|
1
|
Jo D, Choi SY, Ahn SY, Song J. IGF1 enhances memory function in obese mice and stabilizes the neural structure under insulin resistance via AKT-GSK3β-BDNF signaling. Biomed Pharmacother 2025; 183:117846. [PMID: 39805192 DOI: 10.1016/j.biopha.2025.117846] [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: 09/25/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/16/2025] Open
Abstract
Obesity is a prevalent metabolic disorder linked to insulin resistance, hyperglycemia, increased adiposity, chronic inflammation, and cognitive dysfunction. Recent research has focused on developing therapeutic strategies to mitigate cognitive impairment associated with obesity. Insulin growth factor-1 (IGF1) deficiency is linked to insulin resistance, glucose intolerance, and the progression of obesity-related central nervous system (CNS) disorders. In this study, we investigated the neuroprotective effects of IGF1 in two obesity models: diet-induced obesity (high-fat diet mice) and genetic obesity (ob/ob mice which is genetically deficient in leptin), and in vitro Neuro2A neuronal cells and primary cortical neurons under insulin resistance conditions. We performed RNA sequencing analysis using the cortex of high-fat diet mice injected with IGF1. Also, we detected cytokine levels in blood of high-fat diet mice injected with IGF1. In addition, we conducted the Barnes maze test as a spatial memory function test and open field test as an anxiety behavior test in ob/ob mice. We measured the levels of proteins and mRNAs related to insulin signaling, including synaptic density proteins in brain cortex of ob/ob mice. Our results showed that IGF1 injection enhanced spatial memory function and synaptic plasticity in obese mice. Furthermore, in vitro data demonstrated that IGF1 treated neurons revealed enhanced neural complexity and improved neurite outgrowth under insulin resistance condition through the AKT-GSK3β-BDNF pathway related to antidepressant, cognitive function and anti-apoptotic mechanisms. Therefore, our results provided that IGF1 have potential to alleviate cognitive impairment by promoting synaptic plasticity and neural complexity in the obese brain.
Collapse
Affiliation(s)
- Danbi Jo
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Republic of Korea.
| | - Seo Yoon Choi
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Republic of Korea; Biomedical Science Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Republic of Korea.
| | - Seo Yeon Ahn
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Republic of Korea; Biomedical Science Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Republic of Korea.
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Republic of Korea; Biomedical Science Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Republic of Korea.
| |
Collapse
|
|
2
|
Jones MA, Jadeja RN, Flandrin O, Abdelrahman AA, Thounojam MC, Thomas S, Dai C, Xiao H, Chen JK, Smith SB, Bartoli M, Martin PM, Powell FL. Autonomous regulation of retinal insulin biosynthesis in diabetes. Neuropeptides 2022; 94:102258. [PMID: 35660758 PMCID: PMC10440820 DOI: 10.1016/j.npep.2022.102258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 05/08/2022] [Accepted: 05/15/2022] [Indexed: 10/18/2022]
Abstract
Diabetic retinopathy (DR) is a neurodegenerative disease that results as a complication of dysregulated glucose metabolism, or diabetes. The signaling of insulin is lost or dampened in diabetes, but this hormone has also been shown to be an important neurotrophic factor which supports neurons of the brain. The role of local insulin synthesis and secretion in the retina, however, is unclear. We have investigated whether changes in local insulin synthesis occur in the diabetic retina and in response to stressors known to initiate retinal neurodegenerative processes. The expression of insulin and its cleavage product, c-peptide, were examined in retinas of a Type I diabetes animal model and human postmortem donors with DR. We detected mRNAs for insulin I (Ins1), insulin II (Ins2) and human insulin (Ins) by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. Using an ex-vivo system, isolated neuroretinas and retinal pigmented epithelium (RPE) layers were exposed to glycemic, oxidative and inflammatory environments to measure insulin gene transcripts produced de novo in the retina under disease-relevant conditions. The expression of insulin in the retina was altered with the progression of diabetes in STZ mice and donors with DR. Transcription factors for insulin, were simultaneously expressed in a pattern matching insulin genes. Furthermore, de novo insulin mRNA in isolated retinas was induced by acute stress. RPE explants displayed the most pronounced changes in Ins1 and Ins2. This data reveals that the retina, like the brain, is an organ capable of producing local insulin and this synthesis is altered in diabetes.
