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Khalil MAM, Sadagah NM, Tan J, Syed FO, Chong VH, Al-Qurashi SH. Pros and cons of live kidney donation in prediabetics: A critical review and way forward. World J Transplant 2024; 14:89822. [PMID: 38576756 PMCID: PMC10989475 DOI: 10.5500/wjt.v14.i1.89822] [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: 11/13/2023] [Revised: 12/11/2023] [Accepted: 01/16/2024] [Indexed: 03/15/2024] Open
Abstract
There is shortage of organs, including kidneys, worldwide. Along with deceased kidney transplantation, there is a significant rise in live kidney donation. The prevalence of prediabetes (PD), including impaired fasting glucose and impaired glucose tolerance, is on the rise across the globe. Transplant teams frequently come across prediabetic kidney donors for evaluation. Prediabetics are at risk of diabetes, chronic kidney disease, cardiovascular events, stroke, neuropathy, retinopathy, dementia, depression and nonalcoholic liver disease along with increased risk of all-cause mortality. Unfortunately, most of the studies done in prediabetic kidney donors are retrospective in nature and have a short follow up period. There is lack of prospective long-term studies to know about the real risk of complications after donation. Furthermore, there are variations in recommendations from various guidelines across the globe for donations in prediabetics, leading to more confusion among clinicians. This increases the responsibility of transplant teams to take appropriate decisions in the best interest of both donors and recipients. This review focuses on pathophysiological changes of PD in kidneys, potential complications of PD, other risk factors for development of type 2 diabetes, a review of guidelines for kidney donation, the potential role of diabetes risk score and calculator in kidney donors and the way forward for the evaluation and selection of prediabetic kidney donors.
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Affiliation(s)
- Muhammad Abdul Mabood Khalil
- Center of Renal Diseases and Transplantation, King Fahad Armed Forces Hospital Jeddah, Jeddah 23311, Saudi Arabia
| | - Nihal Mohammed Sadagah
- Center of Renal Diseases and Transplantation, King Fahad Armed Forces Hospital Jeddah, Jeddah 23311, Saudi Arabia
| | - Jackson Tan
- Department of Nephrology, RIPAS Hospital Brunei Darussalam, Brunei Muara BA1710, Brunei Darussalam
| | - Furrukh Omair Syed
- Center of Renal Diseases and Transplantation, King Fahad Armed Forces Hospital Jeddah, Jeddah 23311, Saudi Arabia
| | - Vui Heng Chong
- Division of Gastroenterology and Hepatology, Department of Medicine, Raja Isteri Pengiran Anak Saleha Hospital, Bandar Seri Begawan BA1710, Brunei Darussalam
| | - Salem H Al-Qurashi
- Center of Renal Diseases and Transplantation, King Fahad Armed Forces Hospital Jeddah, Jeddah 23311, Saudi Arabia
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2
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Ab-Hamid N, Omar N, Ismail CAN, Long I. Diabetes and cognitive decline: Challenges and future direction. World J Diabetes 2023; 14:795-807. [PMID: 37383592 PMCID: PMC10294066 DOI: 10.4239/wjd.v14.i6.795] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 02/07/2023] [Accepted: 05/06/2023] [Indexed: 06/14/2023] Open
Abstract
There is growing evidence that diabetes can induce cognitive decline and dementia. It is a slow, progressive cognitive decline that can occur in any age group, but is seen more frequently in older individuals. Symptoms related to cognitive decline are worsened by chronic metabolic syndrome. Animal models are frequently utilized to elucidate the mechanisms of cognitive decline in diabetes and to assess potential drugs for therapy and prevention. This review addresses the common factors and pathophysiology involved in diabetes-related cognitive decline and outlines the various animal models used to study this condition.
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Affiliation(s)
- Norhamidar Ab-Hamid
- Biomedicine program, School of Health Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu 16150, Kelantan, Malaysia
| | - Norsuhana Omar
- Department of Physiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu 16150, Kelantan, Malaysia
| | - Che Aishah Nazariah Ismail
- Department of Physiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu 16150, Kelantan, Malaysia
| | - Idris Long
- Biomedicine program, School of Health Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu 16150, Kelantan, Malaysia
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Rhea EM, Banks WA, Raber J. Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites. Biomedicines 2022; 10:1582. [PMID: 35884888 PMCID: PMC9312939 DOI: 10.3390/biomedicines10071582] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/27/2022] [Accepted: 06/29/2022] [Indexed: 12/12/2022] Open
Abstract
The concept of insulin resistance has been around since a few decades after the discovery of insulin itself. To allude to the classic Charles Dicken's novel published 62 years before the discovery of insulin, in some ways, this is the best of times, as the concept of insulin resistance has expanded to include the brain, with the realization that insulin has a life beyond the regulation of glucose. In other ways, it is the worst of times as insulin resistance is implicated in devastating diseases, including diabetes mellitus, obesity, and Alzheimer's disease (AD) that affect the brain. Peripheral insulin resistance affects nearly a quarter of the United States population in adults over age 20. More recently, it has been implicated in AD, with the degree of brain insulin resistance correlating with cognitive decline. This has led to the investigation of brain or central nervous system (CNS) insulin resistance and the question of the relation between CNS and peripheral insulin resistance. While both may involve dysregulated insulin signaling, the two conditions are not identical and not always interlinked. In this review, we compare and contrast the similarities and differences between peripheral and CNS insulin resistance. We also discuss how an apolipoprotein involved in insulin signaling and related to AD, apolipoprotein E (apoE), has distinct pools in the periphery and CNS and can indirectly affect each system. As these systems are both separated but also linked via the blood-brain barrier (BBB), we discuss the role of the BBB in mediating some of the connections between insulin resistance in the brain and in the peripheral tissues.
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Affiliation(s)
- Elizabeth M. Rhea
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98195, USA; (E.M.R.); (W.A.B.)
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
| | - William A. Banks
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98195, USA; (E.M.R.); (W.A.B.)
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
| | - Jacob Raber
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA
- Departments of Neurology and Radiation Medicine, Division of Neuroscience, ONPRC, Oregon Health & Science University, Portland, OR 97239, USA
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4
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Leirós M, Amenedo E, Rodríguez M, Pazo-Álvarez P, Franco L, Leis R, Martínez-Olmos MÁ, Arce C. Cognitive Status and Nutritional Markers in a Sample of Institutionalized Elderly People. Front Aging Neurosci 2022; 14:880405. [PMID: 35686024 PMCID: PMC9171327 DOI: 10.3389/fnagi.2022.880405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/19/2022] [Indexed: 11/13/2022] Open
Abstract
Background Since many of the risk factors for cognitive decline can be modified by diet, the study of nutrition and its relationships with cognitive status in aging has increased considerably in recent years. However, there are hardly any studies that have assessed cognitive status using a comprehensive set of neuropsychological tests along with measures of functional capacity and mood and that have related it to nutritional status measured from several nutritional parameters that have shown its relationships with cognitive function. Objective To test the differences in depressive symptomatology and in several measures of nutritional status between three groups classified according to their cognitive status (CS hereafter). Method One hundred thirteen participants from nursing homes in Galicia, Spain, underwent a comprehensive neuropsychological examination, including a general screening test (MMSE) and tests for different cognitive domains along with measures of activities of daily living (ADL) and assessment of depressive symptomatology (GDS-SF). According to established clinical criteria, participants were divided into three CS groups, Cognitively Intact (CI), Mild Cognitive Impairment (MCI), and All-Cause Dementia (ACD). Nutritional status was also examined using blood-derived measures, body mass index (BMI) and a nutritional screening test (MNA-SF). Differences between CS groups in all nutritional variables were studied by one-way ANOVAs with post-hoc Bonferroni correction or Kruskal-Wallis with Games-Howell post-hoc correction when appropriate. Multinomial logistic regression was also applied to test the association between nutritional variables and CS. Results Differences between CS groups were statistically significant for depressive symptomatology, vitamin A and D, albumin, selenium (Se), uric acid (UA), and BMI. The results of multinomial logistic regression found positive associations between groups with better CS and higher concentrations of vitamins A and D, transthyretin (TTR), albumin, Se, and UA, while negative associations were found for BMI. Conclusion Higher serum levels of vitamin A, vitamin D, TTR, albumin, Se, and UA could act as protective factors against cognitive decline, whereas higher BMI could act as a risk factor.
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Affiliation(s)
- María Leirós
- Research Group in Cognitive and Affective Neuroscience (NECEA), Department of Clinical Psychology and Psychobiology, University of Santiago de Compostela, A Coruña, Spain
| | - Elena Amenedo
- Research Group in Cognitive and Affective Neuroscience (NECEA), Department of Clinical Psychology and Psychobiology, University of Santiago de Compostela, A Coruña, Spain
| | - Marina Rodríguez
- Research Group in Cognitive and Affective Neuroscience (NECEA), Department of Clinical Psychology and Psychobiology, University of Santiago de Compostela, A Coruña, Spain
| | - Paula Pazo-Álvarez
- Research Group in Cognitive and Affective Neuroscience (NECEA), Department of Clinical Psychology and Psychobiology, University of Santiago de Compostela, A Coruña, Spain
| | - Luis Franco
- Economic Analysis and Modeling Group, Instituto de Estudios y Desarrollo de Galicia (IDEGA), Santiago de Compostela, Spain
| | - Rosaura Leis
- Pediatric Gastroenterology, Hepatology and Nutrition Unit, Hospital Clínico Universitario de Santiago, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain.,Unit of Investigation in Nutrition, Growth and Human Development of Galicia, Department of Forensic Sciences, Pathological Anatomy, Gynecology and Obstetrics, and Pediatrics, University of Santiago de Compostela, Santiago de Compostela, Spain.,CIBEROBN (Physiopathology of Obesity and Nutrition), Institute of Health Carlos III (ISCIII), Madrid, Spain
| | - Miguel-Ángel Martínez-Olmos
- CIBEROBN (Physiopathology of Obesity and Nutrition), Institute of Health Carlos III (ISCIII), Madrid, Spain.,Section of Endocrinology-Nutrition Area, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain
| | - Constantino Arce
- Department of Social, Basic and Methodology Psychology, University of Santiago de Compostela, Santiago de Compostela, Spain
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Lanz M, Janeiro MH, Milagro FI, Puerta E, Ludwig IA, Pineda-Lucena A, Ramírez MJ, Solas M. Trimethylamine N-Oxide (TMAO) drives insulin resistance and cognitive deficiencies in a senescence accelerated mouse model. Mech Ageing Dev 2022; 204:111668. [PMID: 35341897 DOI: 10.1016/j.mad.2022.111668] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/09/2022] [Accepted: 03/22/2022] [Indexed: 12/20/2022]
Abstract
It has been established that ageing is the major risk factor for cognitive deficiency and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. In the present study, peripheral and central insulin resistance was found in SAMP8 mice (aging mouse model) accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state was observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across an aging-disrupted blood brain barrier. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment that decreases TMAO levels. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between aging, insulin resistance and dementia. Thus, pharmacological intervention that leads to decreased TMAO levels, such as DMB, could open a new avenue for the future treatment of neurodegenerative diseases.
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Affiliation(s)
- María Lanz
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain
| | - Manuel H Janeiro
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain; IdISNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Fermin I Milagro
- IdISNA, Navarra Institute for Health Research, Pamplona, Spain; Department of Nutrition, Food Science and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain; CIBERobn, CIBER Fisiopatología de Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Elena Puerta
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain; IdISNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Iziar A Ludwig
- Program of Molecular Therapeutics, Center for Applied Medical Research (CIMA), Universidad de Navarra, Avda. Pío XII 55, E-31008 Pamplona, Spain
| | - Antonio Pineda-Lucena
- Program of Molecular Therapeutics, Center for Applied Medical Research (CIMA), Universidad de Navarra, Avda. Pío XII 55, E-31008 Pamplona, Spain
| | - María J Ramírez
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain; IdISNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Maite Solas
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain; IdISNA, Navarra Institute for Health Research, Pamplona, Spain.
