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Sviderskiy VO, Vasudevaraja V, Dubois LG, Stafford J, Liu EK, Serrano J, Possemato R, Snuderl M. Metabolic profiling of adult and pediatric gliomas reveals enriched glucose availability in pediatric gliomas and increased fatty acid oxidation in adult gliomas. Acta Neuropathol Commun 2025; 13:61. [PMID: 40087788 PMCID: PMC11909955 DOI: 10.1186/s40478-025-01961-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 02/15/2025] [Indexed: 03/17/2025] Open
Abstract
Gliomas are the most common primary brain tumors and a major source of mortality and morbidity in adults and children. Recent genomic studies have identified multiple molecular subtypes; however metabolic characterization of these tumors has thus far been limited. We performed metabolic profiling of 114 adult and pediatric primary gliomas and integrated metabolomic data with transcriptomics and DNA methylation classes. We identified that pediatric tumors have higher levels of glucose and reduced lactate compared to adult tumors regardless of underlying genetics or grade, suggesting differences in availability of glucose and/or utilization of glucose for downstream pathways. Differences in glucose utilization in pediatric gliomas may be facilitated through overexpression of SLC2A4, which encodes the insulin-stimulated glucose transporter GLUT4. Transcriptomic comparison of adult and pediatric tumors suggests that adult tumors may have limited access to glucose and experience more hypoxia, which is supported by enrichment of lactate, 2-hydroxyglutarate (2-HG), even in isocitrate dehydrogenase (IDH) wild-type tumors, and 3-hydroxybutyrate, a ketone body that is produced by oxidation of fatty acids and ketogenic amino acids during periods of glucose scarcity. Our data support adult tumors relying more on fatty acid oxidation, as they have an abundance of acyl carnitines compared to pediatric tumors and have significant enrichment of transcripts needed for oxidative phosphorylation. Our findings suggest striking differences exist in the metabolism of pediatric and adult gliomas, which can provide new insight into metabolic vulnerabilities for therapy.
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Affiliation(s)
- Vladislav O Sviderskiy
- Department of Pathology, NYU Langone Health, New York, NY, USA
- Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO, USA
| | | | - Luiz Gustavo Dubois
- Department of Pathology, NYU Langone Health, New York, NY, USA
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - James Stafford
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, VT, USA
| | - Elisa K Liu
- NYU Grossman School of Medicine, New York, NY, 10016, USA
| | | | - Richard Possemato
- Department of Pathology, NYU Langone Health, New York, NY, USA.
- NYU Grossman School of Medicine, New York, NY, 10016, USA.
- Laura and Isaac Perlmutter Cancer Center, New York, NY, 10016, USA.
- Department of Pathology, NYU Langone Health, 550 First Avenue, Smilow 611, New York, NY, 10016, USA.
| | - Matija Snuderl
- Department of Pathology, NYU Langone Health, New York, NY, USA.
- NYU Grossman School of Medicine, New York, NY, 10016, USA.
- Laura and Isaac Perlmutter Cancer Center, New York, NY, 10016, USA.
- Department of Pathology, NYU Langone Health, 240 E 38Th Street, 22Nd Floor, New York, NY, 10016, USA.
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Affuso F, Micillo F, Fazio S. Insulin Resistance, a Risk Factor for Alzheimer's Disease: Pathological Mechanisms and a New Proposal for a Preventive Therapeutic Approach. Biomedicines 2024; 12:1888. [PMID: 39200352 PMCID: PMC11351221 DOI: 10.3390/biomedicines12081888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/31/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Peripheral insulin resistance (IR) is a well-documented, independent risk factor for the development of type 2 diabetes, cardiovascular disease, cancer and cellular senescence. Recently, the brain has also been identified as an insulin-responsive region, where insulin acts as regulator of the brain metabolism. Despite the clear link between IR and the brain, the exact mechanisms underlying this relationship remain unclear. Therapeutic intervention in patients showing symptoms of neurodegenerative diseases has produced little or no results. It has been demonstrated that insulin resistance plays a significant role in the pathogenesis of neurodegenerative diseases, particularly cognitive decline. Peripheral and brain IR may represent a modifiable state that could be used to prevent major brain disorders. In this review, we will analyse the scientific literature supporting IR as a risk factor for Alzheimer's disease and suggest some therapeutic strategies to provide a new proposal for the prevention of brain IR and its consequences.
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Affiliation(s)
- Flora Affuso
- Independent Researcher, Viale Raffaello, 74, 80129 Napoli, Italy
| | - Filomena Micillo
- UOC of Geriatric Medicine AORN S.G. Moscati, 83100 Avellino, Italy
| | - Serafino Fazio
- Department of Internal Medicine, School of Medicine, Federico II University of Naples, 80138 Naples, Italy;
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Guarnieri L, Bosco F, Leo A, Citraro R, Palma E, De Sarro G, Mollace V. Impact of micronutrients and nutraceuticals on cognitive function and performance in Alzheimer's disease. Ageing Res Rev 2024; 95:102210. [PMID: 38296163 DOI: 10.1016/j.arr.2024.102210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 01/10/2024] [Accepted: 01/25/2024] [Indexed: 02/13/2024]
Abstract
Alzheimer's disease (AD) is a major global health problem today and is the most common form of dementia. AD is characterized by the formation of β-amyloid (Aβ) plaques and neurofibrillary clusters, leading to decreased brain acetylcholine levels in the brain. Another mechanism underlying the pathogenesis of AD is the abnormal phosphorylation of tau protein that accumulates at the level of neurofibrillary aggregates, and the areas most affected by this pathological process are usually the cholinergic neurons in cortical, subcortical, and hippocampal areas. These effects result in decreased cognitive function, brain atrophy, and neuronal death. Malnutrition and weight loss are the most frequent manifestations of AD, and these are also associated with greater cognitive decline. Several studies have confirmed that a balanced low-calorie diet and proper nutritional intake may be considered important factors in counteracting or slowing the progression of AD, whereas a high-fat or hypercholesterolemic diet predisposes to an increased risk of developing AD. Especially, fruits, vegetables, antioxidants, vitamins, polyunsaturated fatty acids, and micronutrients supplementation exert positive effects on aging-related changes in the brain due to their antioxidant, anti-inflammatory, and radical scavenging properties. The purpose of this review is to summarize some possible nutritional factors that may contribute to the progression or prevention of AD, understand the role that nutrition plays in the formation of Aβ plaques typical of this neurodegenerative disease, to identify some potential therapeutic strategies that may involve some natural compounds, in delaying the progression of the disease.
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Affiliation(s)
- Lorenza Guarnieri
- Section of Pharmacology, Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
| | - Francesca Bosco
- Section of Pharmacology, Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
| | - Antonio Leo
- Section of Pharmacology, Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy; Research Center FAS@UMG, Department of Health Science, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
| | - Rita Citraro
- Section of Pharmacology, Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy; Research Center FAS@UMG, Department of Health Science, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
| | - Ernesto Palma
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Giovambattista De Sarro
- Section of Pharmacology, Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy; Research Center FAS@UMG, Department of Health Science, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
| | - Vincenzo Mollace
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
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Cutler HB, Madsen S, Masson SWC, Cooke KC, Potter M, Burchfield JG, Stöckli J, Nelson ME, Cooney GJ, James DE. Dual Tracer Test to Measure Tissue-Specific Insulin Action in Individual Mice Identifies In Vivo Insulin Resistance Without Fasting Hyperinsulinemia. Diabetes 2024; 73:359-373. [PMID: 37699358 PMCID: PMC10882155 DOI: 10.2337/db23-0035] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 08/30/2023] [Indexed: 09/14/2023]
Abstract
The ability of metabolically active tissues to increase glucose uptake in response to insulin is critical to whole-body glucose homeostasis. This report describes the Dual Tracer Test, a robust method involving sequential retro-orbital injection of [14C]2-deoxyglucose ([14C]2DG) alone, followed 40 min later by injection of [3H]2DG with a maximal dose of insulin to quantify both basal and insulin-stimulated 2DG uptake in the same mouse. The collection of both basal and insulin-stimulated measures from a single animal is imperative for generating high-quality data since differences in insulin action may be misinterpreted mechanistically if basal glucose uptake is not accounted for. The approach was validated in a classic diet-induced model of insulin resistance and a novel transgenic mouse with reduced GLUT4 expression that, despite ubiquitous peripheral insulin resistance, did not exhibit fasting hyperinsulinemia. This suggests that reduced insulin-stimulated glucose disposal is not a primary contributor to chronic hyperinsulinemia. The Dual Tracer Test offers a technically simple assay that enables the study of insulin action in many tissues simultaneously. By administering two tracers and accounting for both basal and insulin-stimulated glucose transport, this assay halves the required sample size for studies in inbred mice and demonstrates increased statistical power to detect insulin resistance, relative to other established approaches, using a single tracer. The Dual Tracer Test is a valuable addition to the metabolic phenotyping toolbox. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Harry B Cutler
- School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
| | - Søren Madsen
- School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
| | - Stewart W C Masson
- School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
| | - Kristen C Cooke
- School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
| | - Meg Potter
- School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
| | - James G Burchfield
- School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
| | - Jacqueline Stöckli
- School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
| | - Marin E Nelson
- School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
| | - Gregory J Cooney
- Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
| | - David E James
- School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
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Franklin ZJ, Croce L, Dekeryte R, Delibegovic M, Platt B. BACE cleavage of APP does not drive the diabetic phenotype of PLB4 mice. Neurobiol Dis 2023; 182:106142. [PMID: 37137417 DOI: 10.1016/j.nbd.2023.106142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 04/26/2023] [Accepted: 04/29/2023] [Indexed: 05/05/2023] Open
Abstract
BACKGROUND Alzheimer's Disease (AD) and Type 2 Diabetes Mellitus (T2DM), two prevalent diseases related to ageing, often share common pathologies including increased inflammation, endoplasmic reticulum (ER) stress, and impaired metabolic homeostasis predominantly affecting different organs. Therefore, it was unexpected to find in a previous study that neuronal hBACE1 knock-in (PLB4 mouse) leads to both an AD- and T2DM- like phenotype. The complexity of this co-morbidity phenotype required a deeper systems approach to explore the age-related changes in AD and T2DM-like pathologies of the PLB4 mouse. Therefore, we here analysed key neuronal and metabolic tissues comparing associated pathologies to those of normal ageing. METHODS Glucose tolerance, insulin sensitivity and protein turnover were assessed in 5-h fasted 3- and 8-month-old male PLB4 and wild-type mice. Western Blot and quantitative PCR were performed to determine regulation of homeostatic and metabolic pathways in insulin-stimulated brain, liver and muscle tissue. RESULTS Neuronal hBACE1 expression caused early pathological cleavage of APP (increased monomeric Aβ (mAβ) levels at 3-months), in parallel with brain ER stress (increased phosphorylation of the translation regulation factor (p-eIF2α) and the chaperone binding immunoglobulin protein (BIP)). However, APP processing shifted over time (higher full-length APP and sAPPβ levels, alongside lower mAβ and secreted APPα at 8 months), along with increased ER stress (phosphorylated/total inositol-requiring enzyme 1α (IRE1α)) in brain and liver. Metabolically, systemic glucose intolerance was evident from 3 months, yet metabolic signalling varied greatly between tissues and ages, and was confined to the periphery (muscle insulin receptors (IR), dipeptidyl-peptidase-4 (DPP4) levels, and decreased phosphorylated protein Kinase B (p-Akt), alongside increased liver DPP4 and fibroblast growth factor 21 (FGF21)), all of which normalised to wild-type levels at 8 months. CONCLUSION Our data suggest that the murine nervous system is affected early by APP misprocessing as a result of hBACE1 introduction, which coincided with ER stress, but not IR changes, and was alleviated with age. Peripheral metabolic alterations occurred early and revealed tissue-specific (liver vs. muscle) adaptations in metabolic markers but did not correlate with neuronal APP processing. Compensatory vs. contributory neuronal mechanisms associated with hBACE1 expression at different ages may explain why mice intrinsically do not develop AD pathologies and may offer new insights for future interventions.
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Affiliation(s)
- Z J Franklin
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK
| | - L Croce
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK
| | - R Dekeryte
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK
| | - M Delibegovic
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK
| | - B Platt
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK.
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Muñoz VR, Botezelli JD, Gaspar RC, da Rocha AL, Vieira RFL, Crisol BM, Braga RR, Severino MB, Nakandakari SCBR, Antunes GC, Brunetto SQ, Ramos CD, Velloso LA, Simabuco FM, de Moura LP, da Silva ASR, Ropelle ER, Cintra DE, Pauli JR. Effects of short-term endurance and strength exercise in the molecular regulation of skeletal muscle in hyperinsulinemic and hyperglycemic Slc2a4 +/- mice. Cell Mol Life Sci 2023; 80:122. [PMID: 37052684 PMCID: PMC11072257 DOI: 10.1007/s00018-023-04771-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 03/08/2023] [Accepted: 03/28/2023] [Indexed: 04/14/2023]
Abstract
OBJECTIVE Intriguingly, hyperinsulinemia, and hyperglycemia can predispose insulin resistance, obesity, and type 2 diabetes, leading to metabolic disturbances. Conversely, physical exercise stimulates skeletal muscle glucose uptake, improving whole-body glucose homeostasis. Therefore, we investigated the impact of short-term physical activity in a mouse model (Slc2a4+/-) that spontaneously develops hyperinsulinemia and hyperglycemia even when fed on a chow diet. METHODS Slc2a4+/- mice were used, that performed 5 days of endurance or strength exercise training. Further analysis included physiological tests (GTT and ITT), skeletal muscle glucose uptake, skeletal muscle RNA-sequencing, mitochondrial function, and experiments with C2C12 cell line. RESULTS When Slc2a4+/- mice were submitted to the endurance or strength training protocol, improvements were observed in the skeletal muscle glucose uptake and glucose metabolism, associated with broad transcriptomic modulation, that was, in part, related to mitochondrial adaptations. The endurance training, but not the strength protocol, was effective in improving skeletal muscle mitochondrial activity and unfolded protein response markers (UPRmt). Moreover, experiments with C2C12 cells indicated that insulin or glucose levels could contribute to these mitochondrial adaptations in skeletal muscle. CONCLUSIONS Both short-term exercise protocols were efficient in whole-body glucose homeostasis and insulin resistance. While endurance exercise plays an important role in transcriptome and mitochondrial activity, strength exercise mostly affects post-translational mechanisms and protein synthesis in skeletal muscle. Thus, the performance of both types of physical exercise proved to be a very effective way to mitigate the impacts of hyperglycemia and hyperinsulinemia in the Slc2a4+/- mouse model.
