potential of these effects to counteract the development and progression of age-related diseases. In case of inflammation-related dysfunctions, cardiovascular- and neurodegenerative diseases, it might be essential to strengthen antioxidant defense mechanisms in advance by low ROS level rises to boost the individual ROS defense mechanisms. In contrast, induction of overwhelming ROS production might be helpful to fight pathogens and kill cancer cells. While we outline the potential of ROS manipulation to counteract age-related dysfunction and diseases, we also raise the question about the proper intervention time and dosage.
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Affiliation(s)
- Carolin Thomas
- Laboratory of Energy Metabolism Institute of Translational Medicine Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Lia Wurzer
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Ernst Malle
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Michael Ristow
- Laboratory of Energy Metabolism Institute of Translational Medicine Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
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Zhang Y, Zhang Y, Shi X, Han J, Lin B, Peng W, Mei Z, Lin Y. Metformin and the risk of neurodegenerative diseases in patients with diabetes: A meta-analysis of population-based cohort studies. Diabet Med 2022; 39:e14821. [PMID: 35213749 DOI: 10.1111/dme.14821] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 02/23/2022] [Indexed: 11/29/2022]
Abstract
AIMS The association between metformin use and neurodegenerative disease (ND) onset remains controversial. In this systematic review and meta-analysis, we aimed to determine the relationship between metformin use and ND risk based on data from population-based cohort studies. METHODS Articles were systematically searched in PubMed, EMBASE and Cochrane Library databases. Pooled relative risks (RRs) with 95% CIs were obtained using a random-effects model. Subgroup analyses, sensitivity analyses and meta-regression were performed to identify the sources of heterogeneity and strengthen the results. RESULTS Twelve population-based cohort studies involving 194,792 participants (94,462 metformin users and 100,330 metformin non-users) were eligible for inclusion in this meta-analysis. The pooled RR of NDs reached 0.77 (95% CI 0.67-0.88) when comparing metformin users with non-users. The effects were more prominent in long-term metformin users (≥4 years) (RR 0.29, 95% CI 0.13-0.44) and studies from Asian countries (RR 0.69, 95% CI 0.64-0.74). The effect estimates were stable when stratified by subtypes of NDs, study designs, and control definitions (p for interaction >0.05). Meta-regression did not identify the coefficients as the sources of heterogeneity (all p > 0.05). CONCLUSIONS This systematic review and meta-analysis found that metformin use, especially long-term use, was associated with lower ND risk. However, because there was substantial heterogeneity among studies, high-quality randomized controlled trials are still needed to confirm this finding.
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Affiliation(s)
- Yunnan Zhang
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- School of Pharmaceutical Sciences, Capital Medical University, Beijing, China
| | - Yi Zhang
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- School of Pharmaceutical Sciences, Capital Medical University, Beijing, China
| | - Xiujin Shi
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Jialun Han
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- School of Pharmaceutical Sciences, Capital Medical University, Beijing, China
| | - Baidi Lin
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- School of Pharmaceutical Sciences, Capital Medical University, Beijing, China
| | - Wenxing Peng
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Zubing Mei
- Department of Anorectal Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Anorectal Disease Institute of Shuguang Hospital, Shanghai, China
| | - Yang Lin
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- School of Pharmaceutical Sciences, Capital Medical University, Beijing, China
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Tabatabaei Malazy O, Bandarian F, Qorbani M, Mohseni S, Mirsadeghi S, Peimani M, Larijani B. The effect of metformin on cognitive function: A systematic review and meta-analysis. J Psychopharmacol 2022; 36:666-679. [PMID: 35297284 DOI: 10.1177/02698811211057304] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Most people are familiar with metformin as a diabetic treatment option. Different positive benefits have been found for it, in addition to its anti-diabetes properties. Cognitive function enhancement is the most recent characteristic that has been studied. This study aimed to look at the evidence on the effects of metformin on cognitive performance. Web of Science, PubMed, Scopus, the Cochrane Library, EMBASE, and PsycINFO databases were searched systematically. After eliminating duplicates and irrelevant documents, the findings were screened. The documents that remained were scanned and data were extracted. Nineteen studies were qualified for meta-analysis after evaluating 3827 identified records. There was no significant relationship between metformin therapy and cognitive performance in none of the studies including cross-sectionals, cohorts, and clinical trials (p > 0.05). Results show that metformin has no significant effect on improving cognitive function or protecting against any dementia including vascular dementia and Alzheimer's disease, and cognitive impairment as well.