Collapse
Affiliation(s)
- Malita A Jones
- Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Ravirajsinh N Jadeja
- Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Orneika Flandrin
- UC Berkeley School of Optometry, University of California, Berkeley, CA, USA
| | - Ammar A Abdelrahman
- Department of Pharmacology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Menaka C Thounojam
- Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Shakera Thomas
- Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Caihong Dai
- Department of Cell Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Haiyan Xiao
- Department of Cell Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Jian-Kang Chen
- Department of Cell Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Sylvia B Smith
- Department of Cell Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Manuela Bartoli
- Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Pamela M Martin
- Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; Department of Cell Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Folami L Powell
- Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.
| |
Collapse
|
|
3
|
Kovacs P, Hajnal A. Short-term high-fat diet consumption increases body weight and body adiposity and alters brain stem taste information processing in rats. Chem Senses 2022; 47:6673811. [PMID: 35997757 DOI: 10.1093/chemse/bjac020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Diet-induced obesity is known to develop whether exposed to a high-energy diet (HED) or a high-fat diet (HFD). However, it is still not clear whether the elevated energy content or the macronutrient imbalance is the key factor in early disease progression. Therefore, this study compared the short-term effects of 2 widely used rodent obesogenic diets, an HFD with 60 kcal% fat content and a carbohydrate-based HED, on the body weight, body fat content, glucose tolerance, and neuronal taste responses in rats. We found that only HFD induced an early significant body weight increase compared with the control normal diet (ND) group, starting on week 4, and resulting in a significantly elevated body adiposity compared with both the ND and HED groups. Oral glucose tolerance test revealed no difference across groups. Subsequently, we also found that HFD resulted in a significant body weight gain even under energy-restricted (isocaloric to ND) conditions. In vivo electrophysiological recordings revealed that only the ad libitum HFD and not the isocaloric-HFD altered the brain stem gustatory neural responses to oral taste stimulation. In conclusion, this study showed that increased fat intake might result in significant body weight gain even under isocaloric and metabolically healthy conditions and demonstrated changes in central taste processing in an early stage of dietary obesity. A better understanding of these initial physiological changes may offer new drug targets for preventing obesity.
Collapse
Affiliation(s)
- Peter Kovacs
- Department of Neural and Behavioral Sciences, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA
| | - Andras Hajnal
- Department of Neural and Behavioral Sciences, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA
| |
Collapse
|
|
4
|
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: 275] [Impact Index Per Article: 55.0] [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.
Collapse
|
|
5
|
Gralle M, Labrecque S, Salesse C, De Koninck P. Spatial dynamics of the insulin receptor in living neurons. J Neurochem 2020; 156:88-105. [PMID: 31886886 DOI: 10.1111/jnc.14950] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/11/2019] [Accepted: 12/27/2019] [Indexed: 12/23/2022]
Abstract
Insulin signaling through the insulin receptor has long been studied in classic target organs, such as adipose tissue and skeletal muscle, where one of its effects is to increase glucose uptake. Insulin and insulin receptor are present in many areas of the brain, but the functions of brain insulin signaling outside feeding circuits are not well defined. It has been proposed that hippocampal insulin signaling is important for memory, that brain insulin signaling is deficient in Alzheimer's disease, and that intranasal insulin treatment improves cognition, but the mechanisms remain unclear and do not seem to involve increased glucose uptake by neurons. The molecular behavior of the insulin receptor itself is not well known in living neurons; therefore, we investigated the spatial dynamics of the insulin receptor on somatodendritic membranes of live rat hippocampal neurons in culture. Using single-molecule tracking of quantum dot-tagged insulin receptors and single-particle tracking photoactivation localization microscopy, we show that the insulin receptor is distributed over both dendritic shafts and spines. Using colocalization with synaptic markers, we also show that in contrast to the glutamate receptor subunit glutamate receptor subunit A1, the dynamics of the insulin receptor are not affected by association with excitatory synapses; however, the insulin receptor is immobilized by components of inhibitory synapses. The mobility of the insulin receptor is reduced both by low concentrations of the pro-inflammatory cytokine tumor necrosis factor α and by cholesterol depletion, suggesting an association with sphingolipid-rich membrane domains. On the other hand, the insulin receptor dynamics in hippocampal neurons are not affected by increased excitatory signaling. Finally, using real-time single-event quantification, we find evidence of strong insulin receptor exocytosis on dendritic shafts. Our results suggest an association of the neuronal insulin receptor with specific elements of the dendritic shaft, rather than excitatory synapses.