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Affiliation(s)
- Vitor Rosetto Muñoz
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil.
| | - José Diego Botezelli
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Rafael Calais Gaspar
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Alisson L da Rocha
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Renan Fudoli Lins Vieira
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Barbara Moreira Crisol
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Renata Rosseto Braga
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Matheus Brandemarte Severino
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | | | - Gabriel Calheiros Antunes
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Sérgio Q Brunetto
- Biomedical Engineering Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Celso D Ramos
- Biomedical Engineering Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Radiology, University of Campinas, Campinas, São Paulo, 13084-970, Brazil
| | - Lício Augusto Velloso
- OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas, Campinas, São Paulo, 13084-970, Brazil
| | - Fernando Moreira Simabuco
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Leandro Pereira de Moura
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
- OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Adelino Sanchez Ramos da Silva
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão, Preto Medical School, University of São Paulo (USP), School of Physical Education and Sport of Ribeirão Preto , Ribeirão Preto, São Paulo, Brazil
| | - Eduardo Rochete Ropelle
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
- OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- National Institute of Science and Technology of Obesity and Diabetes, University of Campinas (UNICAMP), Campinas , São Paulo, Brazil
| | - Dennys Esper Cintra
- Laboratory of Nutritional Genomics, University of Campinas (UNICAMP), Limeira,, São Paulo, Brazil
- OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - José Rodrigo Pauli
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil.
- OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
- National Institute of Science and Technology of Obesity and Diabetes, University of Campinas (UNICAMP), Campinas , São Paulo, Brazil.
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Sullivan M, Fernandez-Aranda F, Camacho-Barcia L, Harkin A, Macrì S, Mora-Maltas B, Jiménez-Murcia S, O'Leary A, Ottomana AM, Presta M, Slattery D, Scholtz S, Glennon JC. Insulin and Disorders of Behavioural Flexibility. Neurosci Biobehav Rev 2023; 150:105169. [PMID: 37059405 DOI: 10.1016/j.neubiorev.2023.105169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 04/03/2023] [Accepted: 04/10/2023] [Indexed: 04/16/2023]
Abstract
Behavioural inflexibility is a symptom of neuropsychiatric and neurodegenerative disorders such as Obsessive-Compulsive Disorder, Autism Spectrum Disorder and Alzheimer's Disease, encompassing the maintenance of a behaviour even when no longer appropriate. Recent evidence suggests that insulin signalling has roles apart from its regulation of peripheral metabolism and mediates behaviourally-relevant central nervous system (CNS) functions including behavioural flexibility. Indeed, insulin resistance is reported to generate anxious, perseverative phenotypes in animal models, with the Type 2 diabetes medication metformin proving to be beneficial for disorders including Alzheimer's Disease. Structural and functional neuroimaging studies of Type 2 diabetes patients have highlighted aberrant connectivity in regions governing salience detection, attention, inhibition and memory. As currently available therapeutic strategies feature high rates of resistance, there is an urgent need to better understand the complex aetiology of behaviour and develop improved therapeutics. In this review, we explore the circuitry underlying behavioural flexibility, changes in Type 2 diabetes, the role of insulin in CNS outcomes and mechanisms of insulin involvement across disorders of behavioural inflexibility.
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Affiliation(s)
- Mairéad Sullivan
- Conway Institute of Biomedical and Biomolecular Research, School of Medicine, University College Dublin, Dublin, Ireland.
| | - Fernando Fernandez-Aranda
- Department of Psychiatry, University Hospital of Bellvitge, Barcelona, Spain; Psychoneurobiology of Eating and Addictive Behaviors Group, Neurosciences Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain; Department of Clinical Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Lucía Camacho-Barcia
- Department of Psychiatry, University Hospital of Bellvitge, Barcelona, Spain; Psychoneurobiology of Eating and Addictive Behaviors Group, Neurosciences Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain
| | - Andrew Harkin
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Ireland
| | - Simone Macrì
- Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Bernat Mora-Maltas
- Department of Psychiatry, University Hospital of Bellvitge, Barcelona, Spain; Psychoneurobiology of Eating and Addictive Behaviors Group, Neurosciences Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Susana Jiménez-Murcia
- Department of Psychiatry, University Hospital of Bellvitge, Barcelona, Spain; Psychoneurobiology of Eating and Addictive Behaviors Group, Neurosciences Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain; Department of Clinical Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Aet O'Leary
- University Hospital Frankfurt, Frankfurt, Germany
| | - Angela Maria Ottomana
- Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy; Neuroscience Unit, Department of Medicine, University of Parma, 43100 Parma, Italy
| | - Martina Presta
- Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy; Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy
| | | | | | - Jeffrey C Glennon
- Conway Institute of Biomedical and Biomolecular Research, School of Medicine, University College Dublin, Dublin, Ireland
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8
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Qiu W, Wu Q, Zhang K, Da X, Tang K, Yuan N, Deng L, Wu M, Zhang Y, Quan J, Ma Q, Li X, Chen J. Xiaoyaosan ameliorates depressive-like behavior and susceptibility to glucose intolerance in rat: involvement of LepR-STAT3/PI3K pathway in hypothalamic arcuate nucleus. BMC Complement Med Ther 2023; 23:116. [PMID: 37046230 PMCID: PMC10091664 DOI: 10.1186/s12906-023-03942-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/29/2023] [Indexed: 04/14/2023] Open
Abstract
BACKGROUND Accumulating evidence has demonstrated that arcuate nucleus (ARC) of the hypothalamus is likely responsible for the close association between chronic stress, depression, and diabetes. Xiaoyaosan (XYS), a Chinese herbal formula, remarkably improves depressive-like behavior and glucose intolerance, but the mechanism remains unclear. Leptin receptor (LepR) regulates energy expenditure and depression by mediating the action of leptin on the ARC. Therefore, we hypothesized that XYS may regulate depressive-like behavior and glucose intolerance via the leptin and its cascade LepR-STAT3/PI3K pathway in the ARC. METHODS A rat model of depressive-like behavior and susceptibility to glucose intolerance was induced by exposure to chronic unpredictable mild stress (CUMS) for six weeks. XYS (2.224 g/kg) was orally gavaged for six weeks, and fluoxetine (2.0 mg/kg) was administrated to the positive control group. Depressive-like behaviors were assessed using the open field test (OFT), sucrose preference test (SPT) and forced swim test (FST). Fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were performed to evaluate the effects of XYS on blood glucose. Peripheral leptin and blood lipids were detected using enzyme-linked immunosorbent assay and an automatic biochemical analyzer, respectively. The effects of XYS on the LepR-STAT3/PI3K pathway were detected by quantitative real-time PCR and western blotting. RESULTS XYS ameliorated CUMS-induced depressive-like behaviors and elevated blood glucose. XYS improved the food intake but have no significant effects on the body weight. Peripheral leptin and its central receptor were also suppressed by XYS, accompanied by the downregulation of JAK2/STAT3 and PI3K/AKT pathway in the ARC. Additionally, XYS increased AGRP and NPY expression but inhibited POMC in the ARC. CONCLUSIONS XYS improves depressive-like behaviors and susceptibility to glucose intolerance induced by CUMS, which may be achieved by the downregulation of the LepR-STAT3/PI3K signaling pathway in the ARC.
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Affiliation(s)
- Wenqi Qiu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Qian Wu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Kaiwen Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xiaoli Da
- Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China
| | - Kairui Tang
- Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China
| | - Naijun Yuan
- Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China
| | - Lijuan Deng
- Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China
| | - Mansi Wu
- Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China
| | - Ying Zhang
- Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China
| | - Jiangyan Quan
- Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China
| | - Qingyu Ma
- Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China.
| | - Xiaojuan Li
- Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China.
| | - Jiaxu Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
- Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China.
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9
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Li H, Ren J, Li Y, Wu Q, Wei J. Oxidative stress: The nexus of obesity and cognitive dysfunction in diabetes. Front Endocrinol (Lausanne) 2023; 14:1134025. [PMID: 37077347 PMCID: PMC10107409 DOI: 10.3389/fendo.2023.1134025] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 03/02/2023] [Indexed: 04/05/2023] Open
Abstract
Obesity has been associated with oxidative stress. Obese patients are at increased risk for diabetic cognitive dysfunction, indicating a pathological link between obesity, oxidative stress, and diabetic cognitive dysfunction. Obesity can induce the biological process of oxidative stress by disrupting the adipose microenvironment (adipocytes, macrophages), mediating low-grade chronic inflammation, and mitochondrial dysfunction (mitochondrial division, fusion). Furthermore, oxidative stress can be implicated in insulin resistance, inflammation in neural tissues, and lipid metabolism disorders, affecting cognitive dysfunction in diabetics.
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Affiliation(s)
- Huimin Li
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jing Ren
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Yusi Li
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qian Wu
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Junping Wei
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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10
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Melloni E, Grassilli S, Romani A, Rimondi E, Marcuzzi A, Zauli E, Secchiero P, Paganetto G, Guerrini A, Sacchetti G, Tacchini M. Convolvulus pluricaulis Choisy’s Extraction, Chemical Characterization and Evaluation of the Potential Effects on Glycaemic Balance in a 3T3-L1 Adipocyte Cell Model. Nutrients 2023; 15:nu15071727. [PMID: 37049568 PMCID: PMC10097163 DOI: 10.3390/nu15071727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/21/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Convolvulus pluricaulis (CP) is a common Indian herb, largely employed in Ayurvedic medicine and known for its neuroprotective and neuroinflammatory action. Its effectiveness against several pathologic/sub-pathologic conditions is widely accepted, but it is not yet completely chemically characterized. In recent years, several researchers have pointed out the involvement of CP and other Convolvulaceae in lipidic and glucidic metabolism, particularly in the control of hyperlipidaemia and diabetic conditions. In this scenario, the aim of the study was to chemically characterize the medium polarity part of the CP whole plant and its fractions and to shed light on their biological activity in adipocyte differentiation using the 3T3-L1 cell model. Our results demonstrated that the CP extract and fractions could upregulate the adipocyte differentiation through the modulation of the nuclear receptor PPARγ (Peroxisome Proliferator-Activated Receptor γ), broadly recognized as a key regulator of adipocyte differentiation, and the glucose transporter GLUT-4, which is fundamental for cellular glucose uptake and for metabolism control. CP also showed the ability to exert an anti-inflammatory effect, downregulating cytokines such as Rantes, MCP-1, KC, eotaxin, and GM-CSF, which are deeply involved in insulin resistance and glucose intolerance. Taken together, these data suggest that CP could exert a potential beneficial effect on glycemia and could be employed as an anti-diabetic adjuvant or, in any case, a means to better control glucose homeostasis.
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Affiliation(s)
- Elisabetta Melloni
- Department of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy
| | - Silvia Grassilli
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Arianna Romani
- Department of Environmental and Prevention Sciences and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy
| | - Erika Rimondi
- Department of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy
| | - Annalisa Marcuzzi
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Enrico Zauli
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Paola Secchiero
- Department of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy
| | - Guglielmo Paganetto
- Department of Life Sciences and Biotechnology (SVeB), UR7 Terra&Acqua Tech, University of Ferrara, 44121 Ferrara, Italy
| | - Alessandra Guerrini
- Department of Life Sciences and Biotechnology (SVeB), UR7 Terra&Acqua Tech, University of Ferrara, 44121 Ferrara, Italy
| | - Gianni Sacchetti
- Department of Life Sciences and Biotechnology (SVeB), UR7 Terra&Acqua Tech, University of Ferrara, 44121 Ferrara, Italy
| | - Massimo Tacchini
- Department of Life Sciences and Biotechnology (SVeB), UR7 Terra&Acqua Tech, University of Ferrara, 44121 Ferrara, Italy
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11
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Ferris HA. Insulin and neurodegenerative diseases. INSULIN 2023:315-338. [DOI: 10.1016/b978-0-323-91707-0.00012-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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12
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Zhu DY, Lu J, Xu R, Yang JZ, Meng XR, Ou-Yang XN, Yan QY, Nie RF, Zhao T, Chen YD, Lu Y, Zhang YN, Li WJ, Shen X. FX5, a non-steroidal glucocorticoid receptor antagonist, ameliorates diabetic cognitive impairment in mice. Acta Pharmacol Sin 2022; 43:2495-2510. [PMID: 35260821 PMCID: PMC9525278 DOI: 10.1038/s41401-022-00884-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 02/06/2022] [Indexed: 12/15/2022]
Abstract
Diabetic cognitive impairment (DCI) is a common diabetic complication characterized by learning and memory deficits. In diabetic patients, hyperactivated hypothalamic-pituitary-adrenal (HPA) axis leads to abnormal increase of glucocorticoids (GCs), which causes the damage of hippocampal neurons and cognitive impairment. In this study we investigated the cognition-improving effects of a non-steroidal glucocorticoid receptor (GR) antagonist 5-chloro-N-[4-chloro-3-(trifluoromethyl) phenyl]thiophene-2-sulfonamide (FX5) in diabetic mice. Four weeks after T1DM or T2DM was induced, the mice were administered FX5 (20, 40 mg·kg-1·d-1, i.g.) for 8 weeks. Cognitive impairment was assessed in open field test, novel object recognition test, Y-maze test, and Morris water maze test. We showed that FX5 administration significantly ameliorated the cognitive impairments in both type 1 and 2 diabetic mice. Similar cognitive improvement was observed in diabetic mice following brain GR-specific knockdown by injecting AAV-si-GR. Moreover, AAV-si-GR injection occluded the cognition-improving effects of FX5, suggesting that FX5 functioning as a non-steroidal GR antagonist. In PA-treated primary neurons (as DCI model in vitro), we demonstrated that FX5 (2, 5, 10 μM) dose-dependently ameliorated synaptic impairment via upregulating GR/BDNF/TrkB/CREB pathway, protected against neuronal apoptosis through repressing GR/PI3K/AKT/GSK3β-mediated tauopathy and subsequent endoplasmic reticulum stress. In LPS-treated primary microglia, FX5 dose-dependently inhibited inflammation through GR/NF-κB/NLRP3/ASC/Caspase-1 pathway. These beneficial effects were also observed in the hippocampus of diabetic mice following FX5 administration. Collectively, we have elucidated the mechanisms underlying the beneficial effects of non-steroidal GR antagonist FX5 on DCI and highlighted the potential of FX5 in the treatment of the disease.