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6
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Loss of association between plasma irisin levels and cognition in Alzheimer's disease. Psychoneuroendocrinology 2022; 136:105624. [PMID: 34902775 DOI: 10.1016/j.psyneuen.2021.105624] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 11/08/2021] [Accepted: 12/06/2021] [Indexed: 01/12/2023]
Abstract
BACKGROUND Irisin, an exercise-induced myokine, has been shown to have beneficial effects on cognitive and metabolic functions. However, previous studies assessing the levels of circulating irisin in patients with Alzheimer's disease (AD) or diabetes mellitus (DM) have provided inconsistent results. This suggests that the normal physiological action of irisin may be altered by disease-associated pathological conditions in target organs. OBJECTIVE To investigate the association of plasma levels of irisin with cognition and brain structures according to the presence or absence of AD and DM. METHODS Plasma levels of irisin, multi-domain cognition, and volumes of relevant brain regions were assessed using enzyme-linked immunoassay, neuropsychological test, and magnetic resonance imaging, respectively. We classified 107 participants by cognitive (cognitively normal [CN, n = 23], mild cognitive impairment [MCI, n = 49], and AD [n = 35]) and metabolic (non-DM [n = 75] and DM [n = 32]) states. RESULTS Disease state-stratified multiple regression analyses showed that plasma levels of irisin were positively associated with cognition only in participants without AD (CN plus MCI). By contrast, in participants with AD, these associations lost significance, and furthermore, higher levels of irisin indicated smaller hippocampal, superior temporal, and inferior frontal volumes. The association between plasma irisin levels and cognition was not affected by the presence of DM. Consistently, moderation analysis revealed that the relationship between plasma irisin levels and cognition or brain structures was significantly modified by the presence of AD, not that of DM. CONCLUSION Our findings suggest that the beneficial actions of circulating irisin on cognition may be attenuated by AD-induced pathological conditions in the brain.
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7
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Tjahyo AS, Gandy J, Porter J, Henry CJ. Is Weight Loss More Severe in Older People with Dementia? J Alzheimers Dis 2021; 81:57-73. [PMID: 33720896 DOI: 10.3233/jad-201496] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Weight loss, a hallmark feature of dementia, is associated with higher mortality in older people. However, there is a lack of consensus in the literature as to whether the weight loss commonly observed in older people with dementia results from reduced energy intake and/or increased energy expenditure. Understanding the cause of energy imbalance in older people with dementia would allow more targeted interventions to avoid detrimental health effects in this vulnerable group. In this paper, we review studies that have considered weight change, energy intake, and energy expenditure in older people with and without dementia. We critically assess the studies' methodology and outline the various factors which may decrease and increase energy intake and expenditure respectively in older people with and without dementia. Current available literature does not support the view that there is a lower energy intake and/or a higher energy expenditure in older people with dementia when compared to those without dementia. The need for more high-quality studies is also highlighted in order to shed more light towards this issue which continues to elude researchers and clinicians alike.
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Affiliation(s)
- Alvin Surya Tjahyo
- Clinical Nutrition Research Centre, Singapore Institute of Food and Biotechnology Innovation, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | | | - Judi Porter
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
| | - Christiani Jeyakumar Henry
- Clinical Nutrition Research Centre, Singapore Institute of Food and Biotechnology Innovation, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, Singapore, Singapore
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8
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Hölscher C. Evidence for pathophysiological commonalities between metabolic and neurodegenerative diseases. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 155:65-89. [PMID: 32854859 DOI: 10.1016/bs.irn.2020.01.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Diabetes mellitus is a risk factor for developing neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. This relationship seems counter-intuitive as these pathological syndromes appear to be very different. However, they share underlying mechanisms such as desensitization of insulin signaling. Insulin not only regulates blood glucose levels, but also acts as a growth factor that is important for neuronal activity and repair. Insulin signaling desensitization has been found in the brains of people with progressive neurodegenerative diseases, which is most likely driven by chronic inflammation. Based on this, insulin has been tested in patients with Alzheimer's disease, and it was found that memory formation was improved and brain pathology reduced. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, and numerous drugs that mimic this peptide are on the market to treat type 2 diabetes mellitus. Preclinical studies have provided robust evidence that some of these drugs, such as liraglutide or lixisenatide can enter the brain and improve key pathological parameters, such as memory loss, impairment of motor activity, synapse loss, reduced energy utilization by neurons and chronic inflammation in the brain. First clinical trials with a GLP-1 mimetic show good effects in patients with Parkinson's disease, improving motor control and insulin signaling in the brain. This is a proof of concept that this approach is viable and that drug treatment affects the main drivers of the disease and does not just modify the symptoms. It demonstrates that this new research area is a promising and fertile space for the development of novel treatments for neurodegenerative diseases.
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Affiliation(s)
- Christian Hölscher
- Neurology Department of the Second Associated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China; Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan, PR China.
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9
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Abstract
Tau protein which was discovered in 1975 [310] became of great interest when it was identified as the main component of neurofibrillary tangles (NFT), a pathological feature in the brain of patients with Alzheimer's disease (AD) [39, 110, 232]. Tau protein is expressed mainly in the brain as six isoforms generated by alternative splicing [46, 97]. Tau is a microtubule associated proteins (MAPs) and plays a role in microtubules assembly and stability, as well as diverse cellular processes such as cell morphogenesis, cell division, and intracellular trafficking [49]. Additionally, Tau is involved in much larger neuronal functions particularly at the level of synapses and nuclei [11, 133, 280]. Tau is also physiologically released by neurons [233] even if the natural function of extracellular Tau remains to be uncovered (see other chapters of the present book).
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10
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Trujillo‐Estrada L, Nguyen C, da Cunha C, Cai L, Forner S, Martini AC, Ager RR, Prieto GA, Cotman CW, Baglietto‐Vargas D, LaFerla FM. Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models. Aging Cell 2019; 18:e12919. [PMID: 30809950 PMCID: PMC6516168 DOI: 10.1111/acel.12919] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 12/25/2018] [Accepted: 01/13/2019] [Indexed: 01/07/2023] Open
Abstract
Diabetes mellitus (DM) is one of the most devastating diseases that currently affects the aging population. Recent evidence indicates that DM is a risk factor for many brain disorders, due to its direct effects on cognition. New findings have shown that the microtubule-associated protein tau is pathologically processed in DM; however, it remains unknown whether pathological tau modifications play a central role in the cognitive deficits associated with DM. To address this question, we used a gain-of-function and loss-of-function approach to modulate tau levels in type 1 diabetes (T1DM) and type 2 diabetes (T2DM) mouse models. Our study demonstrates that tau differentially contributes to cognitive and synaptic deficits induced by DM. On one hand, overexpressing wild-type human tau further exacerbates cognitive and synaptic impairments induced by T1DM, as human tau mice treated under T1DM conditions show robust deficits in learning and memory processes. On the other hand, neither a reduction nor increase in tau levels affects cognition in T2DM mice. Together, these results shine new light onto the different molecular mechanisms that underlie the cognitive and synaptic impairments associated with T1DM and T2DM.
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Affiliation(s)
- Laura Trujillo‐Estrada
- Institute for Memory Impairments and Neurological DisordersUniversity of CaliforniaIrvineCalifornia
| | - Cassidy Nguyen
- Institute for Memory Impairments and Neurological DisordersUniversity of CaliforniaIrvineCalifornia
| | - Celia da Cunha
- Institute for Memory Impairments and Neurological DisordersUniversity of CaliforniaIrvineCalifornia
| | - Lena Cai
- Institute for Memory Impairments and Neurological DisordersUniversity of CaliforniaIrvineCalifornia
| | - Stefania Forner
- Institute for Memory Impairments and Neurological DisordersUniversity of CaliforniaIrvineCalifornia
| | - Alessandra C. Martini
- Institute for Memory Impairments and Neurological DisordersUniversity of CaliforniaIrvineCalifornia
| | - Rahasson R. Ager
- Institute for Memory Impairments and Neurological DisordersUniversity of CaliforniaIrvineCalifornia
| | - Gilberto Aleph Prieto
- Institute for Memory Impairments and Neurological DisordersUniversity of CaliforniaIrvineCalifornia
| | - Carl W. Cotman
- Institute for Memory Impairments and Neurological DisordersUniversity of CaliforniaIrvineCalifornia
- Department of Neurobiology and BehaviorUniversity of CaliforniaIrvineCalifornia
- Department of NeurologyUniversity of CaliforniaIrvineCalifornia
| | - David Baglietto‐Vargas
- Institute for Memory Impairments and Neurological DisordersUniversity of CaliforniaIrvineCalifornia
- Department of Neurobiology and BehaviorUniversity of CaliforniaIrvineCalifornia
| | - Frank M. LaFerla
- Institute for Memory Impairments and Neurological DisordersUniversity of CaliforniaIrvineCalifornia
- Department of Neurobiology and BehaviorUniversity of CaliforniaIrvineCalifornia
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11
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Abdel-Rahman EA, Bhattacharya S, Buabeid M, Majrashi M, Bloemer J, Tao YX, Dhanasekaran M, Escobar M, Amin R, Suppiramaniam V. PPAR-δ Activation Ameliorates Diabetes-Induced Cognitive Dysfunction by Modulating Integrin-linked Kinase and AMPA Receptor Function. J Am Coll Nutr 2019; 38:693-702. [PMID: 31008686 DOI: 10.1080/07315724.2019.1598307] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
An estimated 9% of the American population experiences type II diabetes mellitus (T2DM) due to diet or genetic predisposition. Recent reports indicate that patients with T2DM are at increased risk for cognitive dysfunctions, as observed in conditions like Alzheimer's disease (AD). In addition, AD is the leading cause of dementia, highlighting the urgency of developing novel therapeutic targets for T2DM-induced cognitive deficits. The peroxisome proliferator activated receptor-δ (PPAR-δ) is highly expressed in the brain and has been shown to play an important role in spatial memory and hippocampal neurogenesis. However, the effect of PPAR-δ agonists on T2DM-induced cognitive impairment has not been explored. In this study, the effects of GW0742 (a selective PPAR-δ agonist) on hippocampal synaptic transmission, plasticity, and spatial memory were investigated in the db/db mouse model of T2DM. Oral administration of GW0742 for 2 weeks significantly improved hippocampal long-term potentiation. In addition, GW0742 effectively prevented deficits in hippocampal dependent spatial memory in db/db mice. PPAR-δ-mediated improvements in synaptic plasticity and behavior were accompanied by a significant recovery in hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic transmission. Our findings suggest that activation of PPAR-δ might ameliorate T2DM-induced impairments in hippocampal synaptic plasticity and memory.