Collapse
Affiliation(s)
- Matthias Gralle
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,CERVO Brain Research Center, Québec, QC, Canada
| | | | | | - Paul De Koninck
- CERVO Brain Research Center, Québec, QC, Canada.,Département de biochimie, microbiologie et bio-informatique, Université Laval, Québec, QC, Canada
| |
Collapse
|
|
6
|
Simon KU, Neto EW, Tramontin NDS, Canteiro PB, Pereira BDC, Zaccaron RP, Silveira PCL, Muller AP. Intranasal insulin treatment modulates the neurotropic, inflammatory, and oxidant mechanisms in the cortex and hippocampus in a low-grade inflammation model. Peptides 2020; 123:170175. [PMID: 31639435 DOI: 10.1016/j.peptides.2019.170175] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 10/10/2019] [Accepted: 10/11/2019] [Indexed: 01/05/2023]
Abstract
The inflammatory process plays a critical role in the development of neurodegenerative diseases. Insulin is used in preclinical and clinical studies of neurological disorders. Its intranasal (IN) administration directly in the brain allows for its peripheral metabolic effects to be avoided. Swiss male mice were injected with lipopolysaccharide (LPS) (0.1 mg/kg) to induce low-grade inflammation. IN insulin treatment was initiated 4 h later at a dose of 1.7 IU once daily for 5 days. LPS induced cognitive deficits, which the IN insulin treatment reversed. LPS significantly decreased, whereas IN insulin significantly increased the levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor-β in the cortex. In the hippocampus, IN insulin significantly decreased the BDNF level. LPS significantly increased the interleukin (IL)-6 levels in the cortex, while IN Insulin significantly decreased its levels in the hippocampus. The tumor necrosis factor-α levels were significantly decreased by IN insulin both in the cortex and hippocampus. Moreover, IN insulin significantly increased the IL-10 levels in the cortex. The levels of oxidative and nitrosative stress were significantly higher in the LPS-treated mice; however, IN insulin had a modulatory effect on both. LPS significantly increased the antioxidant enzyme activity both in the cortex and hippocampus, whereas IN insulin significantly increased the activity of both superoxide dismutase and catalase in the hippocampus and that of catalase in the cortex. The hydrogen peroxide levels revealed that LPS significantly affected the electron transport chain. Therefore, IN insulin could be useful in the treatment of neuroinflammatory diseases.
Collapse
Affiliation(s)
- Kellen Ugioni Simon
- Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), 88806-00 Criciúma, SC, Brazil
| | - Elias Wiggers Neto
- Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), 88806-00 Criciúma, SC, Brazil
| | - Natalia Dos Santos Tramontin
- Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), 88806-00 Criciúma, SC, Brazil
| | - Paula Bortoluzzi Canteiro
- Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), 88806-00 Criciúma, SC, Brazil
| | - Barbara da Costa Pereira
- Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), 88806-00 Criciúma, SC, Brazil
| | - Rubya Pereira Zaccaron
- Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), 88806-00 Criciúma, SC, Brazil
| | - Paulo Cesar Lock Silveira
- Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), 88806-00 Criciúma, SC, Brazil
| | - Alexandre Pastoris Muller
- Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), 88806-00 Criciúma, SC, Brazil; Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Catarina (UFSC), 88040-900 Florianópolis, SC, Brazil.
| |
Collapse
|
|
7
|
Insulin attenuates epileptiform discharge-induced oxidative stress by increasing zinc-α2-glycoprotein in primary cultured cortical neurons. Neuroreport 2019; 30:580-585. [DOI: 10.1097/wnr.0000000000001250] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
|
8
|
Hamer JA, Testani D, Mansur RB, Lee Y, Subramaniapillai M, McIntyre RS. Brain insulin resistance: A treatment target for cognitive impairment and anhedonia in depression. Exp Neurol 2019; 315:1-8. [DOI: 10.1016/j.expneurol.2019.01.016] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 01/22/2019] [Accepted: 01/24/2019] [Indexed: 12/12/2022]
|
|
9
|
Expression and Function of Zinc-α2-Glycoprotein. Neurosci Bull 2019; 35:540-550. [PMID: 30610461 DOI: 10.1007/s12264-018-00332-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 09/26/2018] [Indexed: 12/13/2022] Open
Abstract
Zinc-α2-glycoprotein (ZAG), encoded by the AZGP1 gene, is a major histocompatibility complex I molecule and a lipid-mobilizing factor. ZAG has been demonstrated to promote lipid metabolism and glucose utilization, and to regulate insulin sensitivity. Apart from adipose tissue, skeletal muscle, liver, and kidney, ZAG also occurs in brain tissue, but its distribution in brain is debatable. Only a few studies have investigated ZAG in the brain. It has been found in the brains of patients with Krabbe disease and epilepsy, and in the cerebrospinal fluid of patients with Alzheimer disease, frontotemporal lobe dementia, and amyotrophic lateral sclerosis. Both ZAG protein and AZGP1 mRNA are decreased in epilepsy patients and animal models, while overexpression of ZAG suppresses seizure and epileptic discharges in animal models of epilepsy, but knowledge of the specific mechanism of ZAG in epilepsy is limited. In this review, we summarize the known roles and molecular mechanisms of ZAG in lipid metabolism and glucose metabolism, and in the regulation of insulin sensitivity, and discuss the possible mechanisms by which it suppresses epilepsy.