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Affiliation(s)
- Dan-Yang Zhu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jian Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Rui Xu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Juan-Zhen Yang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xiang-Rui Meng
- Faculty of Art and Science, Queens University, Kingston, ON, K7L 3N6, Canada
| | - Xing-Nan Ou-Yang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Qiu-Ying Yan
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Rui-Fang Nie
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Tong Zhao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yi-di Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yi-Nan Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Wen-Jun Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Xu Shen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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13
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Čater M, Hölter SM. A Pathophysiological Intersection of Diabetes and Alzheimer's Disease. Int J Mol Sci 2022; 23:11562. [PMID: 36232867 PMCID: PMC9569835 DOI: 10.3390/ijms231911562] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/22/2022] [Accepted: 09/26/2022] [Indexed: 12/06/2022] Open
Abstract
Diabetes is among the most prevalent diseases of the modern world and is strongly linked to an increased risk of numerous neurodegenerative disorders, although the exact pathophysiological mechanisms are not clear yet. Insulin resistance is a serious pathological condition, connecting type 2 diabetes, metabolic syndrome, and obesity. Recently, insulin resistance has been proven to be connected also to cognitive decline and dementias, including the most prevalent form, Alzheimer's disease. The relationship between diabetes and Alzheimer's disease regarding pathophysiology is so significant that it has been proposed that some presentations of the condition could be termed type 3 diabetes.
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Affiliation(s)
- Maša Čater
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, 1230 Domžale, Slovenia
| | - Sabine M. Hölter
- Institute of Developmental Genetics, Helmholtz Munich, 85764 Neuherberg, Germany
- School of Life Sciences, Technical University Munich, 85354 Freising, Germany
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14
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Wicik Z, Nowak A, Jarosz-Popek J, Wolska M, Eyileten C, Siller-Matula JM, von Lewinski D, Sourij H, Filipiak KJ, Postuła M. Characterization of the SGLT2 Interaction Network and Its Regulation by SGLT2 Inhibitors: A Bioinformatic Analysis. Front Pharmacol 2022; 13:901340. [PMID: 36046822 PMCID: PMC9421436 DOI: 10.3389/fphar.2022.901340] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/22/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Sodium–glucose cotransporter 2 (SGLT2), also known as solute carrier family 5 member 2 (SLC5A2), is a promising target for a new class of drugs primarily established as kidney-targeting, effective glucose-lowering agents used in diabetes mellitus (DM) patients. Increasing evidence indicates that besides renal effects, SGLT2 inhibitors (SGLT2i) have also a systemic impact via indirectly targeting the heart and other tissues. Our hypothesis states that the pleiotropic effects of SGLT2i are associated with their binding force, location of targets in the SGLT2 networks, targets involvement in signaling pathways, and their tissue-specific expression. Methods: Thus, to investigate differences in SGLT2i impact on human organisms, we re-created the SGLT2 interaction network incorporating its inhibitors and metformin and analyzed its tissue-specific expression using publicly available datasets. We analyzed it in the context of the so-called key terms ( autophagy, oxidative stress, aging, senescence, inflammation, AMPK pathways, and mTOR pathways) which seem to be crucial to elucidating the SGLT2 role in a variety of clinical manifestations. Results: Analysis of SGLT2 and its network components’ expression confidence identified selected organs in the following order: kidney, liver, adipose tissue, blood, heart, muscle, intestine, brain, and artery according to the TISSUES database. Drug repurposing analysis of known SGLT2i pointed out the influence of SGLT1 regulators on the heart and intestine tissue. Additionally, dapagliflozin seems to also have a stronger impact on brain tissue through the regulation of SGLT3 and SLC5A11. The shortest path analysis identified interaction SIRT1-SGLT2 among the top five interactions across six from seven analyzed networks associated with the key terms. Other top first-level SGLT2 interactors associated with key terms were not only ADIPOQ, INS, GLUT4, ACE, and GLUT1 but also less recognized ILK and ADCY7. Among other interactors which appeared in multiple shortest-path analyses were GPT, COG2, and MGAM. Enrichment analysis of SGLT2 network components showed the highest overrepresentation of hypertensive disease, DM-related diseases for both levels of SGLT2 interactors. Additionally, for the extended SGLT2 network, we observed enrichment in obesity (including SGLT1), cancer-related terms, neuroactive ligand–receptor interaction, and neutrophil-mediated immunity. Conclusion: This study provides comprehensive and ranked information about the SGLT2 interaction network in the context of tissue expression and can help to predict the clinical effects of the SGLT2i.
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Affiliation(s)
- Zofia Wicik
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
| | - Anna Nowak
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
- Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Joanna Jarosz-Popek
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
- Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Marta Wolska
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
- Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Ceren Eyileten
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
- Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Jolanta M. Siller-Matula
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
- Department of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Dirk von Lewinski
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Harald Sourij
- Division of Endocrinology and Diabetology, Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria
| | | | - Marek Postuła
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
- *Correspondence: Marek Postuła,
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15
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Ávalos Y, Hernández-Cáceres MP, Lagos P, Pinto-Nuñez D, Rivera P, Burgos P, Díaz-Castro F, Joy-Immediato M, Venegas-Zamora L, Lopez-Gallardo E, Kretschmar C, Batista-Gonzalez A, Cifuentes-Araneda F, Toledo-Valenzuela L, Rodriguez-Peña M, Espinoza-Caicedo J, Perez-Leighton C, Bertocchi C, Cerda M, Troncoso R, Parra V, Budini M, Burgos PV, Criollo A, Morselli E. Palmitic acid control of ciliogenesis modulates insulin signaling in hypothalamic neurons through an autophagy-dependent mechanism. Cell Death Dis 2022; 13:659. [PMID: 35902579 PMCID: PMC9334645 DOI: 10.1038/s41419-022-05109-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 01/21/2023]
Abstract
Palmitic acid (PA) is significantly increased in the hypothalamus of mice, when fed chronically with a high-fat diet (HFD). PA impairs insulin signaling in hypothalamic neurons, by a mechanism dependent on autophagy, a process of lysosomal-mediated degradation of cytoplasmic material. In addition, previous work shows a crosstalk between autophagy and the primary cilium (hereafter cilium), an antenna-like structure on the cell surface that acts as a signaling platform for the cell. Ciliopathies, human diseases characterized by cilia dysfunction, manifest, type 2 diabetes, among other features, suggesting a role of the cilium in insulin signaling. Cilium depletion in hypothalamic pro-opiomelanocortin (POMC) neurons triggers obesity and insulin resistance in mice, the same phenotype as mice deficient in autophagy in POMC neurons. Here we investigated the effect of chronic consumption of HFD on cilia; and our results indicate that chronic feeding with HFD reduces the percentage of cilia in hypothalamic POMC neurons. This effect may be due to an increased amount of PA, as treatment with this saturated fatty acid in vitro reduces the percentage of ciliated cells and cilia length in hypothalamic neurons. Importantly, the same effect of cilia depletion was obtained following chemical and genetic inhibition of autophagy, indicating autophagy is required for ciliogenesis. We further demonstrate a role for the cilium in insulin sensitivity, as cilium loss in hypothalamic neuronal cells disrupts insulin signaling and insulin-dependent glucose uptake, an effect that correlates with the ciliary localization of the insulin receptor (IR). Consistently, increased percentage of ciliated hypothalamic neuronal cells promotes insulin signaling, even when cells are exposed to PA. Altogether, our results indicate that, in hypothalamic neurons, impairment of autophagy, either by PA exposure, chemical or genetic manipulation, cause cilia loss that impairs insulin sensitivity.
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Affiliation(s)
- Yenniffer Ávalos
- grid.412179.80000 0001 2191 5013Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - María Paz Hernández-Cáceres
- grid.7870.80000 0001 2157 0406Laboratory of Autophagy and Metabolism, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile ,grid.443909.30000 0004 0385 4466Cellular and Molecular Biology Laboratory, Institute in Dentistry Sciences, Dentistry Faculty, Universidad de Chile, Santiago, Chile
| | - Pablo Lagos
- grid.7870.80000 0001 2157 0406Laboratory of Autophagy and Metabolism, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Daniela Pinto-Nuñez
- grid.7870.80000 0001 2157 0406Laboratory of Autophagy and Metabolism, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Patricia Rivera
- grid.7870.80000 0001 2157 0406Laboratory of Autophagy and Metabolism, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Paulina Burgos
- grid.7870.80000 0001 2157 0406Laboratory of Autophagy and Metabolism, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Francisco Díaz-Castro
- grid.7870.80000 0001 2157 0406Laboratory of Autophagy and Metabolism, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Michelle Joy-Immediato
- grid.7870.80000 0001 2157 0406Laboratory for Molecular Mechanics of Cell Adhesion, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Leslye Venegas-Zamora
- grid.443909.30000 0004 0385 4466Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Erik Lopez-Gallardo
- grid.443909.30000 0004 0385 4466Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Catalina Kretschmar
- grid.443909.30000 0004 0385 4466Cellular and Molecular Biology Laboratory, Institute in Dentistry Sciences, Dentistry Faculty, Universidad de Chile, Santiago, Chile
| | - Ana Batista-Gonzalez
- grid.443909.30000 0004 0385 4466Cellular and Molecular Biology Laboratory, Institute in Dentistry Sciences, Dentistry Faculty, Universidad de Chile, Santiago, Chile
| | - Flavia Cifuentes-Araneda
- grid.7870.80000 0001 2157 0406Laboratory of Autophagy and Metabolism, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Lilian Toledo-Valenzuela
- grid.7870.80000 0001 2157 0406Laboratory of Autophagy and Metabolism, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marcelo Rodriguez-Peña
- grid.443909.30000 0004 0385 4466Cellular and Molecular Biology Laboratory, Institute in Dentistry Sciences, Dentistry Faculty, Universidad de Chile, Santiago, Chile
| | - Jasson Espinoza-Caicedo
- grid.7870.80000 0001 2157 0406Laboratory of Autophagy and Metabolism, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Claudio Perez-Leighton
- grid.7870.80000 0001 2157 0406Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Cristina Bertocchi
- grid.7870.80000 0001 2157 0406Laboratory for Molecular Mechanics of Cell Adhesion, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Mauricio Cerda
- grid.443909.30000 0004 0385 4466Integrative Biology Program, Institute of Biomedical Sciences, Facultad de Medicina, Universidad de Chile, Santiago, Chile ,grid.443909.30000 0004 0385 4466Center for Medical Informatics and Telemedicine, Facultad de Medicina, Universidad de Chile, Santiago, Chile ,grid.443909.30000 0004 0385 4466Biomedical Neuroscience Institute, Santiago, Chile
| | - Rodrigo Troncoso
- grid.443909.30000 0004 0385 4466Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile ,grid.443909.30000 0004 0385 4466Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile ,Autophagy Research Center, Santiago, Chile
| | - Valentina Parra
- grid.443909.30000 0004 0385 4466Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile ,Autophagy Research Center, Santiago, Chile ,grid.443909.30000 0004 0385 4466Network for the Study of High-Lethality Cardiopulmonary Diseases (REECPAL), Universidad de Chile, Santiago, Chile
| | - Mauricio Budini
- Autophagy Research Center, Santiago, Chile ,grid.443909.30000 0004 0385 4466Laboratory of Molecular and Cellular Pathology, Institute in Dentistry Sciences, Dentistry Faculty, Universidad de Chile, Santiago, Chile
| | - Patricia V. Burgos
- Autophagy Research Center, Santiago, Chile ,grid.442215.40000 0001 2227 4297Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile ,grid.7870.80000 0001 2157 0406Centro de Envejecimiento y Regeneración (CARE-UC), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alfredo Criollo
- grid.443909.30000 0004 0385 4466Cellular and Molecular Biology Laboratory, Institute in Dentistry Sciences, Dentistry Faculty, Universidad de Chile, Santiago, Chile ,grid.443909.30000 0004 0385 4466Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile ,Autophagy Research Center, Santiago, Chile
| | - Eugenia Morselli
- grid.7870.80000 0001 2157 0406Laboratory of Autophagy and Metabolism, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile ,Autophagy Research Center, Santiago, Chile ,grid.442215.40000 0001 2227 4297Department of Basic Sciences, Faculty of Medicine and Sciences, Universidad San Sebastián, Santiago, Chile
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16
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Piccialli I, Tedeschi V, Caputo L, D’Errico S, Ciccone R, De Feo V, Secondo A, Pannaccione A. Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes. Front Pharmacol 2022; 13:876614. [PMID: 35600880 PMCID: PMC9114803 DOI: 10.3389/fphar.2022.876614] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/11/2022] [Indexed: 12/21/2022] Open
Abstract
Alzheimer’s disease (AD) is a chronic, complex neurodegenerative disorder mainly characterized by the irreversible loss of memory and cognitive functions. Different hypotheses have been proposed thus far to explain the etiology of this devastating disorder, including those centered on the Amyloid-β (Aβ) peptide aggregation, Tau hyperphosphorylation, neuroinflammation and oxidative stress. Nonetheless, the therapeutic strategies conceived thus far to treat AD neurodegeneration have proven unsuccessful, probably due to the use of single-target drugs unable to arrest the progressive deterioration of brain functions. For this reason, the theoretical description of the AD etiology has recently switched from over-emphasizing a single deleterious process to considering AD neurodegeneration as the result of different pathogenic mechanisms and their interplay. Moreover, much relevance has recently been conferred to several comorbidities inducing insulin resistance and brain energy hypometabolism, including diabetes and obesity. As consequence, much interest is currently accorded in AD treatment to a multi-target approach interfering with different pathways at the same time, and to life-style interventions aimed at preventing the modifiable risk-factors strictly associated with aging. In this context, phytochemical compounds are emerging as an enormous source to draw on in the search for multi-target agents completing or assisting the traditional pharmacological medicine. Intriguingly, many plant-derived compounds have proven their efficacy in counteracting several pathogenic processes such as the Aβ aggregation, neuroinflammation, oxidative stress and insulin resistance. Many strategies have also been conceived to overcome the limitations of some promising phytochemicals related to their poor pharmacokinetic profiles, including nanotechnology and synthetic routes. Considering the emerging therapeutic potential of natural medicine, the aim of the present review is therefore to highlight the most promising phytochemical compounds belonging to two major classes, polyphenols and monoterpenes, and to report the main findings about their mechanisms of action relating to the AD pathogenesis.