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Affiliation(s)
- Engy A Abdel-Rahman
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, USA.,Department of Pharmacology, Faculty of Medicine, Assuit University, Assuit, Egypt**
| | - Subhrajit Bhattacharya
- Department of Pharmacology, Rollins Research Center, Emory University, Atlanta, Georgia, USA**
| | - Manal Buabeid
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, USA.,College of Pharmacy and Health Sciences, Ajman University, Ajman, UAE**
| | - Mohammed Majrashi
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, USA.,Department of Pharmacology, Faculty of Medicine, University of Jeddah, Jeddah, Saudi Arabia
| | - Jenna Bloemer
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, USA
| | - Ya-Xiong Tao
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA.,Center for Neuroscience Initiative, Auburn University, Auburn, Alabama, USA
| | - Muralikrishnan Dhanasekaran
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, USA.,Center for Neuroscience Initiative, Auburn University, Auburn, Alabama, USA
| | - Martha Escobar
- Department of Psychology, Auburn University, Auburn, Alabama, USA.,Department of Psychology, Oakland University, Rochester, Michigan, USA*
| | - Rajesh Amin
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, USA.,Center for Neuroscience Initiative, Auburn University, Auburn, Alabama, USA
| | - Vishnu Suppiramaniam
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, USA.,Center for Neuroscience Initiative, Auburn University, Auburn, Alabama, USA
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12
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Frazier HN, Ghoweri AO, Anderson KL, Lin RL, Porter NM, Thibault O. Broadening the definition of brain insulin resistance in aging and Alzheimer's disease. Exp Neurol 2019; 313:79-87. [PMID: 30576640 PMCID: PMC6370304 DOI: 10.1016/j.expneurol.2018.12.007] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 12/05/2018] [Accepted: 12/17/2018] [Indexed: 12/17/2022]
Abstract
It has been >20 years since studies first revealed that the brain is insulin sensitive, highlighted by the expression of insulin receptors in neurons and glia, the presence of circulating brain insulin, and even localized insulin production. Following these discoveries, evidence of decreased brain insulin receptor number and function was reported in both clinical samples and animal models of aging and Alzheimer's disease, setting the stage for the hypothesis that neuronal insulin resistance may underlie memory loss in these conditions. The development of therapeutic insulin delivery to the brain using intranasal insulin administration has been shown to improve aspects of memory or learning in both humans and animal models. However, whether this approach functions by compensating for poorly signaling insulin receptors, for reduced insulin levels in the brain, or for reduced trafficking of insulin into the brain remains unclear. Direct measures of insulin's impact on cellular physiology and metabolism in the brain have been sparse in models of Alzheimer's disease, and even fewer studies have analyzed these processes in the aged brain. Nevertheless, recent evidence supports the role of brain insulin as a mediator of glucose metabolism through several means, including altering glucose transporters. Here, we provide a review of contemporary literature on brain insulin resistance, highlight the rationale for improving memory function using intranasal insulin, and describe initial results from experiments using a molecular approach to more directly measure the impact of insulin receptor activation and signaling on glucose uptake in neurons.
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Affiliation(s)
- Hilaree N Frazier
- University of Kentucky, Department of Pharmacology and Nutritional Sciences, 800 Rose St., Lexington, KY 40536, United States.
| | - Adam O Ghoweri
- University of Kentucky, Department of Pharmacology and Nutritional Sciences, 800 Rose St., Lexington, KY 40536, United States.
| | - Katie L Anderson
- University of Kentucky, Department of Pharmacology and Nutritional Sciences, 800 Rose St., Lexington, KY 40536, United States.
| | - Ruei-Lung Lin
- University of Kentucky, Department of Pharmacology and Nutritional Sciences, 800 Rose St., Lexington, KY 40536, United States.
| | - Nada M Porter
- University of Kentucky, Department of Pharmacology and Nutritional Sciences, 800 Rose St., Lexington, KY 40536, United States.
| | - Olivier Thibault
- University of Kentucky, Department of Pharmacology and Nutritional Sciences, 800 Rose St., Lexington, KY 40536, United States.
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Li H, Luo Y, Xu Y, Yang L, Hu C, Chen Q, Yang Y, Ma J, Zhang J, Xia H, Li Y, Yang J. Meloxicam Improves Cognitive Impairment of Diabetic Rats through COX2-PGE2-EPs-cAMP/pPKA Pathway. Mol Pharm 2018; 15:4121-4131. [PMID: 30109938 DOI: 10.1021/acs.molpharmaceut.8b00532] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Diabetics often face greater risk of cognitive impairment than nondiabetics. However, how to prevent this disease is still unconfirmed. In this study, we investigated the potential protection and mechanism of meloxicam on cognitive impairment in diabetic rats. The diabetic rat model was established with a high-fat diet and a small dose of streptozotocin (40 mg/kg). The changes of spatial learning and memory, histopathology, and the protein expressions of amyloid protein precursor (APP) and β-amyloid (Aβ) indicated that diabetic rats had neuronal injury and cognitive impairment. Tumor necrosis factor α (TNFα), interleukin 6 (IL-6), C reactive protein (CRP) and prostaglandin E2 (PGE2) levels, and microglial cell number were significantly increased in the diabetic rat brain. Meanwhile, the protein expressions of APP, Aβ, cyclooxygenases2 (COX2), E-type prostanoid recptors 1 (EP1) and EP2, and the level of cyclic adenosine monophosphate (cAMP) were significantly increased, while the protein expressions of EP3 and phosphorylated protein kinase A (pPKA) were significantly decreased in the diabetic rat hippocampus and cortex. However, the EP4 protein expression had no significant changes. Meloxicam significantly improved neuronal injury and cognitive impairment, and significantly decreased inflammatory cytokines levels. Meloxicam also significantly decreased the protein expressions of APP, Aβ, COX2, EP1 and EP2, and the level of cAMP and significantly increased the EP3 and pPKA protein expressions in rat hippocampus and cortex. However, meloxicam did not significantly influence the levels of blood glucose, lipids, and insulin of rats. Our results suggest that meloxicam could significantly protect diabetic rats from cognitive impairment via a mechanism that may be associated with rebalancing the COX2-PGE2-EPs-cAMP/PKA pathway.
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Affiliation(s)
- Huan Li
- The Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology , Chongqing Medical University , Chongqing 400016 , China
| | - Ying Luo
- The Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology , Chongqing Medical University , Chongqing 400016 , China
| | - Ying Xu
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences , State University of New York at Buffalo , Buffalo , New York 14214 , United States
| | - Lu Yang
- The Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology , Chongqing Medical University , Chongqing 400016 , China
| | - Congli Hu
- The Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology , Chongqing Medical University , Chongqing 400016 , China
| | - Qi Chen
- The Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology , Chongqing Medical University , Chongqing 400016 , China
| | - Yang Yang
- The Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology , Chongqing Medical University , Chongqing 400016 , China
| | - Jie Ma
- The Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology , Chongqing Medical University , Chongqing 400016 , China
| | - Jiahua Zhang
- The Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology , Chongqing Medical University , Chongqing 400016 , China
| | - Hui Xia
- The Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology , Chongqing Medical University , Chongqing 400016 , China
| | - Yuke Li
- The Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology , Chongqing Medical University , Chongqing 400016 , China
| | - Junqing Yang
- The Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology , Chongqing Medical University , Chongqing 400016 , China
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Kong SH, Park YJ, Lee JY, Cho NH, Moon MK. Insulin Resistance is Associated with Cognitive Decline Among Older Koreans with Normal Baseline Cognitive Function: A Prospective Community-Based Cohort Study. Sci Rep 2018; 8:650. [PMID: 29330465 PMCID: PMC5766537 DOI: 10.1038/s41598-017-18998-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 12/20/2017] [Indexed: 11/19/2022] Open
Abstract
We evaluated whether metabolic factors were associated with cognitive decline, compared to baseline cognitive function, among geriatric population. The present study evaluated data from an ongoing prospective community-based Korean cohort study. Among 1,387 participants who were >65 years old, 422 participants were evaluated using the Korean mini-mental status examination (K-MMSE) at the baseline and follow-up examinations. The mean age at the baseline was 69.3 ± 2.9 years, and 222 participants (52.6%) were men. The mean duration of education was 7.1 ± 3.6 years. During a mean follow-up of 5.9 ± 0.1 years, the K-MMSE score significantly decreased (−1.1 ± 2.7 scores), although no significant change was observed in the homeostasis model assessment of insulin resistance (HOMA-IR) value. Participants with more decreased percent changes in K-MMSE scores had a shorter duration of education (p = 0.001), older age (p = 0.022), higher baseline K-MMSE score (p < 0.001), and increased insulin resistance (∆HOMA-IR, p = 0.002). The correlation between the percent changes in K-MMSE and ∆HOMA-IR values remained significant after multivariable adjustment (B = −0.201, p = 0.002). During a 6-year follow-up of older Koreans with normal baseline cognitive function, increased insulin resistance was significantly correlated with decreased cognitive function.
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Affiliation(s)
- Sung Hye Kong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Young Joo Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jun-Young Lee
- Department of Psychiatry and Behavioral Science, Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Nam H Cho
- Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Republic of Korea.
| | - Min Kyong Moon
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. .,Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
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15
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Gratuze M, Joly-Amado A, Vieau D, Buée L, Blum D. Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies? Neuroendocrinology 2018; 107:181-195. [PMID: 29439247 DOI: 10.1159/000487641] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 02/13/2018] [Indexed: 12/30/2022]
Abstract
Alzheimer disease (AD) is a progressive neurodegenerative disorder mainly characterized by cognitive deficits and neuropathological changes such as Tau lesions and amyloid plaques, but also associated with non-cognitive symptomatology. Metabolic and neuroendocrine abnormalities, such as alterations in body weight, brain insulin impairments, and lower brain glucose metabolism, which often precede clinical diagnosis, have been extensively reported in AD patients. However, the origin of these symptoms and their relation to pathology and cognitive impairments remain misunderstood. Insulin is a hormone involved in the control of energy homeostasis both peripherally and centrally, and insulin-resistant state has been linked to increased risk of dementia. It is now well established that insulin resistance can exacerbate Tau lesions, mainly by disrupting the balance between Tau kinases and phosphatases. On the other hand, the emerging literature indicates that Tau protein can also modulate insulin signalling in the brain, thus creating a detrimental vicious circle. The following review will highlight our current understanding of the role of insulin in the brain and its relation to Tau protein in the context of AD and tauopathies. Considering that insulin signalling is prone to be pharmacologically targeted at multiple levels, it constitutes an appealing approach to improve both insulin brain sensitivity and mitigate brain pathology with expected positive outcome in terms of cognition.
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Affiliation(s)
- Maud Gratuze
- Centre de Recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Université Laval, Québec, Québec, Canada
| | - Aurélie Joly-Amado
- Byrd Alzheimer's Institute, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA
| | - Didier Vieau
- Université de Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, "Alzheimer and Tauopathies,", Lille, France
| | - Luc Buée
- Université de Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, "Alzheimer and Tauopathies,", Lille, France
| | - David Blum
- Université de Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, "Alzheimer and Tauopathies,", Lille, France
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16
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Díaz-Venegas C, Schneider DC, Myrskylä M, Mehta NK. Life expectancy with and without cognitive impairment by diabetes status among older Americans. PLoS One 2017; 12:e0190488. [PMID: 29287106 PMCID: PMC5747473 DOI: 10.1371/journal.pone.0190488] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 12/16/2017] [Indexed: 01/21/2023] Open
Abstract
Diabetes affects mortality and cognitive functioning. It is not known how diabetes influences life expectancy (LE) with and without cognitive impairment. We seek to examine age at onset of cognitive impairment and life expectancy (LE) with and without cognitive impairment by diabetes status among middle- and older-aged Americans. Data come from the U.S. Health and Retirement Study 2000-2012 linked to the National Death Index (N = 13,687). We use multinomial regression models stratified by gender and controlling for age, education and race/ethnicity to estimate diabetes-status specific transition probabilities, then use a Markov chain matrix population model to calculate age at onset of cognitive impairment and LE with and without cognitive impairment by diabetes status at age 50. LE at age 50 was 27.6 (men) and 32.1 (women). From age 50, those with diabetes had a first incidence of cognitive impairment 3 (men) and 4 (women) years earlier than those without. Diabetes reduced total LE by 5-7 years and cognitively healthy LE by 4-6 years. Those with diabetes lived one year less in a cognitively impaired state than those without. Over 80% of the lower LE associated with diabetes is attributable to the loss of cognitively-healthy years. Those with diabetes have a shorter LE with cognitive impairment because of higher mortality. In analyses by educational attainment, education was strongly protective of cognitive health, yet diabetes was associated with lower age of cognitive impairment onset and fewer cognitive healthy years lived in all educational groups. The excess mortality because of diabetes may be decreasing. If the mortality decline is not coupled with a comparable decline in the risk of cognitive impairment, the population level burden of impaired cognition may grow larger.