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Affiliation(s)
- Ozra Tabatabaei Malazy
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Bandarian
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mostafa Qorbani
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Shahrzad Mohseni
- Evidence Based Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Mirsadeghi
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Peimani
- Metabolomics and Genomics Research Center Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Wu CY, Shapiro L, Ouk M, MacIntosh BJ, Black SE, Shah BR, Swardfager W. Glucose-lowering drugs, cognition, and dementia: The clinical evidence. Neurosci Biobehav Rev 2022; 137:104654. [PMID: 35398114 DOI: 10.1016/j.neubiorev.2022.104654] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/01/2022] [Accepted: 04/03/2022] [Indexed: 11/19/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is an important risk factor for dementia. The possibility to mitigate this risk by controlling T2DM is compelling; however, different glucose-lowering drugs have different effects on the brain by virtue of their different mechanisms of action. The clinical and epidemiological data appear mixed, warranting careful critical evaluation of the human studies. Here we examine the evidence in the context of dementia prevention and treatment, both for people with and without T2DM. We discuss the evidence on this scaffold of research directions, identifying methodological complexities in the extant literature (e.g. comparator discrepancies, changes in the therapeutic landscape), and the implications of different outcome measures (e.g. neuropsychological). We consider possible implications of cerebrovascular protection vs. effects on progression of neurodegenerative proteinopathy, and we present a research roadmap for glucose-lowering drugs in cognitive neurology, including neuroimaging, and fluid biomarkers. We conclude that there is great potential to advance personalized strategies to prevent and treat dementia with glucose-lowering drugs.
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Affiliation(s)
- Che-Yuan Wu
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Lila Shapiro
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Michael Ouk
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Bradley J MacIntosh
- Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Sandra E Black
- Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Medicine, Division of Neurology, University of Toronto, Toronto, Ontario, Canada; Toronto Dementia Research Alliance, Toronto, Ontario, Canada
| | - Baiju R Shah
- ICES, Toronto, Ontario, Canada; Divisions of Endocrinology and Obstetric Medicine, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Walter Swardfager
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Ontario, Canada; KITE UHN Toronto Rehabilitation Institute, Toronto, Ontario, Canada
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Kassab A, Rizk N, Prakash S. The Role of Systemic Filtrating Organs in Aging and Their Potential in Rejuvenation Strategies. Int J Mol Sci 2022; 23:ijms23084338. [PMID: 35457154 PMCID: PMC9025381 DOI: 10.3390/ijms23084338] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 04/05/2022] [Accepted: 04/08/2022] [Indexed: 11/26/2022] Open
Abstract
Advances in aging studies brought about by heterochronic parabiosis suggest that aging might be a reversable process that is affected by changes in the systemic milieu of organs and cells. Given the broadness of such a systemic approach, research to date has mainly questioned the involvement of “shared organs” versus “circulating factors”. However, in the absence of a clear understanding of the chronological development of aging and a unified platform to evaluate the successes claimed by specific rejuvenation methods, current literature on this topic remains scattered. Herein, aging is assessed from an engineering standpoint to isolate possible aging potentiators via a juxtaposition between biological and mechanical systems. Such a simplification provides a general framework for future research in the field and examines the involvement of various factors in aging. Based on this simplified overview, the kidney as a filtration organ is clearly implicated, for the first time, with the aging phenomenon, necessitating a re-evaluation of current rejuvenation studies to untangle the extent of its involvement and its possible role as a potentiator in aging. Based on these findings, the review concludes with potential translatable and long-term therapeutics for aging while offering a critical view of rejuvenation methods proposed to date.