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Affiliation(s)
- Ilaria Piccialli
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, University of Naples “Federico II”, Naples, Italy
| | - Valentina Tedeschi
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, University of Naples “Federico II”, Naples, Italy
| | - Lucia Caputo
- Department of Pharmacy, University of Salerno, Salerno, Italy
| | - Stefano D’Errico
- Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
| | - Roselia Ciccone
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, University of Naples “Federico II”, Naples, Italy
| | - Vincenzo De Feo
- Department of Pharmacy, University of Salerno, Salerno, Italy
| | - Agnese Secondo
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, University of Naples “Federico II”, Naples, Italy
| | - Anna Pannaccione
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, University of Naples “Federico II”, Naples, Italy
- *Correspondence: Anna Pannaccione,
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17
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Sanchez-Rangel E, Gunawan F, Jiang L, Savoye M, Dai F, Coppoli A, Rothman DL, Mason GF, Hwang JJ. Reversibility of brain glucose kinetics in type 2 diabetes mellitus. Diabetologia 2022; 65:895-905. [PMID: 35247067 PMCID: PMC8960594 DOI: 10.1007/s00125-022-05664-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 12/02/2021] [Indexed: 11/20/2022]
Abstract
AIMS/HYPOTHESIS We have previously shown that individuals with uncontrolled type 2 diabetes have a blunted rise in brain glucose levels measured by 1H magnetic resonance spectroscopy. Here, we investigate whether reductions in HbA1c normalise intracerebral glucose levels. METHODS Eight individuals (two men, six women) with poorly controlled type 2 diabetes and mean ± SD age 44.8 ± 8.3 years, BMI 31.4 ± 6.1 kg/m2 and HbA1c 84.1 ± 16.2 mmol/mol (9.8 ± 1.4%) underwent 1H MRS scanning at 4 Tesla during a hyperglycaemic clamp (~12.21 mmol/l) to measure changes in cerebral glucose at baseline and after a 12 week intervention that improved glycaemic control through the use of continuous glucose monitoring, diabetes regimen intensification and frequent visits to an endocrinologist and nutritionist. RESULTS Following the intervention, mean ± SD HbA1c decreased by 24.3 ± 15.3 mmol/mol (2.1 ± 1.5%) (p=0.006), with minimal weight changes (p=0.242). Using a linear mixed-effects regression model to compare glucose time courses during the clamp pre and post intervention, the pre-intervention brain glucose level during the hyperglycaemic clamp was significantly lower than the post-intervention brain glucose (p<0.001) despite plasma glucose levels during the hyperglycaemic clamp being similar (p=0.266). Furthermore, the increases in brain glucose were correlated with the magnitude of improvement in HbA1c (r = 0.71, p=0.048). CONCLUSION/INTERPRETATION These findings highlight the potential reversibility of cerebral glucose transport capacity and metabolism that can occur in individuals with type 2 diabetes following improvement of glycaemic control. Trial registration ClinicalTrials.gov NCT03469492.
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Affiliation(s)
- Elizabeth Sanchez-Rangel
- Department of Internal Medicine/Section of Endocrinology, Yale University School of Medicine, New Haven, CT, USA
| | - Felona Gunawan
- Department of Internal Medicine/Section of Endocrinology, Yale University School of Medicine, New Haven, CT, USA
| | - Lihong Jiang
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Mary Savoye
- Department of Pediatric Endocrinology and General Clinical Research Center, Yale University School of Medicine, New Haven, CT, USA
| | - Feng Dai
- Yale Center for Analytical Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Anastasia Coppoli
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Douglas L Rothman
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
- Department of Biomedical Engineering, Yale University School of Medicine, New Haven, CT, USA
| | - Graeme F Mason
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
- Department of Biomedical Engineering, Yale University School of Medicine, New Haven, CT, USA
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Janice Jin Hwang
- Department of Internal Medicine/Section of Endocrinology, Yale University School of Medicine, New Haven, CT, USA.
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18
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Chen X, Yu H, Li Z, Ye W, Liu Z, Gao J, Wang Y, Li X, Zhang L, Alenina N, Bader M, Ding H, Li P, Aung LHH. Oxidative RNA Damage in the Pathogenesis and Treatment of Type 2 Diabetes. Front Physiol 2022; 13:725919. [PMID: 35418873 PMCID: PMC8995861 DOI: 10.3389/fphys.2022.725919] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 03/11/2022] [Indexed: 12/17/2022] Open
Abstract
Excessive production of free radicals can induce cellular damage, which is associated with many diseases. RNA is more susceptible to oxidative damage than DNA due to its single-stranded structure, and lack of protective proteins. Yet, oxidative damage to RNAs received little attention. Accumulating evidence reveals that oxidized RNAs may be dysfunctional and play fundamental role in the occurrence and development of type 2 diabetes (T2D) and its complications. Oxidized guanine nucleoside, 8-oxo-7, 8-dihydroguanine (8-oxoGuo) is a biomarker of RNA oxidation that could be associated with prognosis in patients with T2D. Nowadays, some clinical trials used antioxidants for the treatment of T2D, though the pharmacological effects remained unclear. In this review, we overview the cellular handling mechanisms and the consequences of the oxidative RNA damage for the better understanding of pathogenesis of T2D and may provide new insights to better therapeutic strategy.
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Affiliation(s)
- Xiatian Chen
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Hua Yu
- The Affiliated Cardiovascular Hospital of Qingdao University, Qingdao, China
| | - Zhe Li
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Wei Ye
- Jiangsu Provincial Engineering Research Center for Biomedical Materials and Advanced Medical Device, Huaiyin Institute of Technology, Huaian, China
| | - Ziqian Liu
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Jinning Gao
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Yin Wang
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Xin Li
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Lei Zhang
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Natalia Alenina
- Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany
| | - Michael Bader
- Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany
| | - Hongyan Ding
- School of Bioengineering, Suqian University, Suqian, China
| | - Peifeng Li
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Lynn Htet Htet Aung
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
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19
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Wang R, Zhang L, Zhang Q, Zhang J, Liu S, Li C, Wang L. Glycolipid Metabolism and Metagenomic Analysis of the Therapeutic Effect of a Phenolics-Rich Extract from Noni Fruit on Type 2 Diabetic Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:2876-2888. [PMID: 35175775 DOI: 10.1021/acs.jafc.1c07441] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The phenolics of noni fruit possess antihyperglycemic activity; however, the molecular mechanisms remain unclear. To understand the potential effects it has on type 2 diabetes (T2D), the glycolipid metabolism and gut microbiota regulation of phenolic-rich extracts from noni fruit (NFEs) were investigated. The results indicated that NFE could remarkably ameliorate hyperglycemia, insulin resistance, oxidative stress, and glycolipid metabolism via the adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway in T2D mice. Furthermore, metagenomic sequencing results revealed that NFE intervention modulated the gut microbiota composition in T2D mice, characterized by increased abundance of unclassified_o_Bacteroidales, Alistipes, Prevotella, Lactobacillus, and Akkermansia and decreased abundance of Oscillibacter, Desulfovibrio, and significantly decreased the pathways related to carbohydrate metabolism, translation, amino acid metabolism, and nucleotide metabolism. Taken together, the results provided new evidence that the hypoglycemic and hypolipidemic activities of NFE in T2D were likely attributed to the activation of the liver AMPK pathway and modulation of gut microbiota.
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Affiliation(s)
- Ruimin Wang
- School of Food Science and Engineering, Hainan University, Haikou 570228, China
| | - Lin Zhang
- School of Food Science and Engineering, Hainan University, Haikou 570228, China
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Haikou 570228, China
- Key Laboratory of Tropical Agricultural Products Processing Technology of Haikou, Haikou 570228, China
| | - Qingyang Zhang
- School of Food Science and Engineering, Hainan University, Haikou 570228, China
| | - Jiachao Zhang
- School of Food Science and Engineering, Hainan University, Haikou 570228, China
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Haikou 570228, China
- Key Laboratory of Tropical Agricultural Products Processing Technology of Haikou, Haikou 570228, China
| | - Sixin Liu
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Haikou 570228, China
- Key Laboratory of Tropical Agricultural Products Processing Technology of Haikou, Haikou 570228, China
- School of Science, Hainan University, Haikou 570228, China
| | - Congfa Li
- School of Food Science and Engineering, Hainan University, Haikou 570228, China
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Haikou 570228, China
- Key Laboratory of Tropical Agricultural Products Processing Technology of Haikou, Haikou 570228, China
| | - Lu Wang
- School of Food Science and Engineering, Hainan University, Haikou 570228, China
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Haikou 570228, China
- Key Laboratory of Tropical Agricultural Products Processing Technology of Haikou, Haikou 570228, China
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20
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Mehan S, Bhalla S, Siddiqui EM, Sharma N, Shandilya A, Khan A. Potential Roles of Glucagon-Like Peptide-1 and Its Analogues in Dementia Targeting Impaired Insulin Secretion and Neurodegeneration. Degener Neurol Neuromuscul Dis 2022; 12:31-59. [PMID: 35300067 PMCID: PMC8921673 DOI: 10.2147/dnnd.s247153] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 02/16/2022] [Indexed: 12/20/2022] Open
Abstract
Dementia is a chronic, irreversible condition marked by memory loss, cognitive decline, and mental instability. It is clinically related to various progressive neurological diseases, including Parkinson’s disease, Alzheimer’s disease, and Huntington’s. The primary cause of neurological disorders is insulin desensitization, demyelination, oxidative stress, and neuroinflammation accompanied by various aberrant proteins such as amyloid-β deposits, Lewy bodies accumulation, tau formation leading to neurofibrillary tangles. Impaired insulin signaling is directly associated with amyloid-β and α-synuclein deposition, as well as specific signaling cascades involved in neurodegenerative diseases. Insulin dysfunction may initiate various intracellular signaling cascades, including phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinases (JNK), and mitogen-activated protein kinase (MAPK). Neuronal death, inflammation, neuronal excitation, mitochondrial malfunction, and protein deposition are all influenced by insulin. Recent research has focused on GLP-1 receptor agonists as a potential therapeutic target. They increase glucose-dependent insulin secretion and are beneficial in neurodegenerative diseases by reducing oxidative stress and cytokine production. They reduce the deposition of abnormal proteins by crossing the blood-brain barrier. The purpose of this article is to discuss the role of insulin dysfunction in the pathogenesis of neurological diseases, specifically dementia. Additionally, we reviewed the therapeutic target (GLP-1) and its receptor activators as a possible treatment of dementia.
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Affiliation(s)
- Sidharth Mehan
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
- Correspondence: Sidharth Mehan, Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India, Tel +91 8059889909; +91 9461322911, Email ;
| | - Sonalika Bhalla
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Ehraz Mehmood Siddiqui
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Nidhi Sharma
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Ambika Shandilya
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Andleeb Khan
- Department of Pharmacology & Toxicology, College of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia
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21
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Wang TN, Hu XG, Chen GX. Uses of knockout, knockdown, and transgenic models in the studies of glucose transporter 4. World J Meta-Anal 2022; 10:1-11. [DOI: 10.13105/wjma.v10.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 12/10/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
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22
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Wei J, Tian J, Tang C, Fang X, Miao R, Wu H, Wang X, Tong X. The Influence of Different Types of Diabetes on Vascular Complications. J Diabetes Res 2022; 2022:3448618. [PMID: 35242879 PMCID: PMC8888068 DOI: 10.1155/2022/3448618] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 01/27/2022] [Accepted: 02/03/2022] [Indexed: 12/12/2022] Open
Abstract
The final outcome of diabetes is chronic complications, of which vascular complications are the most serious, which is the main cause of death for diabetic patients and the direct cause of the increase in the cost of diabetes. Type 1 and type 2 diabetes are the main types of diabetes, and their pathogenesis is completely different. Type 1 diabetes is caused by genetics and immunity to destroy a large number of β cells, and insulin secretion is absolutely insufficient, which is more prone to microvascular complications. Type 2 diabetes is dominated by insulin resistance, leading to atherosclerosis, which is more likely to progress to macrovascular complications. This article explores the pathogenesis of two types of diabetes, analyzes the pathogenesis of different vascular complications, and tries to explain the different trends in the progression of different types of diabetes to vascular complications, in order to better prevent diabetes and its vascular complications.