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Affiliation(s)
| | | | - Mikko Myrskylä
- Max Planck Institute for Demographic Research, Rostock, Germany
- Department of Social Policy, London School of Economics, London, England
- Department of Social Research, University of Helsinki, Helsinki, Finland
| | - Neil K. Mehta
- School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America
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17
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Ryu CW, Coutu JP, Greka A, Rosas HD, Jahng GH, Rosen BR, Salat DH. Differential associations between systemic markers of disease and white matter tissue health in middle-aged and older adults. J Cereb Blood Flow Metab 2017; 37:3568-3579. [PMID: 27298238 PMCID: PMC5669337 DOI: 10.1177/0271678x16653613] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Age-associated cerebrovascular disease impacts brain tissue integrity, but other factors, including normal variation in blood markers of systemic health, may also influence the structural integrity of the brain. This cross-sectional study included 139 individuals between 40 to 86 years old who were physically healthy and cognitively intact. Eleven markers (total-cholesterol, high-density lipoprotein, low-density lipoprotein, triglyceride, insulin, fasting glucose, glycated hemoglobin, creatinine, blood urea nitrogen, albumin, total protein) and five derived indicators (estimated glomerular filtration rate, creatinine clearance rate, insulin-resistance, average glucose, and cholesterol/high-density lipoprotein ratio) were obtained from blood sampling. Diffusion tensor imaging was used to evaluate white matter tissue health. Blood markers were clustered into five factors. The first factor (defined as insulin/high-density lipoprotein factor) was associated with markers of integrity in the deep white matter and projection fiber systems, while the third factor (defined as kidney function factor) was associated with different markers of integrity in the periventricular and watershed white matter regions. Differential segregated associations for insulin and high-density lipoprotein levels and serum markers of kidney function may provide information about distinct mechanisms of brain changes across the lifespan. These results emphasize the need to determine whether therapeutic modulation of systemic health and organ function may prevent decline in brain structural integrity.
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Affiliation(s)
- Chang-Woo Ryu
- 1 MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.,2 Department of Radiology, School of Medicine, Kyung Hee University, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Jean-Philippe Coutu
- 1 MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.,3 Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Anna Greka
- 4 Renal Division, Department of Medicine, Glom-NExT Center, Brigham and Women's Hospital, Boston MA, USA.,5 Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - H Diana Rosas
- 1 MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.,6 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Geon-Ho Jahng
- 2 Department of Radiology, School of Medicine, Kyung Hee University, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Bruce R Rosen
- 1 MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.,7 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - David H Salat
- 1 MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.,7 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,8 Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, USA
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18
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Tundo GR, Sbardella D, Ciaccio C, Grasso G, Gioia M, Coletta A, Polticelli F, Di Pierro D, Milardi D, Van Endert P, Marini S, Coletta M. Multiple functions of insulin-degrading enzyme: a metabolic crosslight? Crit Rev Biochem Mol Biol 2017. [PMID: 28635330 DOI: 10.1080/10409238.2017.1337707] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Insulin-degrading enzyme (IDE) is a ubiquitous zinc peptidase of the inverzincin family, which has been initially discovered as the enzyme responsible for insulin catabolism; therefore, its involvement in the onset of diabetes has been largely investigated. However, further studies on IDE unraveled its ability to degrade several other polypeptides, such as β-amyloid, amylin, and glucagon, envisaging the possible implication of IDE dys-regulation in the "aggregopathies" and, in particular, in neurodegenerative diseases. Over the last decade, a novel scenario on IDE biology has emerged, pointing out a multi-functional role of this enzyme in several basic cellular processes. In particular, latest advances indicate that IDE behaves as a heat shock protein and modulates the ubiquitin-proteasome system, suggesting a major implication in proteins turnover and cell homeostasis. In addition, recent observations have highlighted that the regulation of glucose metabolism by IDE is not merely based on its largely proposed role in the degradation of insulin in vivo. There is increasing evidence that improper IDE function, regulation, or trafficking might contribute to the etiology of metabolic diseases. In addition, the enzymatic activity of IDE is affected by metals levels, thus suggesting a role also in the metal homeostasis (metallostasis), which is thought to be tightly linked to the malfunction of the "quality control" machinery of the cell. Focusing on the physiological role of IDE, we will address a comprehensive vision of the very complex scenario in which IDE takes part, outlining its crucial role in interconnecting several relevant cellular processes.
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Affiliation(s)
- Grazia R Tundo
- a Department of Clinical Sciences and Translation Medicine , University of Roma Tor Vergata , Roma , Italy.,b CIRCMSB , Bari , Italy
| | - Diego Sbardella
- a Department of Clinical Sciences and Translation Medicine , University of Roma Tor Vergata , Roma , Italy.,b CIRCMSB , Bari , Italy.,c Center for TeleInfrastructures, University of Roma Tor Vergata , Roma , Italy
| | - Chiara Ciaccio
- a Department of Clinical Sciences and Translation Medicine , University of Roma Tor Vergata , Roma , Italy.,b CIRCMSB , Bari , Italy
| | - Giuseppe Grasso
- d Department of Chemistry , University of Catania , Catania , Italy.,e CNR IBB , Catania , Italy
| | - Magda Gioia
- a Department of Clinical Sciences and Translation Medicine , University of Roma Tor Vergata , Roma , Italy.,b CIRCMSB , Bari , Italy
| | - Andrea Coletta
- f Department of Chemistry , University of Aarhus , Aarhus , Denmark
| | | | - Donato Di Pierro
- a Department of Clinical Sciences and Translation Medicine , University of Roma Tor Vergata , Roma , Italy.,b CIRCMSB , Bari , Italy
| | | | - Peter Van Endert
- h Université Paris Descartes, INSERM, U1151, CNRS , Paris , France
| | - Stefano Marini
- a Department of Clinical Sciences and Translation Medicine , University of Roma Tor Vergata , Roma , Italy.,b CIRCMSB , Bari , Italy.,c Center for TeleInfrastructures, University of Roma Tor Vergata , Roma , Italy
| | - Massimo Coletta
- a Department of Clinical Sciences and Translation Medicine , University of Roma Tor Vergata , Roma , Italy.,b CIRCMSB , Bari , Italy.,c Center for TeleInfrastructures, University of Roma Tor Vergata , Roma , Italy
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19
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Song J, Jung C, Kim OY. The Novel Implication of Androgen in Diabetes-induced Alzheimer's Disease. J Lipid Atheroscler 2017. [DOI: 10.12997/jla.2017.6.2.66] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea
| | - Chaeyong Jung
- Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea
| | - Oh Yoen Kim
- Department of Food Science and Nutrition, Dong-A University, Busan, Korea
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20
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Ponce-Lopez T, Hong E, Abascal-Díaz M, Meneses A. Role of GSK3<i>β</i> and PP2A on Regulation of Tau Phosphorylation in Hippocampus and Memory Impairment in ICV-STZ Animal Model of Alzheimer’s Disease. ACTA ACUST UNITED AC 2017. [DOI: 10.4236/aad.2017.61002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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21
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Estato V, Nascimento A, Antunes B, Gomes F, Coelho L, Rangel R, Garzoni L, Daliry A, Bousquet P, Tibiriçá E. Cerebral Microvascular Dysfunction and Inflammation Are Improved by Centrally Acting Antihypertensive Drugs in Metabolic Syndrome. Metab Syndr Relat Disord 2016; 15:26-35. [PMID: 27929741 DOI: 10.1089/met.2016.0085] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND We aimed to investigate the effects of chronic oral treatment with centrally acting antihypertensive drugs, such as clonidine (CLO), an α2-adrenoceptor agonist, or LNP599, a selective I1 imidazoline receptor agonist, on brain microvascular function in rats with high-fat diet (HFD)-induced metabolic syndrome. METHODS Male Wistar Kyoto rats were maintained on a normal diet (CON) or a HFD for 20 weeks. After this period, the HFD group received oral CLO (0.1 mg/kg), LNP599 (20 mg/kg), or vehicle daily for 4 weeks. Systolic blood pressure and heart rate (HR) were evaluated by photoplethysmography. Functional capillary density, endothelial function, and endothelial-leukocyte interactions in the brain were investigated by intravital video microscopy. Cerebral microcirculatory flow was evaluated by laser speckle contrast imaging. Brain tissue endothelial nitric oxide synthase, oxidative enzyme, and inflammatory marker expression levels were analyzed. RESULTS Metabolic syndrome decreased brain functional capillary density and microvascular blood perfusion, changes accompanied by deficient brain microcirculation vasodilatory responses to acetylcholine. Significant numbers of rolling and adherent leukocytes were also observed in the brain venules. Chronic sympathetic inhibition with clonidine and LNP599 reduced blood pressure and HR. These effects were accompanied by reversals of cerebral capillary rarefaction, improvements in cerebral microvascular blood flow and endothelial function, and decreases in endothelial-leukocyte interactions in the cerebral venules. CONCLUSIONS Our results suggest that central sympathetic inhibition exerts beneficial effects by increasing perfusion and reducing inflammatory marker expression and oxidative stress in the brains of rats with metabolic syndrome. Centrally acting antihypertensive drugs may be helpful in regulating cerebral microcirculatory function and vascular inflammation in metabolic syndrome.
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Affiliation(s)
- Vanessa Estato
- 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .,2 Institute of Drug Technology , Owaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Alessandro Nascimento
- 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil
| | - Barbara Antunes
- 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil
| | - Fabiana Gomes
- 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil
| | - Laura Coelho
- 3 Laboratory for Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil
| | - Raquel Rangel
- 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil
| | - Luciana Garzoni
- 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .,3 Laboratory for Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil
| | - Anissa Daliry
- 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil
| | - Pascal Bousquet
- 4 Laboratory of Neurobiology and Cardiovascular Pharmacology, Faculty of Medicine, University of Strasbourg , Strasbourg, France
| | - Eduardo Tibiriçá
- 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .,5 National Institute of Cardiology , Rio de Janeiro, Brazil
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22
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Executive functions in patients with Alzheimer's disease, type 2 diabetes mellitus patients and cognitively healthy older adults. Exp Gerontol 2016; 83:47-55. [DOI: 10.1016/j.exger.2016.07.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 06/16/2016] [Accepted: 07/20/2016] [Indexed: 01/21/2023]
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23
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Salem L, Saleh N, Désaméricq G, Youssov K, Dolbeau G, Cleret L, Bourhis ML, Azulay JP, Krystkowiak P, Verny C, Morin F, Moutereau S, The French Huntington Study Group, Bachoud-Lévi AC, Maison P. Insulin-Like Growth Factor-1 but Not Insulin Predicts Cognitive Decline in Huntington's Disease. PLoS One 2016; 11:e0162890. [PMID: 27627435 PMCID: PMC5023180 DOI: 10.1371/journal.pone.0162890] [Citation(s) in RCA: 9] [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: 03/21/2016] [Accepted: 08/30/2016] [Indexed: 01/05/2023] Open
Abstract
Background Huntington's disease (HD) is one of several neurodegenerative disorders that have been associated with metabolic alterations. Changes in Insulin Growth Factor 1 (IGF-1) and/or insulin input to the brain may underlie or contribute to the progress of neurodegenerative processes. Here, we investigated the association over time between changes in plasma levels of IGF-1 and insulin and the cognitive decline in HD patients. Methods We conducted a multicentric cohort study in 156 patients with genetically documented HD aged from 22 to 80 years. Among them, 146 patients were assessed at least twice with a follow-up of 3.5 ± 1.8 years. We assessed their cognitive decline using the Unified Huntington’s Disease Rating Scale, and their IGF-1 and insulin plasmatic levels, at baseline and once a year during the follow-up. Associations were evaluated using a mixed-effect linear model. Results In the cross-sectional analysis at baseline, higher levels of IGF-1 and insulin were associated with lower cognitive scores and thus with a higher degree of cognitive impairment. In the longitudinal analysis, the decrease of all cognitive scores, except the Stroop interference, was associated with the IGF-1 level over time but not of insulin. Conclusions IGF-1 levels, unlike insulin, predict the decline of cognitive function in HD.