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Affiliation(s)
- Amal Kassab
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, 3775 University Street, Montreal, QC H3A 2BA, Canada
| | - Nasser Rizk
- Department of Biomedical Sciences, College of Health Sciences-QU-Health, Qatar University, Doha 2713, Qatar
| | - Satya Prakash
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, 3775 University Street, Montreal, QC H3A 2BA, Canada
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Yang Y, Zhao JJ, Yu XF. Expert Consensus on Cognitive Dysfunction in Diabetes. Curr Med Sci 2022; 42:286-303. [PMID: 35290601 DOI: 10.1007/s11596-022-2549-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 02/02/2022] [Indexed: 12/14/2022]
Abstract
The incidence of diabetes is gradually increasing in China, and diabetes and associated complications, such as cognitive dysfunction have gained much attention in recent time. However, the concepts, clinical treatment, and prevention of cognitive dysfunction in patients with diabetes remain unclear. The Chinese Society of Endocrinology investigated the current national and overseas situation of cognitive dysfunction associated with diabetes. Based on research both in China and other countries worldwide, the Expert Consensus on Cognitive Dysfunction in Diabetes was established to guide physicians in the comprehensive standardized management of cognitive dysfunction in diabetes and to improve clinical outcomes in Chinese patients. This consensus presents an overview, definition and classification, epidemiology and pathogenesis, risk factors, screening, diagnosis, differential diagnosis, treatment, and prevention of cognitive dysfunction in patients with diabetes.
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Affiliation(s)
- Yan Yang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jia-Jun Zhao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 25000, China.
| | - Xue-Feng Yu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Ondaro J, Hernandez-Eguiazu H, Garciandia-Arcelus M, Loera-Valencia R, Rodriguez-Gómez L, Jiménez-Zúñiga A, Goikolea J, Rodriguez-Rodriguez P, Ruiz-Martinez J, Moreno F, Lopez de Munain A, Holt IJ, Gil-Bea FJ, Gereñu G. Defects of Nutrient Signaling and Autophagy in Neurodegeneration. Front Cell Dev Biol 2022; 10:836196. [PMID: 35419363 PMCID: PMC8996160 DOI: 10.3389/fcell.2022.836196] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/21/2022] [Indexed: 12/27/2022] Open
Abstract
Neurons are post-mitotic cells that allocate huge amounts of energy to the synthesis of new organelles and molecules, neurotransmission and to the maintenance of redox homeostasis. In neurons, autophagy is not only crucial to ensure organelle renewal but it is also essential to balance nutritional needs through the mobilization of internal energy stores. A delicate crosstalk between the pathways that sense nutritional status of the cell and the autophagic processes to recycle organelles and macronutrients is fundamental to guarantee the proper functioning of the neuron in times of energy scarcity. This review provides a detailed overview of the pathways and processes involved in the balance of cellular energy mediated by autophagy, which when defective, precipitate the neurodegenerative cascade of Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis or Alzheimer's disease.
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Affiliation(s)
- Jon Ondaro
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Haizea Hernandez-Eguiazu
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Maddi Garciandia-Arcelus
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Raúl Loera-Valencia
- Department of Neurology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet (KI), Stockholm, Sweden
| | - Laura Rodriguez-Gómez
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Andrés Jiménez-Zúñiga
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Julen Goikolea
- Department of Neurology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet (KI), Stockholm, Sweden
| | - Patricia Rodriguez-Rodriguez
- Department of Neurology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet (KI), Stockholm, Sweden
| | - Javier Ruiz-Martinez
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Donostia University Hospital, San Sebastian, Spain
| | - Fermín Moreno
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Donostia University Hospital, San Sebastian, Spain
| | - Adolfo Lopez de Munain
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Donostia University Hospital, San Sebastian, Spain
| | - Ian James Holt
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom
- IKERBASQUE Basque Foundation for Science, Bilbao, Spain
| | - Francisco Javier Gil-Bea
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Gorka Gereñu
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country (UPV-EHU), Leioa, Spain
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Lewandowski CT, Laham MS, Thatcher GR. Remembering your A, B, C's: Alzheimer's disease and ABCA1. Acta Pharm Sin B 2022; 12:995-1018. [PMID: 35530134 PMCID: PMC9072248 DOI: 10.1016/j.apsb.2022.01.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/27/2021] [Accepted: 01/07/2022] [Indexed: 12/24/2022] Open
Abstract
The function of ATP binding cassette protein A1 (ABCA1) is central to cholesterol mobilization. Reduced ABCA1 expression or activity is implicated in Alzheimer's disease (AD) and other disorders. Therapeutic approaches to boost ABCA1 activity have yet to be translated successfully to the clinic. The risk factors for AD development and progression, including comorbid disorders such as type 2 diabetes and cardiovascular disease, highlight the intersection of cholesterol transport and inflammation. Upregulation of ABCA1 can positively impact APOE lipidation, insulin sensitivity, peripheral vascular and blood–brain barrier integrity, and anti-inflammatory signaling. Various strategies towards ABCA1-boosting compounds have been described, with a bias toward nuclear hormone receptor (NHR) agonists. These agonists display beneficial preclinical effects; however, important side effects have limited development. In particular, ligands that bind liver X receptor (LXR), the primary NHR that controls ABCA1 expression, have shown positive effects in AD mouse models; however, lipogenesis and unwanted increases in triglyceride production are often observed. The longstanding approach, focusing on LXRβ vs. LXRα selectivity, is over-simplistic and has failed. Novel approaches such as phenotypic screening may lead to small molecule NHR modulators that elevate ABCA1 function without inducing lipogenesis and are clinically translatable.