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Affiliation(s)
- Jiahua Wei
- Changchun University of Chinese Medicine, Changchun 130117, China
| | - Jiaxing Tian
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Cheng Tang
- Changchun University of Chinese Medicine, Changchun 130117, China
| | - Xinyi Fang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
- Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Runyu Miao
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
- Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Haoran Wu
- Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Xiuge Wang
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun 130021, China
| | - Xiaolin Tong
- Changchun University of Chinese Medicine, Changchun 130117, China
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
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23
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Sharma S, Shen T, Chitranshi N, Gupta V, Basavarajappa D, Mirzaei M, You Y, Krezel W, Graham SL, Gupta V. Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement. Mol Neurobiol 2022; 59:2027-2050. [PMID: 35015251 PMCID: PMC9015987 DOI: 10.1007/s12035-021-02709-y] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022]
Abstract
Retinoid X receptors (RXRs) present a subgroup of the nuclear receptor superfamily with particularly high evolutionary conservation of ligand binding domain. The receptor exists in α, β, and γ isotypes that form homo-/heterodimeric complexes with other permissive and non-permissive receptors. While research has identified the biochemical roles of several nuclear receptor family members, the roles of RXRs in various neurological disorders remain relatively under-investigated. RXR acts as ligand-regulated transcription factor, modulating the expression of genes that plays a critical role in mediating several developmental, metabolic, and biochemical processes. Cumulative evidence indicates that abnormal RXR signalling affects neuronal stress and neuroinflammatory networks in several neuropathological conditions. Protective effects of targeting RXRs through pharmacological ligands have been established in various cell and animal models of neuronal injury including Alzheimer disease, Parkinson disease, glaucoma, multiple sclerosis, and stroke. This review summarises the existing knowledge about the roles of RXR, its interacting partners, and ligands in CNS disorders. Future research will determine the importance of structural and functional heterogeneity amongst various RXR isotypes as well as elucidate functional links between RXR homo- or heterodimers and specific physiological conditions to increase drug targeting efficiency in pathological conditions.
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Affiliation(s)
- Samridhi Sharma
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
| | - Ting Shen
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Nitin Chitranshi
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Veer Gupta
- School of Medicine, Deakin University, Melbourne, VIC, Australia
| | - Devaraj Basavarajappa
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Mehdi Mirzaei
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Yuyi You
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.,Save Sight Institute, University of Sydney, Sydney, NSW, Australia
| | - Wojciech Krezel
- Institut de Génétique Et de Biologie Moléculaire Et Cellulaire, INSERM U1258, CNRS UMR 7104, Unistra, 67404, Illkirch-Graffenstaden, France
| | - Stuart L Graham
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.,Save Sight Institute, University of Sydney, Sydney, NSW, Australia
| | - Vivek Gupta
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
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24
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Toward the Decipherment of Molecular Interactions in the Diabetic Brain. Biomedicines 2022; 10:biomedicines10010115. [PMID: 35052794 PMCID: PMC8773210 DOI: 10.3390/biomedicines10010115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/01/2022] [Accepted: 01/04/2022] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) has been associated with cognitive complications in the brain resulting from acute and chronic metabolic disturbances happening peripherally and centrally. Numerous studies have reported on the morphological, electrophysiological, biochemical, and cognitive changes in the brains of diabetic individuals. The detailed pathophysiological mechanisms implicated in the development of the diabetic cognitive phenotype remain unclear due to intricate molecular changes evolving over time and space. This review provides an insight into recent advances in understanding molecular events in the diabetic brain, focusing on cerebral glucose and insulin uptake, insulin action in the brain, and the role of the brain in the regulation of glucose homeostasis. Fully competent mitochondria are essential for energy metabolism and proper brain function; hence, the potential contribution of mitochondria to the DM-induced impairment of the brain is also discussed.
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25
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Lee A, Mason ML, Lin T, Kumar SB, Kowdley D, Leung JH, Muhanna D, Sun Y, Ortega-Anaya J, Yu L, Fitzgerald J, DeVries AC, Nelson RJ, Weil ZM, Jiménez-Flores R, Parquette JR, Ziouzenkova O. Amino Acid Nanofibers Improve Glycemia and Confer Cognitive Therapeutic Efficacy to Bound Insulin. Pharmaceutics 2021; 14:pharmaceutics14010081. [PMID: 35056977 PMCID: PMC8778970 DOI: 10.3390/pharmaceutics14010081] [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: 11/22/2021] [Revised: 12/19/2021] [Accepted: 12/23/2021] [Indexed: 12/04/2022] Open
Abstract
Diabetes poses a high risk for debilitating complications in neural tissues, regulating glucose uptake through insulin-dependent and predominantly insulin-independent pathways. Supramolecular nanostructures provide a flexible strategy for combinatorial regulation of glycemia. Here, we compare the effects of free insulin to insulin bound to positively charged nanofibers comprised of self-assembling amino acid compounds (AACs) with an antioxidant-modified side chain moiety (AAC2) in both in vitro and in vivo models of type 1 diabetes. Free AAC2, free human insulin (hINS) and AAC2-bound-human insulin (AAC2-hINS) were tested in streptozotocin (STZ)-induced mouse model of type 1 diabetes. AAC2-hINS acted as a complex and exhibited different properties compared to free AAC2 or hINS. Mice treated with the AAC2-hINS complex were devoid of hypoglycemic episodes, had improved levels of insulin in circulation and in the brain, and increased expression of neurotransmitter taurine transporter, Slc6a6. Consequently, treatment with AAC2-hINS markedly advanced both physical and cognitive performance in mice with STZ-induced and genetic type 1 diabetes compared to treatments with free AAC2 or hINS. This study demonstrates that the flexible nanofiber AAC2 can serve as a therapeutic platform for the combinatorial treatment of diabetes and its complications.
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Affiliation(s)
- Aejin Lee
- Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA; (A.L.); (S.B.K.); (D.K.); (J.H.L.); (D.M.)
| | - McKensie L. Mason
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA; (M.L.M.); (T.L.); (Y.S.); (J.R.P.)
| | - Tao Lin
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA; (M.L.M.); (T.L.); (Y.S.); (J.R.P.)
| | - Shashi Bhushan Kumar
- Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA; (A.L.); (S.B.K.); (D.K.); (J.H.L.); (D.M.)
| | - Devan Kowdley
- Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA; (A.L.); (S.B.K.); (D.K.); (J.H.L.); (D.M.)
| | - Jacob H. Leung
- Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA; (A.L.); (S.B.K.); (D.K.); (J.H.L.); (D.M.)
| | - Danah Muhanna
- Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA; (A.L.); (S.B.K.); (D.K.); (J.H.L.); (D.M.)
| | - Yuan Sun
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA; (M.L.M.); (T.L.); (Y.S.); (J.R.P.)
| | - Joana Ortega-Anaya
- Department of Food Science and Technology, The Ohio State University, Columbus, OH 43210, USA; (J.O.-A.); (R.J.-F.)
| | - Lianbo Yu
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA;
| | - Julie Fitzgerald
- Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA; (J.F.); (A.C.D.); (Z.M.W.)
| | - A. Courtney DeVries
- Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA; (J.F.); (A.C.D.); (Z.M.W.)
- Department of Neuroscience, West Virginia University, Morgantown, WV 26506, USA
| | - Randy J. Nelson
- Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA;
| | - Zachary M. Weil
- Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA; (J.F.); (A.C.D.); (Z.M.W.)
| | - Rafael Jiménez-Flores
- Department of Food Science and Technology, The Ohio State University, Columbus, OH 43210, USA; (J.O.-A.); (R.J.-F.)
| | - Jon R. Parquette
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA; (M.L.M.); (T.L.); (Y.S.); (J.R.P.)
| | - Ouliana Ziouzenkova
- Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA; (A.L.); (S.B.K.); (D.K.); (J.H.L.); (D.M.)
- Correspondence: ; Tel.: +1-614-292-5034
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Abstract
The Akt isoforms-AS160-GLUT4 axis is the primary axis that governs glucose homeostasis in the body. The first step on the path to insulin resistance is deregulated Akt isoforms. This could be Akt isoform expression, its phosphorylation, or improper isoform-specific redistribution to the plasma membrane in a specific tissue system. The second step is deregulated AS160 expression, its phosphorylation, improper dissociation from glucose transporter storage vesicles (GSVs), or its inability to bind to 14-3-3 proteins, thus not allowing it to execute its function. The final step is improper GLUT4 translocation and aberrant glucose uptake. These processes lead to insulin resistance in a tissue-specific way affecting the whole-body glucose homeostasis, eventually progressing to an overt diabetic phenotype. Thus, the relationship between these three key proteins and their proper regulation comes out as the defining axis of insulin signaling and -resistance. This review summarizes the role of this central axis in insulin resistance and disease in a new light.
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Affiliation(s)
- Medha Sharma
- Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi, 110016, India
| | - Chinmoy Sankar Dey
- Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi, 110016, India.
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Dakic T, Lakic I, Zec M, Takic M, Stojiljkovic M, Jevdjovic T. Fructose-rich diet and walnut supplementation differently regulate rat hypothalamic and hippocampal glucose transporters expression. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2021; 101:5984-5991. [PMID: 33856052 DOI: 10.1002/jsfa.11252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/06/2021] [Accepted: 04/15/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND Nutritional modulations may be considered a strategy to protect mental health. Neuronal homeostasis is highly dependent on the availability of glucose, which represents the primary energy source for the brain. In this study, we evaluated the effects of walnut intake and fructose-rich diet on the expression of glucose transporters (GLUTs) in two rat brain regions: hypothalamus and hippocampus. RESULTS Our results show that walnut supplementation of fructose-fed animals restored the hypothalamic content of GLUT1 and GLUT3 protein. Furthermore, walnut intake did not affect increased hypothalamic GLUT2 content upon fructose consumption. These effects were accompanied by distinctive alterations of hippocampal GLUTs levels. Specifically, walnut intake increased GLUT1 content, whereas GLUT2 protein was decreased within the rat hippocampus after both individual and combined treatments. CONCLUSION Overall, our study suggests that walnut supplementation exerted modulatory effects on the glucose transporters within specific brain regions in the presence of developed metabolic disorder. © 2021 Society of Chemical Industry.
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Affiliation(s)
- Tamara Dakic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry 'Ivan Djaja', Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Iva Lakic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry 'Ivan Djaja', Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Manja Zec
- Centre of Excellence for Nutrition and Metabolism Research, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Marija Takic
- Centre of Excellence for Nutrition and Metabolism Research, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Mojca Stojiljkovic
- Department for Molecular Biology and Endocrinology, Vinca Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Tanja Jevdjovic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry 'Ivan Djaja', Faculty of Biology, University of Belgrade, Belgrade, Serbia
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28
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Kaur D, Behl T, Sehgal A, Singh S, Sharma N, Chigurupati S, Alhowail A, Abdeen A, Ibrahim SF, Vargas-De-La-Cruz C, Sachdeva M, Bhatia S, Al-Harrasi A, Bungau S. Decrypting the potential role of α-lipoic acid in Alzheimer's disease. Life Sci 2021; 284:119899. [PMID: 34450170 DOI: 10.1016/j.lfs.2021.119899] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 12/20/2022]
Abstract
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases with motor disturbances, cognitive decline, and behavioral impairment. It is characterized by the extracellular aggregation of amyloid-β plaques and the intracellular accumulation of tau protein. AD patients show a cognitive decline, which has been associated with oxidative stress, as well as mitochondrial dysfunction. Alpha-lipoic acid (α-LA), a natural antioxidant present in food and used as a dietary supplement, has been considered a promising agent for the prevention or treatment of neurodegenerative disorders. Despite multiple preclinical studies indicating beneficial effects of α-LA in memory functioning, and pointing to its neuroprotective effects, to date only a few studies have examined its effects in humans. Studies performed in animal models of memory loss associated with aging and AD have shown that α-LA improves memory in a variety of behavioral paradigms. Furthermore, molecular mechanisms underlying α-LA effects have also been investigated. Accordingly, α-LA shows antioxidant, antiapoptotic, anti-inflammatory, glioprotective, metal chelating properties in both in vivo and in vitro studies. In addition, it has been shown that α-LA reverses age-associated loss of neurotransmitters and their receptors. The review article aimed at summarizing and discussing the main studies investigating the neuroprotective effects of α-LA on cognition as well as its molecular effects, to improve the understanding of the therapeutic potential of α-LA in patients suffering from neurodegenerative disorders, supporting the development of clinical trials with α-LA.
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Affiliation(s)
- Dapinder Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sridevi Chigurupati
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraidah, Saudi Arabia
| | - Ahmed Alhowail
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah, Saudi Arabia
| | - Ahmed Abdeen
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Benha University, Toukh, Egypt; Center of Excellence for Screening of Environmental Contaminants, Benha University, Toukh, Egypt
| | - Samah F Ibrahim
- Clinical Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia; Forensic Medicine and Clinical Toxicology Department, College of Medicine, Cairo University, Cairo, Egypt
| | - Celia Vargas-De-La-Cruz
- Faculty of Pharmacy and Biochemistry, Academic Department of Pharmacology, Bromatology and Toxicology, Centro Latinoamericano de Ensenanza e Investigacion en Bacteriologia Alimentaria, Universidad Nacinol Mayor de San Marcos, Lima, Peru; E-Health Research Center, Universidad de Ciencias y Humanidades, Lima, Peru
| | - Monika Sachdeva
- Fatima College of Health Sciences, Alain, United Arab Emirates
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman; School of Health Science, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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Milstein JL, Ferris HA. The brain as an insulin-sensitive metabolic organ. Mol Metab 2021; 52:101234. [PMID: 33845179 PMCID: PMC8513144 DOI: 10.1016/j.molmet.2021.101234] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 03/26/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The brain was once thought of as an insulin-insensitive organ. We now know that the insulin receptor is present throughout the brain and serves important functions in whole-body metabolism and brain function. Brain insulin signaling is involved not only in brain homeostatic processes but also neuropathological processes such as cognitive decline and Alzheimer's disease. SCOPE OF REVIEW In this review, we provide an overview of insulin signaling within the brain and the metabolic impact of brain insulin resistance and discuss Alzheimer's disease, one of the neurologic diseases most closely associated with brain insulin resistance. MAJOR CONCLUSIONS While brain insulin signaling plays only a small role in central nervous system glucose regulation, it has a significant impact on the brain's metabolic health. Normal insulin signaling is important for mitochondrial functioning and normal food intake. Brain insulin resistance contributes to obesity and may also play an important role in neurodegeneration.