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Affiliation(s)
- Linda Salem
- Université Paris Est, Faculté de médecine, Créteil, France
- Inserm, U955, Equipe 01, Neuropsychologie interventionnelle, Créteil, France
- Ecole Normale Supérieure, Département d'études Cognitives, Paris, France
- AP-HP, Hôpital H. Mondor- A. Chenevier, Centre de référence maladie de Huntington, Neurologie cognitive, Créteil, France
| | - Nadine Saleh
- Université Paris Est, Faculté de médecine, Créteil, France
- Inserm, U955, Equipe 01, Neuropsychologie interventionnelle, Créteil, France
- Ecole Normale Supérieure, Département d'études Cognitives, Paris, France
- AP-HP, Hôpital H. Mondor- A. Chenevier, Centre de référence maladie de Huntington, Neurologie cognitive, Créteil, France
| | - Gaelle Désaméricq
- Université Paris Est, Faculté de médecine, Créteil, France
- Inserm, U955, Equipe 01, Neuropsychologie interventionnelle, Créteil, France
- Ecole Normale Supérieure, Département d'études Cognitives, Paris, France
- AP-HP, Hôpital H. Mondor- A. Chenevier, Centre de référence maladie de Huntington, Neurologie cognitive, Créteil, France
| | - Katia Youssov
- Université Paris Est, Faculté de médecine, Créteil, France
- Inserm, U955, Equipe 01, Neuropsychologie interventionnelle, Créteil, France
- Ecole Normale Supérieure, Département d'études Cognitives, Paris, France
- AP-HP, Hôpital H. Mondor- A. Chenevier, Centre de référence maladie de Huntington, Neurologie cognitive, Créteil, France
| | - Guillaume Dolbeau
- Université Paris Est, Faculté de médecine, Créteil, France
- Inserm, U955, Equipe 01, Neuropsychologie interventionnelle, Créteil, France
- AP-HP, Hôpital H. Mondor- A. Chenevier, Unité de recherche clinique, Créteil, France
| | - Laurent Cleret
- Université Paris Est, Faculté de médecine, Créteil, France
- Inserm, U955, Equipe 01, Neuropsychologie interventionnelle, Créteil, France
- Ecole Normale Supérieure, Département d'études Cognitives, Paris, France
- AP-HP, Hôpital H. Mondor- A. Chenevier, Centre de référence maladie de Huntington, Neurologie cognitive, Créteil, France
| | - Marie-Laure Bourhis
- AP-HP, Hôpital H. Mondor- A. Chenevier, Unité de recherche clinique, Créteil, France
| | - Jean-Philippe Azulay
- Hôpital de la Timone, Service de Neurologie et pathologie du mouvement, Marseille, France
| | | | - Christophe Verny
- CHU of Angers, Centre de référence des maladies neurogénétiques, service de neurologie, Angers, France
| | - Françoise Morin
- AP-HP-GHU NORD, Hôpital Avicenne, Etablissement Français du sang, Bobigny, France
| | - Stéphane Moutereau
- AP-HP, Hôpital H. Mondor- A. Chenevier, Département de Biochimie-Pharmaco-Toxicologie, Créteil, France
| | | | - Anne-Catherine Bachoud-Lévi
- Université Paris Est, Faculté de médecine, Créteil, France
- Inserm, U955, Equipe 01, Neuropsychologie interventionnelle, Créteil, France
- Ecole Normale Supérieure, Département d'études Cognitives, Paris, France
- AP-HP, Hôpital H. Mondor- A. Chenevier, Centre de référence maladie de Huntington, Neurologie cognitive, Créteil, France
- * E-mail:
| | - Patrick Maison
- Université Paris Est, Faculté de médecine, Créteil, France
- Inserm, U955, Equipe 01, Neuropsychologie interventionnelle, Créteil, France
- Ecole Normale Supérieure, Département d'études Cognitives, Paris, France
- AP-HP, Hôpital H. Mondor- A. Chenevier, Centre de référence maladie de Huntington, Neurologie cognitive, Créteil, France
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Stanley M, Macauley SL, Holtzman DM. Changes in insulin and insulin signaling in Alzheimer's disease: cause or consequence? J Exp Med 2016; 213:1375-85. [PMID: 27432942 PMCID: PMC4986537 DOI: 10.1084/jem.20160493] [Citation(s) in RCA: 153] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 06/20/2016] [Indexed: 12/30/2022] Open
Abstract
Stanley and colleagues explore whether changes in insulin levels and insulin
signaling are a cause or consequence of AD. Individuals with type 2 diabetes have an increased risk for developing
Alzheimer’s disease (AD), although the causal relationship remains poorly
understood. Alterations in insulin signaling (IS) are reported in the AD brain.
Moreover, oligomers/fibrils of amyloid-β (Aβ) can lead to neuronal
insulin resistance and intranasal insulin is being explored as a potential therapy
for AD. Conversely, elevated insulin levels (ins) are found in AD patients and high
insulin has been reported to increase Aβ levels and tau phosphorylation, which
could exacerbate AD pathology. Herein, we explore whether changes in ins and IS are a
cause or consequence of AD.
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Affiliation(s)
- Molly Stanley
- Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
| | - Shannon L Macauley
- Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
| | - David M Holtzman
- Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
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25
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Mwamburi M, Qiu WQ. Different associations of premorbid intelligence vs. current cognition with BMI, insulin and diabetes in the homebound elderly. ACTA ACUST UNITED AC 2016; 3:547-552. [PMID: 27642517 PMCID: PMC5026314 DOI: 10.15761/imm.1000202] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Premorbid intelligence does not decline through life even at the early stages of Alzheimer’s disease (AD). However, other cognitive measures such as Mini Mental State Examination (MMSE) decline with aging and severely with dementia. In this study, we examine the associations of premorbid intelligence vs. current cognition with body mass index (BMI), insulin and diabetes in elderly adults. Using a cross-sectional, population-based study, we assessed BMI, plasma insulin and the evidence of diabetes in homebound elders. The North American Adult Reading Test (NAART) and MMSE were conducted. Associations were assessed by T-test, linear correlation and multivariate regression analysis. Subjects were divided into four subgroups: 1) BMI <25; 2) 25 < BMI <30; 3) 30 < BMI <35 and 4) BMI >35. Lower verbal IQ, assessed by NAART, was associated with higher BMI (β=−0.28; P<0.01), elevated insulin (β= −0.02, P=0.02), and diabetes (β=− 3.18, P<0.01). Multivariate regression analyses showed that all three clinical conditions – obesity, hyperinsulinaemia and diabetes – were associated with lower premorbid intelligence assessed by verbal IQ, but only diabetes was associated with current cognitive impairment assessed by MMSE. These relationships persisted after adjustment for education. Premorbid intelligence is associated with diabetes precursors – obesity and high insulin – and diabetes itself, but cognitive impairment is related to diabetes only. Understanding the mechanisms that link verbal IQ to diabetes precursors might suggest targeted interventions for the prevention of diabetes and cognitive decline caused by diabetes.
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Affiliation(s)
- Mkaya Mwamburi
- Departments of Psychiatry, Boston University School of Medicine, Boston, US A
| | - Wei Qiao Qiu
- Departments of Psychiatry, Boston University School of Medicine, Boston, US A; Pharmacology, Boston University School of Medicine, Boston, USA; Alzheimer's Disease Center, Boston University School of Medicine, Boston, USA
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Abstract
Aging patients with diabetes are at higher risk of developing Alzheimer's disease. Emerging evidences demonstrate the role of brain insulin resistance, which is a key mediator in prediabetes and diabetes mellitus that may lead to Alzheimer's disease. Insulin and insulin-like growth factors regulate many biological processes such as axonal growth, protein synthesis, cell growth, gene expression, proliferation, differentiation, and development. Among these, the energy metabolism and synaptic plasticity are the major transduction processes regulated by insulin, which are the core objectives for learning and memory. It was also proposed that hyper insulinemia induced insulin resistance results in injury to the central nervous system by the activation of glycogen synthase kinase 3β which is the key ailment in the cognitive decline. Hence, the endogenous brain specific insulin impairments and signaling account for the majority of Alzheimer's abnormalities.
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Affiliation(s)
- V R Bitra
- Division of Pharmacology, Andhra University College of Pharmaceutical Sciences, Visakhapatnam-530 003, India
| | - Deepthi Rapaka
- Division of Pharmacology, Andhra University College of Pharmaceutical Sciences, Visakhapatnam-530 003, India
| | - Annapurna Akula
- Division of Pharmacology, Andhra University College of Pharmaceutical Sciences, Visakhapatnam-530 003, India
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27
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Jha NK, Jha SK, Kumar D, Kejriwal N, Sharma R, Ambasta RK, Kumar P. Impact of Insulin Degrading Enzyme and Neprilysin in Alzheimer’s Disease Biology: Characterization of Putative Cognates for Therapeutic Applications. J Alzheimers Dis 2015; 48:891-917. [DOI: 10.3233/jad-150379] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Niraj Kumar Jha
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India
| | - Saurabh Kumar Jha
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India
| | - Dhiraj Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India
| | - Noopur Kejriwal
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India
| | - Renu Sharma
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India
| | - Rashmi K. Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India
- Department of Neurology, Tufts University School of Medicine, Boston, MA, USA
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28
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Redondo MT, Beltrán-Brotóns JL, Reales JM, Ballesteros S. Word-stem priming and recognition in type 2 diabetes mellitus, Alzheimer’s disease patients and healthy older adults. Exp Brain Res 2015; 233:3163-74. [DOI: 10.1007/s00221-015-4385-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 07/09/2015] [Indexed: 11/25/2022]
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29
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Moradkhani S, Salehi I, Abdolmaleki S, Komaki A. Effect of Calendula officinalis hydroalcoholic extract on passive avoidance learning and memory in streptozotocin-induced diabetic rats. Anc Sci Life 2015; 34:156-61. [PMID: 26120230 PMCID: PMC4458906 DOI: 10.4103/0257-7941.157160] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Medicinal plants, owing to their different mechanisms such as antioxidants effects, may improve learning and memory impairments in diabetic rats. Calendula officinalis (CO), has a significant antioxidant activity. AIMS To examine the effect of hydroalcoholic extract of CO on passive avoidance learning (PAL) and memory in streptozotocin (STZ)-induced diabetic male rats. SETTINGS AND DESIGN A total of 32 adult male Wistar rats were randomly allocated to four groups: Control, diabetic, control + extract of CO and diabetic control + extract of CO groups with free access to regular rat diet. SUBJECTS AND METHODS Diabetes in diabetic rats was induced by single intraperitoneal injection of 60 mg/kg STZ. After confirmation of diabetes, oral administration of 300 mg/kg CO extract to extract-treated groups have been done. PAL was tested 8 weeks after onset of treatment, and blood glucose and body weight were measured in all groups at the beginning and end of the experiment. STATISTICAL ANALYSIS USED The statistical analysis of data was performed by ANOVA followed by least significant difference post-hoc analysis. RESULTS Diabetes decreased learning and memory. Effect of CO extract in retention test (after 24 and 48 h) has been shown a significant decrease in step-through latency and increase in time spent in the dark compartment part. Also the extract partially improved hyperglycemia and reduced body weight. CONCLUSION Taken together, CO extract can improve PAL and memory impairments in STZ-diabetic rats. This improvement may be due to its antioxidant, anticholinergic activities or its power to reduce hyperglycemia.
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Affiliation(s)
- Shirin Moradkhani
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran ; Department of Pharmacognosy and Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Iraj Salehi
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Somayeh Abdolmaleki
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Alireza Komaki
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
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30
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Abstract
Alzheimer's disease (AD) is a neurological disorder characterized by profound memory loss and progressive dementia. Accumulating evidence suggests that Type 2 diabetes mellitus, a metabolic disorder characterized by insulin resistance and glucose intolerance, significantly increases the risk for developing AD. Whereas amyloid-β (Aβ) deposition and neurofibrillary tangles are major histological hallmarks of AD, impairment of cerebral glucose metabolism precedes these pathological changes during the early stage of AD and likely triggers or exacerbates AD pathology. However, the mechanisms linking disturbed insulin signaling/glucose metabolism and AD pathogenesis remain unclear. The low-density lipoprotein receptor-related protein 1 (LRP1), a major apolipoprotein E receptor, plays critical roles in lipoprotein metabolism, synaptic maintenance, and clearance of Aβ in the brain. Here, we demonstrate that LRP1 interacts with the insulin receptor β in the brain and regulates insulin signaling and glucose uptake. LRP1 deficiency in neurons leads to impaired insulin signaling as well as reduced levels of glucose transporters GLUT3 and GLUT4. Consequently, glucose uptake is reduced. By using an in vivo microdialysis technique sampling brain glucose concentration in freely moving mice, we further show that LRP1 deficiency in conditional knock-out mice resulted in glucose intolerance in the brain. We also found that hyperglycemia suppresses LRP1 expression, which further exacerbates insulin resistance, glucose intolerance, and AD pathology. As loss of LRP1 expression is seen in AD brains, our study provides novel insights into insulin resistance in AD. Our work also establishes new targets that can be explored for AD prevention or therapy.