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Mehan S, Bhalla S, Siddiqui EM, Sharma N, Shandilya A, Khan A. Potential Roles of Glucagon-Like Peptide-1 and Its Analogues in Dementia Targeting Impaired Insulin Secretion and Neurodegeneration. Degener Neurol Neuromuscul Dis 2022; 12:31-59. [PMID: 35300067 PMCID: PMC8921673 DOI: 10.2147/dnnd.s247153] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 02/16/2022] [Indexed: 12/20/2022] Open
Abstract
Dementia is a chronic, irreversible condition marked by memory loss, cognitive decline, and mental instability. It is clinically related to various progressive neurological diseases, including Parkinson’s disease, Alzheimer’s disease, and Huntington’s. The primary cause of neurological disorders is insulin desensitization, demyelination, oxidative stress, and neuroinflammation accompanied by various aberrant proteins such as amyloid-β deposits, Lewy bodies accumulation, tau formation leading to neurofibrillary tangles. Impaired insulin signaling is directly associated with amyloid-β and α-synuclein deposition, as well as specific signaling cascades involved in neurodegenerative diseases. Insulin dysfunction may initiate various intracellular signaling cascades, including phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinases (JNK), and mitogen-activated protein kinase (MAPK). Neuronal death, inflammation, neuronal excitation, mitochondrial malfunction, and protein deposition are all influenced by insulin. Recent research has focused on GLP-1 receptor agonists as a potential therapeutic target. They increase glucose-dependent insulin secretion and are beneficial in neurodegenerative diseases by reducing oxidative stress and cytokine production. They reduce the deposition of abnormal proteins by crossing the blood-brain barrier. The purpose of this article is to discuss the role of insulin dysfunction in the pathogenesis of neurological diseases, specifically dementia. Additionally, we reviewed the therapeutic target (GLP-1) and its receptor activators as a possible treatment of dementia.
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Affiliation(s)
- Sidharth Mehan
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
- Correspondence: Sidharth Mehan, Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India, Tel +91 8059889909; +91 9461322911, Email ;
| | - Sonalika Bhalla
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Ehraz Mehmood Siddiqui
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Nidhi Sharma
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Ambika Shandilya
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Andleeb Khan
- Department of Pharmacology & Toxicology, College of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia
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Beard E, Lengacher S, Dias S, Magistretti PJ, Finsterwald C. Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives. Front Physiol 2022; 12:825816. [PMID: 35087428 PMCID: PMC8787066 DOI: 10.3389/fphys.2021.825816] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 12/20/2021] [Indexed: 12/11/2022] Open
Abstract
Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20–25% of the whole body’s energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer’s disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases.
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Reinke C, Buchmann N, Fink A, Tegeler C, Demuth I, Doblhammer G. Diabetes duration and the risk of dementia: a cohort study based on German health claims data. Age Ageing 2022; 51:6454655. [PMID: 34923587 PMCID: PMC8753043 DOI: 10.1093/ageing/afab231] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 09/14/2021] [Indexed: 01/21/2023] Open
Abstract
Objective Diabetes is a risk factor for dementia but little is known about the impact of diabetes duration on the risk of dementia. We investigated the effect of type 2 diabetes duration on the risk of dementia. Design Prospective cohort study using health claims data representative for the older German population. The data contain information about diagnoses and medical prescriptions from the in- and outpatient sector. Methods We performed piecewise exponential models with a linear and a quadratic term for time since first type 2 diabetes diagnosis to predict the dementia risk in a sample of 13,761 subjects (2,558 dementia cases) older than 65 years. We controlled for severity of diabetes using the Adopted Diabetes Complications Severity Index. Results We found a U-shaped dementia risk over time. After type 2 diabetes diagnosis the dementia risk decreased (26% after 1 year) and reached a minimum at 4.75 years, followed by an increase through the end of follow-up. The pattern was consistent over different treatment groups, with the strongest U-shape for insulin treatment and for those with diabetes complications at the time of diabetes diagnosis. Conclusions We identified a non-linear association of type 2 diabetes duration and the risk of dementia. Physicians should closely monitor cognitive function in diabetic patients beyond the first few years after diagnosis, because the later increase in dementia occurred in all treatment groups.