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Affiliation(s)
- Joshua L Milstein
- Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, USA; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - Heather A Ferris
- Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, USA; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA; Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA.
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30
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Ruze R, Xu Q, Liu G, Li Y, Chen W, Cheng Z, Xiong Y, Liu S, Zhang G, Hu S, Yan Z. Central GLP-1 contributes to improved cognitive function and brain glucose uptake after duodenum-jejunum bypass on obese and diabetic rats. Am J Physiol Endocrinol Metab 2021; 321:E392-E409. [PMID: 34370593 DOI: 10.1152/ajpendo.00126.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/29/2021] [Indexed: 12/19/2022]
Abstract
The improvement of cognitive function following bariatric surgery has been highlighted, yet its underlying mechanisms remain elusive. Finding the improved brain glucose uptake of patients after Roux-en-Y gastric bypass (RYGB), duodenum-jejunum bypass (DJB), and sham surgery (Sham) were performed on obese and diabetic Wistar rats, and intracerebroventricular (ICV) injection of glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira), antagonist exendin-(9-39) (Exe-9), and the viral-mediated GLP-1 receptor (Glp-1r) knockdown (KD) were applied on both groups to elucidate the role of GLP-1 in mediating cognitive function and brain glucose uptake assessed with the Morris water maze (MWM) and positron emission tomography (PET). Insulin and GLP-1 in serum and cerebral spinal fluid (CSF) were measured, and the expression of glucose uptake-related proteins including glucose transporter 1 (GLUT-1), GLUT-4, phospho-Akt substrate of 160kDa (pAS160), AS160, Rab10, Myosin-Va as well as the c-fos marker in the brain were examined. Along with augmented glucose homeostasis following DJB, central GLP-1 was correlated with the improved cognitive function and ameliorated brain glucose uptake, which was further confirmed by the enhancive role of Lira on both groups whereas the Exe-9 and Glp-1r KD were opposite. Known to activate insulin-signaling pathways, central GLP-1 contributes to improved cognitive function and brain glucose uptake after DJB.NEW & NOTEWORTHY The improvement of cognitive function following bariatric surgery has been highlighted while its mechanisms remain elusive. The brain glucose uptake of patients was improved after RYGB, and the DJB and sham surgery performed on obese and diabetic Wistar rats revealed that the elevated central GLP-1 contributes to the dramatic improvement of cognitive function, brain glucose uptake, transport, glucose sensing, and neuronal activation.
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Affiliation(s)
- Rexiati Ruze
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Qian Xu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, People's Republic of China
| | - Guoqin Liu
- Department of General Surgery, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China
| | - Yuekai Li
- Department of Nuclear Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Weijie Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Zhiqiang Cheng
- Department of Colorectal Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Yacheng Xiong
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, People's Republic of China
| | - Shaozhuang Liu
- Department of Bariatric and Metabolic Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Guangyong Zhang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, People's Republic of China
| | - Sanyuan Hu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, People's Republic of China
| | - Zhibo Yan
- Department of Colorectal Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
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31
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Rebelos E, Iozzo P, Guzzardi MA, Brunetto MR, Bonino F. Brain-gut-liver interactions across the spectrum of insulin resistance in metabolic fatty liver disease. World J Gastroenterol 2021; 27:4999-5018. [PMID: 34497431 PMCID: PMC8384743 DOI: 10.3748/wjg.v27.i30.4999] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/29/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
Metabolic associated fatty liver disease (MAFLD), formerly named "nonalcoholic fatty liver disease" occurs in about one-third of the general population of developed countries worldwide and behaves as a major morbidity and mortality risk factor for major causes of death, such as cardiovascular, digestive, metabolic, neoplastic and neuro-degenerative diseases. However, progression of MAFLD and its associated systemic complications occur almost invariably in patients who experience the additional burden of intrahepatic and/or systemic inflammation, which acts as disease accelerator. Our review is focused on the new knowledge about the brain-gut-liver axis in the context of metabolic dysregulations associated with fatty liver, where insulin resistance has been assumed to play an important role. Special emphasis has been given to digital imaging studies and in particular to positron emission tomography, as it represents a unique opportunity for the noninvasive in vivo study of tissue metabolism. An exhaustive revision of targeted animal models is also provided in order to clarify what the available preclinical evidence suggests for the causal interactions between fatty liver, dysregulated endogenous glucose production and insulin resistance.
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Affiliation(s)
- Eleni Rebelos
- Turku PET Centre, University of Turku, Turku 20500, Finland
| | - Patricia Iozzo
- Institute of Clinical Physiology, National Research Council, Pisa 56124, Italy
| | | | - Maurizia Rossana Brunetto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis, Pisa University Hospital, Pisa 56121, Italy
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56121, Italy
- Institute of Biostructure and Bioimaging, National Research Council, Napoli 80145, Italy
| | - Ferruccio Bonino
- Institute of Biostructure and Bioimaging, National Research Council, Napoli 80145, Italy
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32
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Agrawal R, Reno CM, Sharma S, Christensen C, Huang Y, Fisher SJ. Insulin action in the brain regulates both central and peripheral functions. Am J Physiol Endocrinol Metab 2021; 321:E156-E163. [PMID: 34056920 PMCID: PMC8321819 DOI: 10.1152/ajpendo.00642.2020] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The brain has been traditionally thought to be insensitive to insulin, primarily because insulin does not stimulate glucose uptake/metabolism in the brain (as it does in classic insulin-sensitive tissues such as muscle, liver, and fat). However, over the past 20 years, research in this field has identified unique actions of insulin in the brain. There is accumulating evidence that insulin crosses into the brain and regulates central nervous system functions such as feeding, depression, and cognitive behavior. In addition, insulin acts in the brain to regulate systemic functions such as hepatic glucose production, lipolysis, lipogenesis, reproductive competence, and the sympathoadrenal response to hypoglycemia. Decrements in brain insulin action (or brain insulin resistance) can be observed in obesity, type 2 diabetes (T2DM), aging, and Alzheimer's disease (AD), indicating a possible link between metabolic and cognitive health. Here, we describe recent findings on the pleiotropic actions of insulin in the brain and highlight the precise sites, specific neuronal population, and roles for supportive astrocytic cells through which insulin acts in the brain. In addition, we also discuss how boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Overall, this perspective article serves to highlight some of these key scientific findings, identify unresolved issues, and indicate future directions of research in this field that would serve to improve the lives of people with metabolic and cognitive dysfunctions.
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Affiliation(s)
- Rahul Agrawal
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Candace M Reno
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Sunny Sharma
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Camille Christensen
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Yiqing Huang
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Simon J Fisher
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah
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33
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Mikawa T, Shibata E, Shimada M, Ito K, Ito T, Kanda H, Takubo K, Shimada A, Lleonart ME, Inagaki N, Yokode M, Kondoh H. Characterization of genetically modified mice for phosphoglycerate mutase, a vitally-essential enzyme in glycolysis. PLoS One 2021; 16:e0250856. [PMID: 33914812 PMCID: PMC8084212 DOI: 10.1371/journal.pone.0250856] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 04/15/2021] [Indexed: 01/14/2023] Open
Abstract
Glycolytic metabolism is closely involved in physiological homeostasis and pathophysiological states. Among glycolytic enzymes, phosphoglycerate mutase (PGAM) has been reported to exert certain physiological role in vitro, whereas its impact on glucose metabolism in vivo remains unclear. Here, we report the characterization of Pgam1 knockout mice. We observed that homozygous knockout mice of Pgam1 were embryonic lethal. Although we previously reported that both PGAM-1 and -2 affect global glycolytic profile of cancers in vitro, in vivo glucose parameters were less affected both in the heterozygous knockout of Pgam1 and in Pgam2 transgenic mice. Thus, the impact of PGAM on in vivo glucose metabolism is rather complex than expected before.
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Affiliation(s)
- Takumi Mikawa
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Eri Shibata
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Midori Shimada
- Joint Faculty of Veterinary Science, Yamaguchi University, Yamaguchi, Japan
| | - Ken Ito
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomiko Ito
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroaki Kanda
- Department of Pathology, Saitama Cancer Center, Saitama, Japan
| | - Keiyo Takubo
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | | | | | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masayuki Yokode
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Kondoh
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- * E-mail:
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34
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Rebelos E, Rinne JO, Nuutila P, Ekblad LL. Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline-Does Insulin Have Anything to Do with It? A Narrative Review. J Clin Med 2021; 10:jcm10071532. [PMID: 33917464 PMCID: PMC8038699 DOI: 10.3390/jcm10071532] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/01/2021] [Accepted: 04/02/2021] [Indexed: 12/13/2022] Open
Abstract
Imaging brain glucose metabolism with fluorine-labelled fluorodeoxyglucose ([18F]-FDG) positron emission tomography (PET) has long been utilized to aid the diagnosis of memory disorders, in particular in differentiating Alzheimer’s disease (AD) from other neurological conditions causing cognitive decline. The interest for studying brain glucose metabolism in the context of metabolic disorders has arisen more recently. Obesity and type 2 diabetes—two diseases characterized by systemic insulin resistance—are associated with an increased risk for AD. Along with the well-defined patterns of fasting [18F]-FDG-PET changes that occur in AD, recent evidence has shown alterations in fasting and insulin-stimulated brain glucose metabolism also in obesity and systemic insulin resistance. Thus, it is important to clarify whether changes in brain glucose metabolism are just an epiphenomenon of the pathophysiology of the metabolic and neurologic disorders, or a crucial determinant of their pathophysiologic cascade. In this review, we discuss the current knowledge regarding alterations in brain glucose metabolism, studied with [18F]-FDG-PET from metabolic disorders to AD, with a special focus on how manipulation of insulin levels affects brain glucose metabolism in health and in systemic insulin resistance. A better understanding of alterations in brain glucose metabolism in health, obesity, and neurodegeneration, and the relationships between insulin resistance and central nervous system glucose metabolism may be an important step for the battle against metabolic and cognitive disorders.
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Affiliation(s)
- Eleni Rebelos
- Turku PET Centre, University of Turku and Turku University Hospital, 20520 Turku, Finland; (E.R.); (J.O.R.); (P.N.)
| | - Juha O. Rinne
- Turku PET Centre, University of Turku and Turku University Hospital, 20520 Turku, Finland; (E.R.); (J.O.R.); (P.N.)
| | - Pirjo Nuutila
- Turku PET Centre, University of Turku and Turku University Hospital, 20520 Turku, Finland; (E.R.); (J.O.R.); (P.N.)
- Department of Endocrinology, Turku University Hospital, 20520 Turku, Finland
| | - Laura L. Ekblad
- Turku PET Centre, University of Turku and Turku University Hospital, 20520 Turku, Finland; (E.R.); (J.O.R.); (P.N.)
- Correspondence: ; Tel.: +358-2-3138721
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35
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Garcia SM, Hirschberg PR, Sarkar P, Siegel DM, Teegala SB, Vail GM, Routh VH. Insulin actions on hypothalamic glucose-sensing neurones. J Neuroendocrinol 2021; 33:e12937. [PMID: 33507001 PMCID: PMC10561189 DOI: 10.1111/jne.12937] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/22/2020] [Accepted: 12/29/2020] [Indexed: 12/13/2022]
Abstract
Subsequent to the discovery of insulin 100 years ago, great strides have been made in understanding its function, especially in the brain. It is now clear that insulin is a critical regulator of the neuronal circuitry controlling energy balance and glucose homeostasis. This review focuses on the effects of insulin and diabetes on the activity and glucose sensitivity of hypothalamic glucose-sensing neurones. We highlight the role of electrophysiological data in understanding how insulin regulates glucose-sensing neurones. A brief introduction describing the benefits and limitations of the major electrophysiological techniques used to investigate glucose-sensing neurones is provided. The mechanisms by which hypothalamic neurones sense glucose are discussed with an emphasis on those glucose-sensing neurones already shown to be modulated by insulin. Next, the literature pertaining to how insulin alters the activity and glucose sensitivity of these hypothalamic glucose-sensing neurones is described. In addition, the effects of impaired insulin signalling during diabetes and the ramifications of insulin-induced hypoglycaemia on hypothalamic glucose-sensing neurones are covered. To the extent that it is known, we present hypotheses concerning the mechanisms underlying the effects of these insulin-related pathologies. To conclude, electrophysiological data from the hippocampus are evaluated aiming to provide clues regarding how insulin might influence neuronal plasticity in glucose-sensing neurones. Although much has been accomplished subsequent to the discovery of insulin, the work described in our review suggests that the regulation of central glucose sensing by this hormone is both important and understudied.
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Affiliation(s)
- Stephanie M Garcia
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Pamela R Hirschberg
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Pallabi Sarkar
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Dashiel M Siegel
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Suraj B Teegala
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Gwyndolin M Vail
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Vanessa H Routh
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
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36
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Tyagi A, Pugazhenthi S. Targeting Insulin Resistance to Treat Cognitive Dysfunction. Mol Neurobiol 2021; 58:2672-2691. [PMID: 33483903 DOI: 10.1007/s12035-021-02283-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/05/2021] [Indexed: 02/06/2023]
Abstract
Dementia is a devastating disease associated with aging. Alzheimer's disease is the most common form of dementia, followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus, characterized by chronic hyperglycemia and insulin resistance, as a risk factor for Alzheimer's disease and other cognitive disorders. While studies on insulin action have remained traditionally in the domain of peripheral tissues, the detrimental effects of insulin resistance in the central nervous system on cognitive dysfunction are increasingly being reported by recent clinical and preclinical studies. The findings from these studies suggest that antidiabetic drugs have the potential to be used to treat dementia. In this review, we discuss the physiological functions of insulin in the brain, studies on the evaluation of cognitive function under conditions of insulin resistance, and reports on the beneficial actions of antidiabetic drugs in the brain. This review covers clinical studies as well as investigations in animal models and will further highlight the emerging link between insulin resistance and neurodegenerative disorders.