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31
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Akintola AA, van den Berg A, van Buchem MA, Jansen SW, Slagboom EP, Westendorp RG, van der Grond J, van Heemst D. Associations between insulin action and integrity of brain microstructure differ with familial longevity and with age. Front Aging Neurosci 2015; 7:92. [PMID: 26074813 PMCID: PMC4446544 DOI: 10.3389/fnagi.2015.00092] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 05/03/2015] [Indexed: 11/13/2022] Open
Abstract
Impaired glucose metabolism and type 2 diabetes have been associated with cognitive decline, dementia, and with structural and functional brain features. However, it is unclear whether these associations differ in individuals that differ in familial longevity or age. Here, we investigated the association between parameters of glucose metabolism and microstructural brain integrity in offspring of long-lived families (“offspring”) and controls; and age categories thereof. From the Leiden Longevity Study (LLS), 132 participants underwent an oral glucose tolerance test (OGTT) to assess glycemia [fasted glucose and glucose area-under-the-curve (AUC)], insulin resistance [fasted insulin, AUCinsulin, and homeostatic model assessment of insulin resistance (HOMA-IR)], and pancreatic Beta cell secretory capacity (insulinogenic index). 3 Tesla MRI and Magnetization Transfer (MT) imaging MT-ratio (MTR) peak-height was used to quantify differences in microstructural brain parenchymal tissue homogeneity that remain invisible on conventional MRI. Analyses were performed in offspring and age-matched controls, with and without stratification for age. In the full offspring group only, reduced MTR peak-height in gray and white matter was inversely associated with AUCinsulin, fasted insulin, HOMA-IR and insulinogenic-index (all p < 0.01). When dichotomized for age (≤65 years and >65 years): in younger controls, significantly stronger inverse associations were observed between MTR peak-height and fasted glucose, AUCglucose, fasted insulin, AUCinsulin and HOMA-IR in gray matter; and for AUCglucose, fasted insulin and HOMA-IR in white matter (all P-interaction < 0.05). Although the strength of the associations tended to attenuate with age in the offspring group, the difference between age groups was not statistically significant. Thus, associations between impaired insulin action and reduced microstructural brain parenchymal tissue homogeneity were stronger in offspring compared to controls, and seemed to diminish with age.
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Affiliation(s)
- Abimbola A Akintola
- Department of Gerontology and Geriatrics, Leiden University Medical Centre Leiden, Netherlands
| | | | - Mark A van Buchem
- Department of Radiology, Leiden University Medical Centre Leiden, Netherlands ; Netherlands Consortium for Healthy Ageing Leiden, Netherlands ; Leiden Institute for Brain and Cognition, Leiden University Leiden, Netherlands
| | - Steffy W Jansen
- Department of Gerontology and Geriatrics, Leiden University Medical Centre Leiden, Netherlands
| | - Eline P Slagboom
- Netherlands Consortium for Healthy Ageing Leiden, Netherlands ; Department of Molecular Epidemiology, Leiden University Medical Centre Leiden, Netherlands
| | - Rudi G Westendorp
- Department of Gerontology and Geriatrics, Leiden University Medical Centre Leiden, Netherlands ; Department of Public Health, University of Copenhagen Copenhagen, Denmark
| | - Jeroen van der Grond
- Department of Radiology, Leiden University Medical Centre Leiden, Netherlands ; Netherlands Consortium for Healthy Ageing Leiden, Netherlands
| | - Diana van Heemst
- Department of Gerontology and Geriatrics, Leiden University Medical Centre Leiden, Netherlands ; Netherlands Consortium for Healthy Ageing Leiden, Netherlands
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32
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Pani G. Neuroprotective effects of dietary restriction: Evidence and mechanisms. Semin Cell Dev Biol 2015; 40:106-14. [DOI: 10.1016/j.semcdb.2015.03.004] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 03/03/2015] [Accepted: 03/04/2015] [Indexed: 12/30/2022]
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Jeon S, Park JE, Lee J, Liu QF, Jeong HJ, Pak SC, Yi S, Kim MH, Kim CW, Park JK, Kim GW, Koo BS. Illite improves memory impairment and reduces Aβ level in the Tg-APPswe/PS1dE9 mouse model of Alzheimer׳s disease through Akt/CREB and GSK-3β phosphorylation in the brain. JOURNAL OF ETHNOPHARMACOLOGY 2015; 160:69-77. [PMID: 25457987 DOI: 10.1016/j.jep.2014.11.029] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 11/04/2014] [Accepted: 11/18/2014] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The use of illite in Korean medicine has a long history as a therapeutic agent for various cerebrovascular diseases. According to Dongui Bogam, illite can be used for Qi-tonifying, phlegm dispersing and activation of blood circulation which is an important principle for the treatment of brain-associated diseases. AIM OF THE STUDY This study was undertaken to evaluate beneficial effects of illite on the neurodegenerative diseases such as Alzheimer׳s disease (AD). MATERIAL AND METHODS The transgenic mice of AD, Tg-APPswe/PS1dE9, were fed with 1% or 3% of illite for 3 months. Behavioral, immunological and ELISA analyses were used to assess memory impairment with additional measurement of Aβ accumulation and plaque deposition in the brain. Other in vitro studies were performed to examine whether illite inhibits the Aβ-induced neurotoxicity in human neuroblastoma cell line, SH-SY5Y cells. RESULTS Illite treatment rescued Aβ-induced neurotoxicity on SH-SY5Y cells, which was dependent on the PI3K/Akt activation. Intake of illite improved the Aβ-induced memory impairment and suppressed Aβ levels and plaque deposition in the brain of Tg-APPswe/PS1dE9 mice. Illite increased CREB, Akt, and GSK-3β phosphorylation and suppressed tau phosphorylation in the AD-like brains. Moreover, 1% of illite reduced weight gain and suppressed glucose level in the blood. CONCLUSION The present study suggests that illite has the potential to be a useful adjunct as a therapeutic drug for the treatment of AD.
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Affiliation(s)
- Songhee Jeon
- Dongguk University Research Institute of Biotechnology, Seoul 100-715, Republic of Korea.
| | - Jeong-Eun Park
- Dongguk University Research Institute of Biotechnology, Seoul 100-715, Republic of Korea
| | - Jinhee Lee
- Department of Neuropsychiatry, Graduate School of Oriental Medicine, Dongguk University, Gyeongju, Republic of Korea
| | - Quan Feng Liu
- Department of Neuropsychiatry, Graduate School of Oriental Medicine, Dongguk University, Gyeongju, Republic of Korea
| | - Ha Jin Jeong
- Dongguk University Research Institute of Biotechnology, Seoul 100-715, Republic of Korea
| | - Sok Cheon Pak
- School of Biomedical Sciences, Charles Sturt University, Bathurst, NSW 2795, Australia
| | - Sudok Yi
- Yong-dong Illite Co., Ltd., 32, Mocdongnamno Gurogu, Seoul, Republic of Korea
| | - Myung Hun Kim
- Department of Chemisty, University of Cambridge, Cambridge CB2 1EW, UK
| | - Chan-Wha Kim
- School of Life Sciences and Biotechnology, Korea University, 1-5, Anam Dong, Seongbuk-Gu, Seoul 136-701, Republic of Korea
| | - Jung-Keug Park
- Dongguk University Research Institute of Biotechnology, Seoul 100-715, Republic of Korea
| | - Geun Woo Kim
- Department of Korean Neuropsychiatry, Dongguk University Bundang Oriental Hospital, Gyeonggi-do, Republic of Korea
| | - Byung-Soo Koo
- Department of Neuropsychiatry, Graduate School of Oriental Medicine, Dongguk University, Gyeongju, Republic of Korea.
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Zhang H, Wang Y, Yan S, Du F, Wu L, Yan S, Yan SS. Genetic deficiency of neuronal RAGE protects against AGE-induced synaptic injury. Cell Death Dis 2014; 5:e1288. [PMID: 24922072 PMCID: PMC4611721 DOI: 10.1038/cddis.2014.248] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 04/28/2014] [Accepted: 05/05/2014] [Indexed: 01/11/2023]
Abstract
Synaptic dysfunction and degeneration is an early pathological feature of aging and age-related diseases, including Alzheimer's disease (AD). Aging is associated with increased generation and deposition of advanced glycation endproducts (AGEs), resulting from nonenzymatic glycation (or oxidation) proteins and lipids. AGE formation is accelerated in diabetes and AD-affected brain, contributing to cellular perturbation. The extent of AGEs' involvement, if at all, in alterations in synaptic structure and function is currently unknown. Here we analyze the contribution of neuronal receptor of AGEs (RAGE) signaling to AGE-mediated synaptic injury using novel transgenic neuronal RAGE knockout mice specifically targeted to the forebrain and transgenic mice expressing neuronal dominant-negative RAGE (DN-RAGE). Addition of AGEs to brain slices impaired hippocampal long-term potentiation (LTP). Similarly, treatment of hippocampal neurons with AGEs significantly decreases synaptic density. Such detrimental effects are largely reversed by genetic RAGE depletion. Notably, brain slices from mice with neuronal RAGE deficiency or DN-RAGE are resistant to AGE-induced LTP deficit. Further, RAGE deficiency or DN-RAGE blocks AGE-induced activation of p38 signaling. Taken together, these data show that neuronal RAGE functions as a signal transducer for AGE-induced synaptic dysfunction, thereby providing new insights into a mechanism by which the AGEs–RAGE-dependent signaling cascade contributes to synaptic injury via the p38 MAP kinase signal transduction pathway. Thus, RAGE blockade may be a target for development of interventions aimed at preventing the progression of cognitive decline in aging and age-related neurodegenerative diseases.
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Affiliation(s)
- Hongju Zhang
- 1] Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA [2] School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Yongfu Wang
- Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
| | - Shijun Yan
- Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
| | - Fang Du
- Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
| | - Long Wu
- Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
| | - Shiqiang Yan
- School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Shirley S Yan
- Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
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Abstract
Obesity, metabolic syndrome, and type 2 diabetes (T2D) are related disorders with widespread deleterious effects throughout the body. One important target of damage is the brain. Persons with metabolic disorders are at significantly increased risk for cognitive decline and the development of vascular dementia and Alzheimer's disease. Our review of available evidence from epidemiologic, clinical, and basic research suggests that neural dysfunction from T2D-related disease results from several underlying mechanisms, including metabolic, inflammatory, vascular, and oxidative changes. The relationships between T2D and neural dysfunction are regulated by several modifiers. We emphasize 2 such modifiers, the genetic risk factor apolipoprotein E and an age-related endocrine change, low testosterone. Both factors are independent risk factors for Alzheimer's disease that may also cooperatively regulate pathologic interactions between T2D and dementia. Continued elucidation of the links between metabolic disorders and neural dysfunction promises to foster the development of effective therapeutic strategies.