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Affiliation(s)
- Constantin Reinke
- Institute for Sociology and Demography, University of Rostock, 18057 Rostock, Germany
| | - Nikolaus Buchmann
- Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Biology of Aging working group, 13353 Berlin, Germany
| | - Anne Fink
- German Center for Neurodegenerative Diseases, 53127 Bonn, Germany
| | - Christina Tegeler
- Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Biology of Aging working group, 13353 Berlin, Germany
- MSB Medical School Berlin, Department of Psychology, 14197 Berlin, Germany
| | - Ilja Demuth
- Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Biology of Aging working group, 13353 Berlin, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
| | - Gabriele Doblhammer
- Institute for Sociology and Demography, University of Rostock, 18057 Rostock, Germany
- German Center for Neurodegenerative Diseases, 53127 Bonn, Germany
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Little K, Llorián-Salvador M, Scullion S, Hernández C, Simó-Servat O, Del Marco A, Bosma E, Vargas-Soria M, Carranza-Naval MJ, Van Bergen T, Galbiati S, Viganò I, Musi CA, Schlingemann R, Feyen J, Borsello T, Zerbini G, Klaassen I, Garcia-Alloza M, Simó R, Stitt AW. Common pathways in dementia and diabetic retinopathy: understanding the mechanisms of diabetes-related cognitive decline. Trends Endocrinol Metab 2022; 33:50-71. [PMID: 34794851 DOI: 10.1016/j.tem.2021.10.008] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 09/06/2021] [Accepted: 10/29/2021] [Indexed: 12/14/2022]
Abstract
Type 2 diabetes (T2D) is associated with multiple comorbidities, including diabetic retinopathy (DR) and cognitive decline, and T2D patients have a significantly higher risk of developing Alzheimer's disease (AD). Both DR and AD are characterized by a number of pathological mechanisms that coalesce around the neurovascular unit, including neuroinflammation and degeneration, vascular degeneration, and glial activation. Chronic hyperglycemia and insulin resistance also play a significant role, leading to activation of pathological mechanisms such as increased oxidative stress and the accumulation of advanced glycation end-products (AGEs). Understanding these common pathways and the degree to which they occur simultaneously in the brain and retina during diabetes will provide avenues to identify T2D patients at risk of cognitive decline.
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Affiliation(s)
- Karis Little
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - María Llorián-Salvador
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - Sarah Scullion
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - Cristina Hernández
- Vall d'Hebron Research Institute and CIBERDEM (ISCIII), Barcelona, Spain
| | - Olga Simó-Servat
- Vall d'Hebron Research Institute and CIBERDEM (ISCIII), Barcelona, Spain
| | - Angel Del Marco
- Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Cadiz, Spain
| | - Esmeralda Bosma
- Ocular Angiogenesis Group, University of Amsterdam, Amsterdam, The Netherlands
| | - Maria Vargas-Soria
- Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Cadiz, Spain
| | - Maria Jose Carranza-Naval
- Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Cadiz, Spain
| | | | - Silvia Galbiati
- Complications of Diabetes Unit, Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milano, Italy
| | - Ilaria Viganò
- Complications of Diabetes Unit, Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milano, Italy
| | - Clara Alice Musi
- Università Degli Studi di Milano and Istituto di Ricerche Farmacologiche Mario Negri- IRCCS, Milano, Italy
| | - Reiner Schlingemann
- Ocular Angiogenesis Group, University of Amsterdam, Amsterdam, The Netherlands; Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Lausanne, Switzerland
| | | | - Tiziana Borsello
- Università Degli Studi di Milano and Istituto di Ricerche Farmacologiche Mario Negri- IRCCS, Milano, Italy
| | - Gianpaolo Zerbini
- Complications of Diabetes Unit, Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milano, Italy
| | - Ingeborg Klaassen
- Ocular Angiogenesis Group, University of Amsterdam, Amsterdam, The Netherlands
| | - Monica Garcia-Alloza
- Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Cadiz, Spain
| | - Rafael Simó
- Vall d'Hebron Research Institute and CIBERDEM (ISCIII), Barcelona, Spain.