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Affiliation(s)
- Anit Tyagi
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA.,Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.,University of Denver, Denver, CO, USA
| | - Subbiah Pugazhenthi
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA. .,Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.
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Molecular Mechanisms of Glucocorticoid-Induced Insulin Resistance. Int J Mol Sci 2021; 22:ijms22020623. [PMID: 33435513 PMCID: PMC7827500 DOI: 10.3390/ijms22020623] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/29/2020] [Accepted: 01/02/2021] [Indexed: 12/12/2022] Open
Abstract
Glucocorticoids (GCs) are steroids secreted by the adrenal cortex under the hypothalamic-pituitary-adrenal axis control, one of the major neuro-endocrine systems of the organism. These hormones are involved in tissue repair, immune stability, and metabolic processes, such as the regulation of carbohydrate, lipid, and protein metabolism. Globally, GCs are presented as ‘flight and fight’ hormones and, in that purpose, they are catabolic hormones required to mobilize storage to provide energy for the organism. If acute GC secretion allows fast metabolic adaptations to respond to danger, stress, or metabolic imbalance, long-term GC exposure arising from treatment or Cushing’s syndrome, progressively leads to insulin resistance and, in fine, cardiometabolic disorders. In this review, we briefly summarize the pharmacological actions of GC and metabolic dysregulations observed in patients exposed to an excess of GCs. Next, we describe in detail the molecular mechanisms underlying GC-induced insulin resistance in adipose tissue, liver, muscle, and to a lesser extent in gut, bone, and brain, mainly identified by numerous studies performed in animal models. Finally, we present the paradoxical effects of GCs on beta cell mass and insulin secretion by the pancreas with a specific focus on the direct and indirect (through insulin-sensitive organs) effects of GCs. Overall, a better knowledge of the specific action of GCs on several organs and their molecular targets may help foster the understanding of GCs’ side effects and design new drugs that possess therapeutic benefits without metabolic adverse effects.
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Rozjan A, Shan W, Yao Q. Metabolic Consequences of Neuronal HIF1α-Deficiency in Mediobasal Hypothalamus in Mice. Front Endocrinol (Lausanne) 2021; 12:668193. [PMID: 34733235 PMCID: PMC8558296 DOI: 10.3389/fendo.2021.668193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 09/16/2021] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE This study aims to investigate whether hypoxia-inducible factor 1α (HIF1α) in the neurons of the mediobasal hypothalamus is involved in the regulation of body weight, glucose, and lipid metabolism in mice and to explore the underlying molecular mechanisms. METHODS HIF1α flox/flox mice were used. The adeno-associated virus that contained either cre, GFP and syn, or GFP and syn (controls) was injected into the mediobasal hypothalamus to selectively knock out HIF1α in the neurons of the mediobasal hypothalamus. The body weight and food intake were weighed daily. The levels of blood glucose, insulin, total cholesterol (TC), triglyceride (TG), free fatty acid (FFA), high-density lipoprotein (HDL), and low-density lipoprotein (LDL)were tested. Intraperitoneal glucose tolerance test (IPGTT) was performed. The insulin-stimulated Akt phosphorylation in the liver, epididymal fat, and skeletal muscle were examined. Also, the mRNA expression levels of HIF1α, proopiomelanocortin (POMC), neuropeptide Y (NPY), and glucose transporter protein 4 (Glut4) in the hypothalamus were checked. RESULTS After selectively knocking out HIF1α in the neurons of the mediobasal hypothalamus (HIF1αKOMBH), the body weights and food intake of mice increased significantly compared with the control mice (p < 0.001 at 4 weeks). Compared with that of the control group, the insulin level of HIF1αKOMBH mice was 3.5 times higher (p < 0.01). The results of the IPGTT showed that the blood glucose level of the HIF1αKOMBH group at 20-120 min was significantly higher than that of the control group (p < 0.05). The serum TC, FFA, HDL, and LDL content of the HIF1αKOMBH group was significantly higher than those of the control group (p < 0.05). Western blot results showed that compared with those in the control group, insulin-induced AKT phosphorylation levels in liver, epididymal fat, and skeletal muscle in the HIF1αKOMBH group were not as significantly elevated as in the control group. Reverse transcription-polymerase chain reaction (RT-PCR) results in the whole hypothalamus showed a significant decrease in Glut4 mRNA expression. And the mRNA expression levels of HIF1α, POMC, and NPY of the HIF1αKOMBH group decreased significantly in ventral hypothalamus. CONCLUSIONS The hypothalamic neuronal HIF1α plays an important role in the regulation of body weight balance in mice under normoxic condition. In the absence of hypothalamic neuronal HIF1α, the mice gained weight with increased appetite, accompanied with abnormal glucose and lipid metabolism. POMC and Glut4 may be responsible for this effect of HIF1α.
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Affiliation(s)
- Azmat Rozjan
- Department of Physiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
| | - Weibi Shan
- Department of Dermatology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Qiaoling Yao
- Department of Physiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
- *Correspondence: Qiaoling Yao,
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Wang T, Wang J, Hu X, Huang XJ, Chen GX. Current understanding of glucose transporter 4 expression and functional mechanisms. World J Biol Chem 2020; 11:76-98. [PMID: 33274014 PMCID: PMC7672939 DOI: 10.4331/wjbc.v11.i3.76] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/22/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
Glucose is used aerobically and anaerobically to generate energy for cells. Glucose transporters (GLUTs) are transmembrane proteins that transport glucose across the cell membrane. Insulin promotes glucose utilization in part through promoting glucose entry into the skeletal and adipose tissues. This has been thought to be achieved through insulin-induced GLUT4 translocation from intracellular compartments to the cell membrane, which increases the overall rate of glucose flux into a cell. The insulin-induced GLUT4 translocation has been investigated extensively. Recently, significant progress has been made in our understanding of GLUT4 expression and translocation. Here, we summarized the methods and reagents used to determine the expression levels of Slc2a4 mRNA and GLUT4 protein, and GLUT4 translocation in the skeletal muscle, adipose tissues, heart and brain. Overall, a variety of methods such real-time polymerase chain reaction, immunohistochemistry, fluorescence microscopy, fusion proteins, stable cell line and transgenic animals have been used to answer particular questions related to GLUT4 system and insulin action. It seems that insulin-induced GLUT4 translocation can be observed in the heart and brain in addition to the skeletal muscle and adipocytes. Hormones other than insulin can induce GLUT4 translocation. Clearly, more studies of GLUT4 are warranted in the future to advance of our understanding of glucose homeostasis.
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Affiliation(s)
- Tiannan Wang
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
| | - Jing Wang
- College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, Hubei Province, China
| | - Xinge Hu
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
| | - Xian-Ju Huang
- College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
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Haigh JL, New LE, Filippi BM. Mitochondrial Dynamics in the Brain Are Associated With Feeding, Glucose Homeostasis, and Whole-Body Metabolism. Front Endocrinol (Lausanne) 2020; 11:580879. [PMID: 33240218 PMCID: PMC7680879 DOI: 10.3389/fendo.2020.580879] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
The brain is responsible for maintaining whole-body energy homeostasis by changing energy input and availability. The hypothalamus and dorsal vagal complex (DVC) are the primary sites of metabolic control, able to sense both hormones and nutrients and adapt metabolism accordingly. The mitochondria respond to the level of nutrient availability by fusion or fission to maintain energy homeostasis; however, these processes can be disrupted by metabolic diseases including obesity and type II diabetes (T2D). Mitochondrial dynamics are crucial in the development and maintenance of obesity and T2D, playing a role in the control of glucose homeostasis and whole-body metabolism across neurons and glia in the hypothalamus and DVC.
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Affiliation(s)
| | | | - Beatrice M. Filippi
- Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom
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Abstract
The glucose transporter GLUT4 is critical for skeletal muscle glucose uptake in response to insulin and muscle contraction/exercise. Exercise increases GLUT4 translocation to the sarcolemma and t-tubule and, over the longer term, total GLUT4 protein content. Here, we review key aspects of GLUT4 biology in relation to exercise, with a focus on exercise-induced GLUT4 translocation, postexercise metabolism and muscle insulin sensitivity, and exercise effects on GLUT4 expression.
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Affiliation(s)
- Marcelo Flores-Opazo
- Laboratory of Exercise and Physical Activity Sciences, Department of Physiotherapy, University Finis Terrae, Santiago, Chile
| | - Sean L McGee
- Metabolic Research Unit, School of Medicine and Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, Waurn Ponds
| | - Mark Hargreaves
- Department of Physiology, The University of Melbourne, Melbourne, Australia
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Hendrix RD, Ou Y, Davis JE, Odle AK, Groves TR, Allen AR, Childs GV, Barger SW. Alzheimer amyloid-β- peptide disrupts membrane localization of glucose transporter 1 in astrocytes: implications for glucose levels in brain and blood. Neurobiol Aging 2020; 97:73-88. [PMID: 33161213 PMCID: PMC7736209 DOI: 10.1016/j.neurobiolaging.2020.10.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 08/25/2020] [Accepted: 10/02/2020] [Indexed: 12/12/2022]
Abstract
Alzheimer’s disease (AD) is associated with disturbances in blood glucose regulation, and type-2 diabetes elevates the risk for dementia. A role for amyloid-β peptide (Aβ) in linking these age-related conditions has been proposed, tested primarily in transgenic mouse lines that overexpress mutated amyloid precursor protein (APP). Because APP has its own impacts on glucose regulation, we examined the BRI-Aβ42 line (“Aβ42-tg”), which produces extracellular Aβ1–42 in the CNS without elevation of APP. We also looked for interactions with diet-induced obesity (DIO) resulting from a high-fat, high-sucrose (“western”) diet. Aβ42-tg mice were impaired in both spatial memory and glucose tolerance. Although DIO induced insulin resistance, Aβ1–42 accumulation did not, and the impacts of DIO and Aβ on glucose tolerance were merely additive. Aβ42-tg mice exhibited no significant differences from wild-type in insulin production, body weight, lipidemia, appetite, physical activity, respiratory quotient, an-/orexigenic factors, or inflammatory factors. These negative findings suggested that the phenotype in these mice arose from perturbation of glucose excursion in an insulin-independent tissue. To wit, cerebral cortex of Aβ42-tg mice had reduced glucose utilization, similar to human patients with AD. This was associated with insufficient trafficking of glucose transporter 1 to the plasma membrane in parenchymal brain cells, a finding also documented in human AD tissue. Together, the lower cerebral metabolic rate of glucose and diminished function of parenchymal glucose transporter 1 indicate that aberrant regulation of blood glucose in AD likely reflects a central phenomenon, resulting from the effects of Aβ on cerebral parenchyma, rather than a generalized disruption of hypothalamic or peripheral endocrinology. The involvement of a specific glucose transporter in this deficit provides a new target for the design of AD therapies.
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Affiliation(s)
- Rachel D Hendrix
- Department of Neurobiology & Developmental Sciences, Little Rock, AR, USA
| | - Yang Ou
- Department of Geriatrics, Little Rock, AR, USA
| | - Jakeira E Davis
- Graduate Program in Interdisciplinary Biomedical Sciences, Little Rock, AR, USA
| | - Angela K Odle
- Department of Neurobiology & Developmental Sciences, Little Rock, AR, USA
| | - Thomas R Groves
- Department of Neurobiology & Developmental Sciences, Little Rock, AR, USA
| | - Antiño R Allen
- Department of Neurobiology & Developmental Sciences, Little Rock, AR, USA; Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Gwen V Childs
- Department of Neurobiology & Developmental Sciences, Little Rock, AR, USA
| | - Steven W Barger
- Department of Neurobiology & Developmental Sciences, Little Rock, AR, USA; Department of Geriatrics, Little Rock, AR, USA; Geriatric Research, Education & Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
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Zhang YH, Yan XZ, Xu SF, Pang ZQ, Li LB, Yang Y, Fan YG, Wang Z, Yu X, Guo C, Ao Q. α-Lipoic Acid Maintains Brain Glucose Metabolism via BDNF/TrkB/HIF-1α Signaling Pathway in P301S Mice. Front Aging Neurosci 2020; 12:262. [PMID: 32973490 PMCID: PMC7471806 DOI: 10.3389/fnagi.2020.00262] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 07/31/2020] [Indexed: 12/30/2022] Open
Abstract
The microtubule-associated protein tau is closely correlated with hypometabolism in Alzheimer’s disease (AD). α-lipoic acid (LA), which is a naturally occurring cofactor in mitochondrial, has been shown to have properties that can inhibit the tau pathology and neuronal damage in our previous research. However, if LA affects glucose metabolism when it reverses tau pathology remains unclear, especially concerning the potential mechanism. Therefore, we make a further study using the P301S mouse model (a tauopathy and AD mouse model which overexpressing fibrillary tau) to gain a clear idea of the aforementioned problems. Here, we found chronic LA administration significantly increased glucose availability by elevating glucose transporter 3 (GLUT3), GLUT4, vascular endothelial growth factor (VEGF) protein and mRNA level, and heme oxygenase-1 (HO-1) protein level in P301S mouse brains. Meanwhile, we found that LA also promoted glycolysis by directly upregulating hexokinase (HK) activity, indirectly by increasing proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and DNA repair enzymes (OGG1/2 and MTH1). Further, we found the underlying mechanism of restored glucose metabolism might involve in the activation of brain-derived neurotrophic factor (BDNF)/tyrosine Kinase receptor B (TrkB)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway by LA treatment.