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Affiliation(s)
- Anusha Jayaraman
- 3715 McClintock Avenue, Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089-0191 USA, , (213) 740-8244
| | - Christian J. Pike
- 3715 McClintock Avenue, Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089-0191 USA, , (213) 740-4205
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36
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Rettberg JR, Yao J, Brinton RD. Estrogen: a master regulator of bioenergetic systems in the brain and body. Front Neuroendocrinol 2014; 35:8-30. [PMID: 23994581 PMCID: PMC4024050 DOI: 10.1016/j.yfrne.2013.08.001] [Citation(s) in RCA: 350] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 08/09/2013] [Accepted: 08/10/2013] [Indexed: 01/12/2023]
Abstract
Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regulates energy intake and expenditure. During menopause, decline in circulating estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk of late-onset Alzheimer's disease. Estrogen coordinates brain and body metabolism, such that peripheral metabolic state can indicate bioenergetic status of the brain. By generating biomarker profiles that encompass peripheral metabolic changes occurring with menopause, individual risk profiles for decreased brain bioenergetics and cognitive decline can be created. Biomarker profiles could identify women at risk while also serving as indicators of efficacy of hormone therapy or other preventative interventions.
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Affiliation(s)
- Jamaica R Rettberg
- Neuroscience Department, University of Southern California, Los Angeles, CA 90033, United States
| | - Jia Yao
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, United States
| | - Roberta Diaz Brinton
- Neuroscience Department, University of Southern California, Los Angeles, CA 90033, United States; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, United States; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States.
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37
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Ashrafian H, Harling L, Darzi A, Athanasiou T. Neurodegenerative disease and obesity: what is the role of weight loss and bariatric interventions? Metab Brain Dis 2013; 28:341-53. [PMID: 23653255 DOI: 10.1007/s11011-013-9412-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 04/17/2013] [Indexed: 12/20/2022]
Abstract
Neurodegenerative diseases are amongst the leading causes of worldwide disability, morbidity and decreased quality of life. They are increasingly associated with the concomitant worldwide epidemic of obesity. Although the prevalence of both AD and PD continue to rise, the available treatment strategies to combat these conditions remain ineffective against an increase in global neurodegenerative risk factors. There is now epidemiological and mechanistic evidence associating obesity and its related disorders of impaired glucose homeostasis, type 2 diabetes mellitus and metabolic syndrome with both AD and PD. Here we describe the clinical and molecular relationship between obesity and neurodegenerative disease. Secondly we outline the protective role of weight loss, metabolic and caloric modifying interventions in the context of AD and PD. We conclude that the application of caloric restriction through dietary changes, bariatric (metabolic) surgery and gut hormone therapy may offer novel therapeutic strategies against neurodegenerative disorders. Investigating the protective mechanisms of weight loss, metabolic and caloric modifying interventions can increase our understanding of these major public health diseases and their management.
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Affiliation(s)
- Hutan Ashrafian
- The Department of Surgery and Cancer, Imperial College London, Imperial College London at St Mary's Hospital Campus, 10th Floor, Queen Elizabeth the Queen Mother (QEQM) Building, Praed Street, London, W2 1NY, UK.
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Roberts RO, Roberts LA, Geda YE, Cha RH, Pankratz VS, O'Connor HM, Knopman DS, Petersen RC. Relative intake of macronutrients impacts risk of mild cognitive impairment or dementia. J Alzheimers Dis 2013; 32:329-39. [PMID: 22810099 DOI: 10.3233/jad-2012-120862] [Citation(s) in RCA: 112] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
High caloric intake has been associated with an increased risk of cognitive impairment. Total caloric intake is determined by the calories derived from macronutrients. The objective of the study was to investigate the association between percent of daily energy (calories) from macronutrients and incident mild cognitive impairment (MCI) or dementia. Participants were a population-based prospective cohort of elderly persons who were followed over a median 3.7 years (interquartile range, 2.5-3.9) of follow-up. At baseline and every 15 months, participants (median age, 79.5 years) were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis of MCI, normal cognition, or dementia. Participants also completed a 128-item food-frequency questionnaire at baseline; total daily caloric and macronutrient intakes were calculated using an established database. The percent of total daily energy from protein (% protein), carbohydrate (% carbohydrate), and total fat (% fat) was computed. Among 937 subjects who were cognitively normal at baseline, 200 developed incident MCI or dementia. The risk of MCI or dementia (hazard ratio, [95% confidence interval]) was elevated in subjects with high % carbohydrate (upper quartile: 1.89 [1.17-3.06]; p for trend = 0.004), but was reduced in subjects with high % fat (upper quartile: 0.56 [0.34-0.91]; p for trend = 0.03), and high % protein (upper quartile 0.79 [0.52-1.20]; p for trend = 0.03) in the fully adjusted models. A dietary pattern with relatively high caloric intake from carbohydrates and low caloric intake from fat and proteins may increase the risk of MCI or dementia in elderly persons.
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Affiliation(s)
- Rosebud O Roberts
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
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Shaw K. ‘Type 3 diabetes’: linking a brain insulin-resistant state with dementia and Alzheimer's disease. PRACTICAL DIABETES 2013. [DOI: 10.1002/pdi.1752] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Arab L, Sadeghi R, Walker DG, Lue LF, Sabbagh MN. Consequences of Aberrant Insulin Regulation in the Brain: Can Treating Diabetes be Effective for Alzheimer's Disease. Curr Neuropharmacol 2012; 9:693-705. [PMID: 22654727 PMCID: PMC3263463 DOI: 10.2174/157015911798376334] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Revised: 06/22/2010] [Accepted: 07/21/2010] [Indexed: 12/25/2022] Open
Abstract
There is an urgent need for new ways to treat Alzheimer’s disease (AD), the most common cause of dementia in the elderly. Current therapies are modestly effective at treating the symptoms, and do not significantly alter the course of the disease. Over the years, a range of epidemiological and experimental studies have demonstrated interactions between diabetes mellitus and AD. As both diseases are leading causes of morbidity and mortality in the elderly and are frequent co-morbid conditions, it has raised the possibility that treating diabetes might be effective in slowing AD. This is currently being attempted with drugs such as the insulin sensitizer rosiglitazone. These two diseases share many clinical and biochemical features, such as elevated oxidative stress, vascular dysfunction, amyloidogenesis and impaired glucose metabolism suggesting common pathogenic mechanisms. The main thrust of this review will be to explore the evidence from a pathological point of view to determine whether diabetes can cause or exacerbate AD. This was supported by a number of animal models of AD that have been shown to have enhanced pathology when diabetic conditions were induced. The one drawback in linking diabetes and insulin to AD has been the postmortem studies of diabetic brains demonstrating that AD pathology was not increased; in fact decreased pathology has often been reported. In addition, diabetes induces its own distinct features of neuropathology different from AD. There are common pathological features to be considered including vascular abnormalities, a major feature arising from diabetes; there is increasing evidence that vascular abnormalities can contribute to AD. The most important common mechanism between insulin-resistant (type II) diabetes and AD could be impaired insulin signaling; a form of toxic amyloid can damage neuronal insulin receptors and affect insulin signaling and cell survival. It has even been suggested that AD could be considered as “type 3 diabetes” since insulin can be produced in brain. Another common feature of diabetes and AD are increased advanced glycation endproduct-modified proteins are found in diabetes and in the AD brain; the receptor for advanced glycation endproducts plays a prominent role in both diseases. In addition, a major role for insulin degrading enzyme in the degradation of Aβ peptide has been identified. Although clinical trials of certain types of diabetic medications for treatment of AD have been conducted, further understanding the common pathological processes of diabetes and AD are needed to determine whether these diseases share common therapeutic targets.
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Affiliation(s)
- L Arab
- The Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute, Sun City, Arizona, USA
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Insulin receptor expression and activity in the brains of nondiabetic sporadic Alzheimer's disease cases. Int J Alzheimers Dis 2012; 2012:321280. [PMID: 22666619 PMCID: PMC3362009 DOI: 10.1155/2012/321280] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2011] [Revised: 02/10/2012] [Accepted: 02/13/2012] [Indexed: 11/18/2022] Open
Abstract
We investigated the contents of the insulin receptor-beta subunit (IRβ) and [Tyr1162/1163]-phosphorylated IRβ as surrogate indices of total IR content and IR activation in postmortem hippocampal formation brain specimens from nondiabetic sporadic Alzheimer's disease (AD) cases. We found no significant changes in the brain contents of total IRβ or [Tyr1162/1163]-phosphorylated IRβ, suggesting normal IR content and activation in the brains of nondiabetic sporadic AD cases. Moreover, total IRβ and [Tyr1162/1163]-phosphorylated IRβ levels in the hippocampal formation are not correlated with the severity of amyloid or tau-neuropathology. Exploring the regulation of glycogen synthase kinase 3 (GSK3) α/β, key IR-signaling components, we observed significantly lower levels of total GSK3 α/β in brain specimens from nondiabetic AD cases, suggesting that impaired IR signaling mechanisms might contribute to the onset and/or progression of AD dementia. Outcomes from our study support the development of insulin-sensitizing therapeutic strategies to stimulate downstream IR signaling in nondiabetic AD cases.
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Valcour V, Maki P, Bacchetti P, Anastos K, Crystal H, Young M, Mack WJ, Cohen M, Golub ET, Tien PC. Insulin resistance and cognition among HIV-infected and HIV-uninfected adult women: the Women's Interagency HIV Study. AIDS Res Hum Retroviruses 2012; 28:447-53. [PMID: 21878059 DOI: 10.1089/aid.2011.0159] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Cognitive impairment remains prevalent in the era of combination antiretroviral therapy (cART) and may be partially due to comorbidities. We postulated that insulin resistance (IR) is negatively associated with cognitive performance. We completed a cross-sectional analysis among 1547 (1201 HIV(+)) women enrolled in the Women's Interagency HIV Study (WIHS). We evaluated the association of IR with cognitive measures among all WIHS women with concurrent fasting bloods and cognitive testing [Trails A, Trails B, and Symbol Digit Modalities Test (SDMT)] using multiple linear regression models. A smaller subgroup also completed the Stroop test (n=1036). IR was estimated using the Homeostasis Model Assessment (HOMA). Higher HOMA was associated with poorer performance on the SDMT, Stroop Color-Naming (SCN) trial, and Stroop interference trial, but remained statistically significant only for the SCN in models adjusting for important factors [β=3.78 s (95% CI: 0.48-7.08), p=0.025, for highest vs. lowest quartile of HOMA]. HIV status did not appear to substantially impact the relationship of HOMA with SCN. There was a small but statistically significant association of HOMA and reduced neuropsychological performance on the SCN test in this cohort of women.
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Affiliation(s)
- Victor Valcour
- Memory and Aging Center, Department of Neurology and Division of Geriatric Medicine, Department of Medicine, University of California at San Francisco, San Francisco, California
| | - Pauline Maki
- Departments of Psychiatry and Psychology, University of Illinois at Chicago, Chicago, Illinois
| | - Peter Bacchetti
- Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, California
| | - Kathryn Anastos
- Department of Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York
| | | | - Mary Young
- Georgetown University Medical Center, Washington, District of Columbia
| | - Wendy J. Mack
- Department of Preventive Medicine, University of Southern California, Los Angeles, California
| | - Mardge Cohen
- Department of Medicine, Stroger Hospital and Rush University, Chicago, Illinois
| | - Elizabeth T. Golub
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - Phyllis C. Tien
- Department Medicine, University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California
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Isik AT, Bozoglu E, Eker D. aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease. J Nutr Health Aging 2012; 16:139-141. [PMID: 22323348 DOI: 10.1007/s12603-011-0095-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Insulin resistance (IR) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease (LOAD). This study was designed to determine the interaction between inhibition of both butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) with rivastigmine and peripheral insulin resistance (IR) in LOAD. METHODS Seventy-Nine consecutive elderly patients, 31 late onset AD and 48 non-demented patients were evaluated. IR was calculated with HOMA. All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months. RESULTS End of the study, compared to the baseline values, there was a significant increase in the 6th month in both MMSE and IADL scores (t =2.200, p = 0.036 for MMSE and t =2.724, p= 0.011 for IADL, respectively). Rivastigmine was improved both the scores of MMSE and IADL in elderly patients with LOAD, but there was no significance or correlation between HOMA scores and cognitive status. CONCLUSION In conclusion, inhibition of both BuChE and AChE with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA. Due to the complexity of disease pathogenesis, it is too early to make general comments, and further longitudinal and long-term studies on this issue are needed.