Collapse
|
|
10
|
Sripetchwandee J, Chattipakorn N, Chattipakorn SC. Links Between Obesity-Induced Brain Insulin Resistance, Brain Mitochondrial Dysfunction, and Dementia. Front Endocrinol (Lausanne) 2018; 9:496. [PMID: 30233495 PMCID: PMC6127253 DOI: 10.3389/fendo.2018.00496] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 08/07/2018] [Indexed: 12/16/2022] Open
Abstract
It is widely recognized that obesity and associated metabolic changes are considered a risk factor to age-associated cognitive decline. Inflammation and increased oxidative stress in peripheral areas, following obesity, are patently the major contributory factors to the degree of the severity of brain insulin resistance as well as the progression of cognitive impairment in the obese condition. Numerous studies have demonstrated that the alterations in brain mitochondria, including both functional and morphological changes, occurred following obesity. Several studies also suggested that brain mitochondrial dysfunction may be one of underlying mechanism contributing to brain insulin resistance and cognitive impairment in the obese condition. Thus, this review aimed to comprehensively summarize and discuss the current evidence from various in vitro, in vivo, and clinical studies that are associated with obesity, brain insulin resistance, brain mitochondrial dysfunction, and cognition. Contradictory findings and the mechanistic insights about the roles of obesity, brain insulin resistance, and brain mitochondrial dysfunction on cognition are also presented and discussed. In addition, the potential therapies for obese-insulin resistance are reported as the therapeutic strategies which exert the neuroprotective effects in the obese-insulin resistant condition.
Collapse
Affiliation(s)
- Jirapas Sripetchwandee
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nipon Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Siriporn C. Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
- *Correspondence: Siriporn C. Chattipakorn ;
| |
Collapse
|
|
11
|
Chavushyan VA, Simonyan KV, Simonyan RM, Isoyan AS, Simonyan GM, Babakhanyan MA, Hovhannisyian LE, Nahapetyan KH, Avetisyan LG, Simonyan MA. Effects of stevia on synaptic plasticity and NADPH oxidase level of CNS in conditions of metabolic disorders caused by fructose. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:540. [PMID: 29258552 PMCID: PMC5735878 DOI: 10.1186/s12906-017-2049-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 12/06/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Excess dietary fructose intake associated with metabolic syndrome and insulin resistance and increased risk of developing type 2 diabetes. Previous animal studies have reported that diabetic animals have significantly impaired behavioural and cognitive functions, pathological synaptic function and impaired expression of glutamate receptors. Correction of the antioxidant status of laboratory rodents largely prevents the development of fructose-induced plurimetabolic changes in the nervous system. We suggest a novel concept of efficiency of Stevia leaves for treatment of central diabetic neuropathy. METHODS By in vivo extracellular studies induced spike activity of hippocampal neurons during high frequency stimulation of entorhinal cortex, as well as neurons of basolateral amygdala to high-frequency stimulation of the hippocampus effects of Stevia rebaudiana Bertoni plant evaluated in synaptic activity in the brain of fructose-enriched diet rats. In the conditions of metabolic disorders caused by fructose, antioxidant activity of Stevia rebaudiana was assessed by measuring the NOX activity of the hippocampus, amygdala and spinal cord. RESULTS In this study, the characteristic features of the metabolic effects of dietary fructose on synaptic plasticity in hippocampal neurons and basolateral amygdala and the state of the NADPH oxidase (NOX) oxidative system of these brain formations are revealed, as well as the prospects for development of multitarget and polyfunctional phytopreparations (with adaptogenic, antioxidant, antidiabetic, nootropic activity) from native raw material of Stevia rebaudiana. Stevia modulates degree of expressiveness of potentiation/depression (approaches but fails to achieve the norm) by shifting the percentage balance in favor of depressor type of responses during high-frequency stimulation, indicating its adaptogenic role in plasticity of neural networks. Under the action of fructose an increase (3-5 times) in specific quantity of total fraction of NOX isoforms isolated from the central nervous system tissue (amygdala, hippocampus, spinal cord) was revealed. Stevia exhibits an antistress, membrane-stabilizing role reducing the level of total fractions of NOX isoforms from central nervous system tissues and regulates NADPH-dependent O2- -producing activity. CONCLUSION Generally, in condition of metabolic disorders caused by intensive consumption of dietary fructose Stevia leaves contributes to the control of neuronal synaptic plasticity possibly influencing the conjugated NOX-specific targets.