| | - Alan W Stitt
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
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Tseng CH. The Effect of Metformin on Male Reproductive Function and Prostate: An Updated Review. World J Mens Health 2022; 40:11-29. [PMID: 33831975 PMCID: PMC8761231 DOI: 10.5534/wjmh.210001] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 01/18/2021] [Accepted: 01/22/2021] [Indexed: 12/02/2022] Open
Abstract
Metformin is the first-line oral antidiabetic drug that shows multiple pleiotropic effects of anti-inflamation, anti-cancer, anti-aging, anti-microbia, anti-atherosclerosis, and immune modulation. Metformin's effects on men's related health are reviewed here, focusing on reproductive health under subtitles of erectile dysfunction (ED), steroidogenesis and spermatogenesis; and on prostate-related health under subtitles of prostate specific antigen (PSA), prostatitis, benign prostate hyperplasia (BPH), and prostate cancer (PCa). Updated literature suggests a potential role of metformin on arteriogenic ED but controversial and contradictory effects (either protective or harmful) on testicular functions of testosterone synthesis and spermatogenesis. With regards to prostate-related health, metformin use may be associated with lower levels of PSA in humans, but its clinical implications require more research. Although there is a lack of research on metform's effect on prostatitis, it may have potential benefits through its anti-microbial and anti-inflammatory properties. Metformin may reduce the risk of BPH by inhibiting the insulin-like growth factor 1 pathway and some but not all studies suggest a protective role of metformin on the risk of PCa. Many clinical trials are being conducted to investigate the use of metformin as an adjuvant therapy for PCa but results currently available are not conclusive. While some trials suggest a benefit in reducing the metastasis and recurrence of PCa, others do not show any benefit. More research works are warranted to illuminate the potential usefulness of metformin in the promotion of men's health.
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Affiliation(s)
- Chin-Hsiao Tseng
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Division of Environmental Health and Occupational Medicine of the National Health Research Institutes, Zhunan, Taiwan.
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50
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Ha J, Choi DW, Kim KJ, Cho SY, Kim H, Kim KY, Koh Y, Nam CM, Kim E. Association of metformin use with Alzheimer's disease in patients with newly diagnosed type 2 diabetes: a population-based nested case-control study. Sci Rep 2021; 11:24069. [PMID: 34912022 PMCID: PMC8674300 DOI: 10.1038/s41598-021-03406-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 11/22/2021] [Indexed: 01/08/2023] Open
Abstract
Metformin reduces insulin resistance, which constitutes a pathophysiological connection of diabetes with Alzheimer’s disease (AD), but the evidence of metformin on AD development was still insufficient and conflicting. We investigated AD risk in patients with newly diagnosed type 2 DM treated with metformin. This retrospective, observational, nested case–control study included patients with newly diagnosed type 2 DM obtained from the Korean National Health Insurance Service DM cohort (2002–2017). Among 70,499 dementia-free DM patients, 1675 AD cases were matched to 8375 controls for age, sex, and DM onset and duration. The association between AD and metformin was analyzed by multivariable regression analyses, adjusted for comorbidities and cardiometabolic risk profile. Metformin use was associated with an increased odds of AD (adjusted odds ratio [AOR] 1.50; 95% CI 1.23–1.83). The risk of AD was higher in patients with a longer DM duration. Furthermore, AD risk was significantly high in DM patients with depression (AOR 2.05; 95% CI 1.02–4.12). Given the large number of patients with DM who are taking metformin worldwide, a double-blinded, prospective study is required to determine the long-term cognitive safety of metformin.
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Affiliation(s)
- Junghee Ha
- Department of Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Dong-Woo Choi
- Cancer Big Data Center, National Cancer Control Institute, National Cancer Center, Gyeonggi-do, Republic of Korea
| | - Kwang Joon Kim
- Division of Geriatrics, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - So Yeon Cho
- Department of Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunjeong Kim
- Department of Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Keun You Kim
- Department of Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Youngseung Koh
- Department of Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chung Mo Nam
- Department of Preventive Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| | - Eosu Kim
- Department of Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. .,Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
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