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Affiliation(s)
- A T Isik
- Bezmialem Vakif University, Faculty of Medicine, Department of Geriatric Medicine, Istanbul, Turkey.
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Clausen TD, Mortensen EL, Schmidt L, Mathiesen ER, Hansen T, Jensen DM, Holm S, Poulsen L, From M, Damm P. Cognitive function in adult offspring of women with Type 1 diabetes. Diabet Med 2011; 28:838-44. [PMID: 21434994 DOI: 10.1111/j.1464-5491.2011.03300.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIMS Maternal diabetes may affect offspring cognitive function. The objective of the study was to evaluate cognitive function and potential predictors hereof in adult offspring of women with Type 1 diabetes. METHODS We conducted a follow-up study of adult offspring of women with Type 1 diabetes (n = 158) and a reference group from the background population (n = 118). The main outcome measure was offspring cognitive function measured by global cognitive score, derived from Raven's Progressive Matrices and three verbal subtests from the Weschler Adult Intelligence Scale. RESULTS Offspring of women with Type 1 diabetes obtained lower global cognitive scores (94.8 vs. 100.0, P = 0.004) than offspring from the background population. When adjusted for confounders, the groups no longer differed significantly (difference 0.4, 95% CI -3.3 to 4.). Positive predictors of cognitive function in offspring of women with diabetes were family social class, parental educational level, maternal diabetes duration, male gender and offspring age, whereas parity ≥ 1 and gestational age < 34 weeks were negative predictors. We found no association with maternal glycaemia during pregnancy or with neonatal hypoglycaemia. CONCLUSIONS Impaired cognitive function in adult offspring of women with Type 1 diabetes compared with the background population apparently reflects differences with respect to well-known confounders. However, harmful effects of maternal hyperglycaemia may be mediated through delivery at < 34 weeks.
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Affiliation(s)
- T D Clausen
- Department of Obstetrics, Center for Pregnant Women with Diabetes, Rigshospitalet, The Capital Region of Denmark, Faculty of Health Sciences, Copenhagen, Denmark.
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Pasinetti GM, Wang J, Porter S, Ho L. Caloric intake, dietary lifestyles, macronutrient composition, and alzheimer' disease dementia. Int J Alzheimers Dis 2011; 2011:806293. [PMID: 21808725 PMCID: PMC3144673 DOI: 10.4061/2011/806293] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Accepted: 05/12/2011] [Indexed: 12/19/2022] Open
Abstract
Alzheimer's disease is a devastating neurodegenerative condition currently affecting over 5 million elderly individuals in the United States. There is much evidence suggesting that certain dietary lifestyles can help to prevent and possibly treat Alzheimer's disease. In this paper, we discuss how certain cardiovascular and diabetic conditions can induce an increased susceptibility for Alzheimer's disease and the mechanisms through which this occurs. We further discuss how the consumption of certain foods or food components can help to reduce one's risk for Alzheimer's disease and may possibly be developed as a therapeutic agent.
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Affiliation(s)
- Giulio Maria Pasinetti
- Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA
- Geriatric Research, Education and Clinical Center, James J. Peters Veteran Affairs Medical Center, Bronx, NY 10468, USA
| | - Jun Wang
- Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Shanee Porter
- Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Lap Ho
- Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA
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Schuh AF, Rieder CM, Rizzi L, Chaves M, Roriz-Cruz M. Mechanisms of brain aging regulation by insulin: implications for neurodegeneration in late-onset Alzheimer's disease. ISRN NEUROLOGY 2011; 2011:306905. [PMID: 22389813 PMCID: PMC3263551 DOI: 10.5402/2011/306905] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Accepted: 04/09/2011] [Indexed: 01/21/2023]
Abstract
Insulin and IGF seem to be important players in modulating brain aging. Neurons share more similarities with islet cells than any other human cell type. Insulin and insulin receptors are diffusely found in the brain, especially so in the hippocampus. Caloric restriction decreases insulin resistance, and it is the only proven mechanism to expand lifespan. Conversely, insulin resistance increases with age, obesity, and sedentarism, all of which have been shown to be risk factors for late-onset Alzheimer's disease (AD). Hyperphagia and obesity potentiate the production of oxidative reactive species (ROS), and chronic hyperglycemia accelerates the formation of advanced glucose end products (AGEs) in (pre)diabetes—both mechanisms favoring a neurodegenerative milieu. Prolonged high cerebral insulin concentrations cause microvascular endothelium proliferation, chronic hypoperfusion, and energy deficit, triggering β-amyloid oligomerization and tau hyperphosphorylation. Insulin-degrading enzyme (IDE) seems to be the main mechanism in clearing β-amyloid from the brain. Hyperinsulinemic states may deviate IDE utilization towards insulin processing, decreasing β-amyloid degradation.
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Affiliation(s)
- Artur F Schuh
- Division of Geriatric Neurology, Department of Neurology, Clinicas Hospital (HCPA), Federal University of Rio Grande do Sul (UFRGS), Ramiro Barcelos Street 2.350, 90035-903 Porto Alegre, RS, Brazil
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Luchsinger JA. Diabetes, related conditions, and dementia. J Neurol Sci 2011; 299:35-8. [PMID: 20888602 DOI: 10.1016/j.jns.2010.08.063] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2010] [Accepted: 08/27/2010] [Indexed: 01/29/2023]
Abstract
This manuscript provides a brief review of the epidemiologic evidence linking type 2 diabetes (T2D) and its precursor conditions, elevated adiposity and hyperinsulinemia, to dementia. Elevated adiposity in middle age is related to a higher risk of dementia but the data on this association in old age is conflicting. Hyperinsulinemia, a consequence of higher adiposity and insulin resistance is also related to a higher risk of dementia, including late onset Alzheimer's disease (LOAD). Studies have consistently shown a relation of T2D with higher dementia risk, but the associations are stronger for vascular dementia compared to LOAD. One implication of these associations is that strategies used to prevent T2D can be used to prevent dementia. Several studies in the prevention and treatment of T2D are currently measuring cognitive outcomes and will provide information on whether T2D treatment and prevention can prevent cognitive decline and dementia.
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Affiliation(s)
- José A Luchsinger
- Division of General Medicine, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.
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48
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Strachan MWJ. R D Lawrence Lecture 2010. The brain as a target organ in Type 2 diabetes: exploring the links with cognitive impairment and dementia. Diabet Med 2011; 28:141-7. [PMID: 21219420 DOI: 10.1111/j.1464-5491.2010.03199.x] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Type 2 diabetes is associated with cognitive impairment and dementia, but the precise underlying mechanisms remain unresolved. Very high blood glucose concentrations are associated with mood changes and poor memory function, possibly by causing alterations in cerebral blood flow or osmotic changes in neurones, and correction of acute hyperglycaemia appears beneficial. Chronic hyperglycaemia may cause structural changes in the brain, such as cerebral microvascular disease, and there are strong associations between the presence of retinal microvascular abnormalities and cognitive function. Functional insulin deficiency in the brain may also be a factor, but trials with rosiglitazone in people with diabetes and other trials in people with Alzheimer's disease have shown no specific benefit of insulin sensitization. There is an association between hypoglycaemia and cognitive impairment in people with Type 2 diabetes; part of that association may simply be a consequence of the fact that people with cognitive impairment find it more difficult to manage their diabetes and so are more prone to hypoglycaemia. The potential for hypoglycaemia to cause harm to the brain has been debated for many years, and the issue remains unresolved. An ongoing prospective study of risk factors for cognitive impairment in people with Type 2 diabetes (Edinburgh Type 2 Diabetes Study) should improve our understanding of the aetiology of cognitive impairment and inform the design of future intervention trials.
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Affiliation(s)
- M W J Strachan
- Metabolic Unit, Western General Hospital, Crewe Road, Edinburgh, UK.
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Umegaki H, Kawamura T, Kawano N, Umemura T, Kanai A, Sano T. Factors associated with cognitive decline in elderly diabetics. Dement Geriatr Cogn Dis Extra 2011; 1:1-9. [PMID: 22163228 PMCID: PMC3199895 DOI: 10.1159/000323188] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND/AIMS Although recent evidence has indicated that type 2 diabetes mellitus (T2DM) in the elderly is a risk factor for cognitive dysfunction or dementia, few studies have prospectively observed this potential cognitive decline. In the current study, we performed cognitive assessments at baseline and after 3 years in the same patient group in an attempt to reveal the contributions of diabetes-related factors to the increased decline in cognitive function in elderly patients with T2DM. METHODS We recruited 55 consecutive T2DM patients with a Mini-Mental State Examination (MMSE) score ≥24 from the Diabetic Center at the Chubu Rosai Hospital. These patients ranged in age from 65 to 85 years. Cognitive and clinical assessments, including brain MRI, were performed at baseline and at the 3-year follow-up. RESULTS The higher plasma insulin and HbA(1c) levels observed at baseline were significantly associated with a worse cognitive performance at baseline and a more neurocognitive decline at the follow-up visit. CONCLUSION The current prospective study suggests that higher insulin and glycohemoglobin levels may be associated with diabetes-related cognitive dysfunction.
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Affiliation(s)
- Hiroyuki Umegaki
- Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takahiko Kawamura
- Department of Metabolism and Endocrine Internal Medicine, Nagoya, Japan
| | - Naoko Kawano
- Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | | | - Akio Kanai
- Department of Metabolism and Endocrine Internal Medicine, Nagoya, Japan
| | - Takahisa Sano
- Department of Metabolism and Endocrine Internal Medicine, Nagoya, Japan
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Zulian SE, Ilincheta de Boschero MG, Giusto NM. Insulin modifies aging-related inhibition of 1-stearoyl, 2-arachidonoylglycerol phosphorylation in rat synaptic terminals. Neurochem Int 2010; 58:330-6. [PMID: 21167245 DOI: 10.1016/j.neuint.2010.12.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2010] [Revised: 11/08/2010] [Accepted: 12/01/2010] [Indexed: 10/18/2022]
Abstract
The purpose of the present study was to analyze diacylglycerol kinase (DAGK) activity in synaptic terminals from cerebral cortex (CC) and hippocampus (Hp) from adult (3-4 month-old) and aged (26-28 month-old) rats. The effect of insulin through DAGK activity on synaptosomes from adult and aged rats was also analyzed under conditions favoring saturated or unsaturated phosphatidic acid (PA) formation, using exogenous di-palmitoil glycerol (DPG) or 1-stearoyl-2-arachidonoylglycerol (SAG) as substrates. Results showed that the enzymatic activity preferentially uses SAG as substrate, thus indicating the presence of ɛ-type DAGK. A significant decrease in DAGK activity transforming SAG into PA was also observed in both tissues from aged rats. Western blot detection of DAGKɛ showed that enzyme content undergoes no changes with aging. [3H] inositol incorporation into phosphoinosites was also analyzed to evaluate the role of DAGKɛ in their synthesis. Data obtained from 3H-inositol incorporation into phosphoinositides revealed that in synaptosomes from aged rats phosphatidylinositol (PI) synthesis is lower than in adult animals. Interestingly, in the presence of SAG, PI synthesis was restored to adult values. DAGK activity over SAG was more highly stimulated by insulin in CC and Hp synaptosomes of aged rats with respect to adult rats. On the other hand, insulin exerted a stimulatory effect on PI and phosphatidylinositol 4 phosphate (PI(4)P) synthesis in synaptosomal CC from aged rats. Taken together, our findings indicate that in aged rats insulin triggers a stimulatory mechanism that reverts the diminished synaptosomal ability to synthesize arachidonoyl phosphatidic acid (20:4 PA). The recovery of this PA species indicates that insulin positively regulates phosphoinositide synthesis.
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Affiliation(s)
- Sandra E Zulian
- Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur and CONICET, C.C. 857, B8000FWB Bahía Blanca, Argentina.
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