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Affiliation(s)
- Yan-Hui Zhang
- School of Fundamental Sciences, China Medical University, Shenyang, China
| | - Xin-Zhu Yan
- School of Fundamental Sciences, China Medical University, Shenyang, China
| | - Shuang-Feng Xu
- College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Zhong-Qiu Pang
- College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Lin-Bo Li
- College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Yang Yang
- College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Yong-Gang Fan
- Institute of Health Science, China Medical University, Shenyang, China
| | - Zhuo Wang
- Institute of Health Science, China Medical University, Shenyang, China
| | - Xin Yu
- Institute of Health Science, China Medical University, Shenyang, China
| | - Chuang Guo
- College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Qiang Ao
- School of Fundamental Sciences, China Medical University, Shenyang, China
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44
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Glucose transporters in brain in health and disease. Pflugers Arch 2020; 472:1299-1343. [PMID: 32789766 PMCID: PMC7462931 DOI: 10.1007/s00424-020-02441-x] [Citation(s) in RCA: 296] [Impact Index Per Article: 59.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/20/2020] [Accepted: 07/24/2020] [Indexed: 12/15/2022]
Abstract
Energy demand of neurons in brain that is covered by glucose supply from the blood is ensured by glucose transporters in capillaries and brain cells. In brain, the facilitative diffusion glucose transporters GLUT1-6 and GLUT8, and the Na+-d-glucose cotransporters SGLT1 are expressed. The glucose transporters mediate uptake of d-glucose across the blood-brain barrier and delivery of d-glucose to astrocytes and neurons. They are critically involved in regulatory adaptations to varying energy demands in response to differing neuronal activities and glucose supply. In this review, a comprehensive overview about verified and proposed roles of cerebral glucose transporters during health and diseases is presented. Our current knowledge is mainly based on experiments performed in rodents. First, the functional properties of human glucose transporters expressed in brain and their cerebral locations are described. Thereafter, proposed physiological functions of GLUT1, GLUT2, GLUT3, GLUT4, and SGLT1 for energy supply to neurons, glucose sensing, central regulation of glucohomeostasis, and feeding behavior are compiled, and their roles in learning and memory formation are discussed. In addition, diseases are described in which functional changes of cerebral glucose transporters are relevant. These are GLUT1 deficiency syndrome (GLUT1-SD), diabetes mellitus, Alzheimer’s disease (AD), stroke, and traumatic brain injury (TBI). GLUT1-SD is caused by defect mutations in GLUT1. Diabetes and AD are associated with changed expression of glucose transporters in brain, and transporter-related energy deficiency of neurons may contribute to pathogenesis of AD. Stroke and TBI are associated with changes of glucose transporter expression that influence clinical outcome.
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Frazier HN, Ghoweri AO, Anderson KL, Lin RL, Popa GJ, Mendenhall MD, Reagan LP, Craven RJ, Thibault O. Elevating Insulin Signaling Using a Constitutively Active Insulin Receptor Increases Glucose Metabolism and Expression of GLUT3 in Hippocampal Neurons. Front Neurosci 2020; 14:668. [PMID: 32733189 PMCID: PMC7358706 DOI: 10.3389/fnins.2020.00668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/02/2020] [Indexed: 12/31/2022] Open
Abstract
Insulin signaling is an integral component of healthy brain function, with evidence of positive insulin-mediated alterations in synaptic integrity, cerebral blood flow, inflammation, and memory. However, the specific pathways targeted by this peptide remain unclear. Previously, our lab used a molecular approach to characterize the impact of insulin signaling on voltage-gated calcium channels and has also shown that acute insulin administration reduces calcium-induced calcium release in hippocampal neurons. Here, we explore the relationship between insulin receptor signaling and glucose metabolism using similar methods. Mixed, primary hippocampal cultures were infected with either a control lentivirus or one containing a constitutively active human insulin receptor (IRβ). 2-NBDG imaging was used to obtain indirect measures of glucose uptake and utilization. Other outcome measures include Western immunoblots of GLUT3 and GLUT4 on total membrane and cytosolic subcellular fractions. Glucose imaging data indicate that neurons expressing IRβ show significant elevations in uptake and rates of utilization compared to controls. As expected, astrocytes did not respond to the IRβ treatment. Quantification of Western immunoblots show that IRβ is associated with significant elevations in GLUT3 expression, particularly in the total membrane subcellular fraction, but did not alter GLUT4 expression in either fraction. Our work suggests that insulin plays a significant role in mediating neuronal glucose metabolism, potentially through an upregulation in the expression of GLUT3. This provides further evidence for a potential therapeutic mechanism underlying the beneficial impact of intranasal insulin in the clinic.
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Affiliation(s)
- Hilaree N Frazier
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Adam O Ghoweri
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Katie L Anderson
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Ruei-Lung Lin
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Gabriel J Popa
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Michael D Mendenhall
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Lawrence P Reagan
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Rolf J Craven
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Olivier Thibault
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States
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Takeuchi Y, Okinaka Y, Ogawa Y, Kikuchi-Taura A, Kataoka Y, Gul S, Claussen C, Boltze J, Taguchi A. Intravenous Bone Marrow Mononuclear Cells Transplantation in Aged Mice Increases Transcription of Glucose Transporter 1 and Na +/K +-ATPase at Hippocampus Followed by Restored Neurological Functions. Front Aging Neurosci 2020; 12:170. [PMID: 32595487 PMCID: PMC7301702 DOI: 10.3389/fnagi.2020.00170] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 05/15/2020] [Indexed: 01/03/2023] Open
Abstract
We recently reported that intravenous bone marrow mononuclear cell (BM-MNC) transplantation in stroke improves neurological function through improvement of cerebral metabolism. Cerebral metabolism is known to diminish with aging, and the reduction of metabolism is one of the presumed causes of neurological decline in the elderly. We report herein that transcription of glucose transporters, monocarboxylate transporters, and Na+/K+-ATPase is downregulated in the hippocampus of aged mice with impaired neurological functions. Intravenous BM-MNC transplantation in aged mice stimulated the transcription of glucose transporter 1 and Na+/K+-ATPase α1 followed by restoration of neurological function. As glucose transporters and Na+/K+-ATPases are closely related to cerebral metabolism and neurological function, our data indicate that BM-MNC transplantation in aged mice has the potential to restore neurological function by activating transcription of glucose transporter and Na+/K+-ATPase. Furthermore, our data indicate that changes in transcription of glucose transporter and Na+/K+-ATPase could be surrogate biomarkers for age-related neurological impairment as well as quantifying the efficacy of therapies.
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Affiliation(s)
- Yukiko Takeuchi
- Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan
| | - Yuka Okinaka
- Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan
| | - Yuko Ogawa
- Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan
| | - Akie Kikuchi-Taura
- Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan
| | - Yosky Kataoka
- Multi-Modal Microstructure Analysis Unit, RIKEN-JEOL Collaboration Center, RIKEN, Hyogo, Japan.,Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, RIKEN, Hyogo, Japan
| | - Sheraz Gul
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME - ScreeningPort, Hamburg, Germany.,Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hamburg Site, Hamburg, Germany
| | - Carsten Claussen
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME - ScreeningPort, Hamburg, Germany.,Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hamburg Site, Hamburg, Germany
| | - Johannes Boltze
- Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan.,School of Life Sciences, University of Warwick, Coventry, United Kingdom
| | - Akihiko Taguchi
- Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan
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Long XS, Liao ST, Wen P, Zou YX, Liu F, Shen WZ, Hu TG. Superior hypoglycemic activity of mulberry lacking monosaccharides is accompanied by better activation of the PI3K/Akt and AMPK signaling pathways. Food Funct 2020; 11:4249-4258. [PMID: 32356550 DOI: 10.1039/d0fo00427h] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Mulberry has been used as a functional food to treat type 2 diabetes mellitus (T2DM). However, it contains relatively high levels of fructose and glucose, which are not suitable for excess consumption by diabetic patients. In this study we used microbial fermentation to remove fructose and glucose from mulberry fruit, and then determined the effects on glycemia, the phosphatidylinositol 3-hydroxykinase/Akt (PI3K/Akt) and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways and their downstream effectors in T2DM mice. After 5 weeks of administration, fermented mulberry (FM) significantly reduced fasting blood glucose, and also improved insulin sensitivity and glucose tolerance, more effectively than unfermented mulberry (MP). Moreover, compared with MP, FM had a more marked effect on the protein expression of intermediates in the PI3K/Akt and AMPK signaling pathways and their effectors: insulin receptor, phosphorylated Akt (Ser 308), phosphorylated glycogen synthase kinase-3β (Ser 9), glycogen synthetase, phosphorylated forkhead transcription factor 1 (Ser 256), pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-bisphosphatase, glucose-6-phosphatase, lipoprotein lipase, and phosphorylated AMPK (Thr 172), glucose transporter 4 and pyruvate kinase. These findings indicate that mulberry fruit modified to remove fructose and glucose may be more promising than whole mulberry as a treatment for diabetes.
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Affiliation(s)
- Xiao-Shan Long
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, No. 133 Yiheng St., Dongguanzhuang Rd, Tianhe District, Guangzhou 510610, P.R. China.
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Yaribeygi H, Sathyapalan T, Atkin SL, Sahebkar A. Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8609213. [PMID: 32215179 PMCID: PMC7085395 DOI: 10.1155/2020/8609213] [Citation(s) in RCA: 357] [Impact Index Per Article: 71.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 12/07/2019] [Accepted: 02/04/2020] [Indexed: 12/15/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is the most prevalent metabolic disorder characterized by chronic hyperglycemia and an inadequate response to circulatory insulin by peripheral tissues resulting in insulin resistance. Insulin resistance has a complex pathophysiology, and it is contributed to by multiple factors including oxidative stress. Oxidative stress refers to an imbalance between free radical production and the antioxidant system leading to a reduction of peripheral insulin sensitivity and contributing to the development of T2DM via several molecular mechanisms. In this review, we present the molecular mechanisms by which the oxidative milieu contributes to the pathophysiology of insulin resistance and diabetes mellitus.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Thozhukat Sathyapalan
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull HU3 2JZ, UK
| | | | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Hirschberg PR, Sarkar P, Teegala SB, Routh VH. Ventromedial hypothalamus glucose-inhibited neurones: A role in glucose and energy homeostasis? J Neuroendocrinol 2020; 32:e12773. [PMID: 31329314 PMCID: PMC7074896 DOI: 10.1111/jne.12773] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/18/2019] [Accepted: 07/14/2019] [Indexed: 12/20/2022]
Abstract
The ventromedial hypothalamus (VMH) plays a complex role in glucose and energy homeostasis. The VMH is necessary for the counter-regulatory response to hypoglycaemia (CRR) that increases hepatic gluconeogenesis to restore euglycaemia. On the other hand, the VMH also restrains hepatic glucose production during euglycaemia and stimulates peripheral glucose uptake. The VMH is also important for the ability of oestrogen to increase energy expenditure. This latter function is mediated by VMH modulation of the lateral/perifornical hypothalamic area (lateral/perifornical hypothalamus) orexin neurones. Activation of VMH AMP-activated protein kinase (AMPK) is necessary for the CRR. By contrast, VMH AMPK inhibition favours decreased basal glucose levels and is required for oestrogen to increase energy expenditure. Specialised VMH glucose-sensing neurones confer the ability to sense and respond to changes in blood glucose levels. Glucose-excited (GE) neurones increase and glucose-inhibited (GI) neurones decrease their activity as glucose levels rise. VMH GI neurones, in particular, appear to be important in the CRR, although a role for GE neurones cannot be discounted. AMPK mediates glucose sensing in VMH GI neurones suggesting that, although activation of these neurones is important for the CRR, it is necessary to silence them to lower basal glucose levels and enable oestrogen to increase energy expenditure. In support of this, we found that oestrogen reduces activation of VMH GI neurones in low glucose by inhibiting AMPK. In this review, we present the evidence underlying the role of the VMH in glucose and energy homeostasis. We then discuss the role of VMH glucose-sensing neurones in mediating these effects, with a strong emphasis on oestrogenic regulation of glucose sensing and how this may affect glucose and energy homeostasis.
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Affiliation(s)
- Pamela R Hirschberg
- Department of Pharmacology, Physiology and Neurosciences, Rutgers New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Pallabi Sarkar
- Department of Pharmacology, Physiology and Neurosciences, Rutgers New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Suraj B Teegala
- Department of Pharmacology, Physiology and Neurosciences, Rutgers New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Vanessa H Routh
- Department of Pharmacology, Physiology and Neurosciences, Rutgers New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
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Farhadi A, Vosough M, Zhang JS, Tahamtani Y, Shahpasand K. A Possible Neurodegeneration Mechanism Triggered by Diabetes. Trends Endocrinol Metab 2019; 30:692-700. [PMID: 31399291 DOI: 10.1016/j.tem.2019.07.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/08/2019] [Accepted: 07/12/2019] [Indexed: 01/14/2023]
Abstract
Several conditions result in neurodegeneration; among which diabetes mellitus (DM) is of crucial importance. Tau (τ) malfunction is a major pathological process participating in neurodegeneration. Despite extensive considerations, the actual causative link between DM and τ abnormalities remains uncertain thus far. Phosphorylated (p)-τ at Thr-Pro motifs can exist in the two distinct cis and trans conformations. cis is neurotoxic, and is accumulated upon various stress conditions, such as nutrition depletion. We assume that pathogenic cis p-τ is the central mediator of neurodegeneration in DM, and propose why different brain areas give various responses to stress conditions. We herein juxtapose recent approaches in diabetic neurodegeneration and propose a therapeutic target to stop neuronal loss during DM.
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Affiliation(s)
- Aisan Farhadi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IR 19395-4644, Iran; Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Biomedicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Jin-San Zhang
- International Collaborative Center on Growth Factor Research, and School of Pharmaceutical Sciences, Wenzhou Medical University; Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang 325035, China; Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Yaser Tahamtani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IR 19395-4644, Iran.
| | - Koorosh Shahpasand
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IR 19395-4644, Iran.
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