Collapse
Affiliation(s)
- V A Chavushyan
- Orbeli Institute of Physiology NAS RA, 22 Orbeli Bros Street, 0028, Yerevan, Armenia
| | - K V Simonyan
- Orbeli Institute of Physiology NAS RA, 22 Orbeli Bros Street, 0028, Yerevan, Armenia.
| | - R M Simonyan
- H. Buniatian Institute of Biochemistry NAS RA, 5/1 P.Sevag str, 0014, Yerevan, Armenia
| | - A S Isoyan
- Orbeli Institute of Physiology NAS RA, 22 Orbeli Bros Street, 0028, Yerevan, Armenia
| | - G M Simonyan
- H. Buniatian Institute of Biochemistry NAS RA, 5/1 P.Sevag str, 0014, Yerevan, Armenia
| | - M A Babakhanyan
- Scientific Centre of Artsakh, 8 Tigran Mets str, Stepanakert, Nagorno Karabakh, Armenia
| | - L E Hovhannisyian
- Scientific Centre of Artsakh, 8 Tigran Mets str, Stepanakert, Nagorno Karabakh, Armenia
| | - Kh H Nahapetyan
- Orbeli Institute of Physiology NAS RA, 22 Orbeli Bros Street, 0028, Yerevan, Armenia
| | - L G Avetisyan
- Orbeli Institute of Physiology NAS RA, 22 Orbeli Bros Street, 0028, Yerevan, Armenia
| | - M A Simonyan
- H. Buniatian Institute of Biochemistry NAS RA, 5/1 P.Sevag str, 0014, Yerevan, Armenia
| |
Collapse
|
|
12
|
Sousa RALDE, Torres YS, Figueiredo CP, Passos GF, Clarke JR. Consequences of gestational diabetes to the brain and behavior of the offspring. AN ACAD BRAS CIENC 2017; 90:2279-2291. [PMID: 28813108 DOI: 10.1590/0001-3765201720170264] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 05/30/2017] [Indexed: 01/11/2023] Open
Abstract
Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during the second/third trimesters of pregnancy in previously normoglycemic women. It is currently estimated that 10% of all pregnancies in the United States show this condition. For many years, the transient nature of GD has led researchers and physicians to assume that long-term consequences were absent. However, GD diagnosis leads to a six-fold increase in the risk of developing type 2 diabetes (T2D) in women and incidence of obesity and T2D is also higher among their infants. Recent and concerning evidences point to detrimental effects of GD on the behavior and cognition of the offspring, which often persist until adolescence or adulthood. Considering that the perinatal period is critical for determination of adult behavior, it is expected that the intra-uterine exposure to hyperglycemia, hyperinsulinemia and pro-inflammatory mediators, hallmark features of GD, might affect brain development. Here, we review early clinical and experimental evidence linking GD to consequences on the behavior of the offspring, focusing on memory and mood disorders. We also discuss initial evidence suggesting that downregulation of insulin signaling cascades are seen in the brains of GD offspring and could contribute to the consequences on their behavior.
Collapse
Affiliation(s)
- Ricardo A L DE Sousa
- School of Pharmacy, Carlos Chagas Filho Street, 373, Building A, Underground, Room 024, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Yasmin S Torres
- School of Pharmacy, Carlos Chagas Filho Street, 373, Building A, Underground, Room 024, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Claudia P Figueiredo
- School of Pharmacy, Carlos Chagas Filho Street, 373, Building A, Underground, Room 024, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Giselle F Passos
- School of Pharmacy, Carlos Chagas Filho Street, 373, Building A, Underground, Room 024, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Julia R Clarke
- School of Pharmacy, Carlos Chagas Filho Street, 373, Building A, Underground, Room 024, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil
| |
Collapse
|
|
13
|
Bahramian A, Rastegar K, Namavar MR, Moosavi M. Insulin potentiates the therapeutic effect of memantine against central STZ-induced spatial learning and memory deficit. Behav Brain Res 2016; 311:247-254. [DOI: 10.1016/j.bbr.2016.05.046] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 05/17/2016] [Accepted: 05/21/2016] [Indexed: 10/21/2022]
|
|
14
|
Insulin-Independent GABAA Receptor-Mediated Response in the Barrel Cortex of Mice with Impaired Met Activity. J Neurosci 2016; 36:3691-7. [PMID: 27030755 DOI: 10.1523/jneurosci.0006-16.2016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2016] [Accepted: 02/22/2016] [Indexed: 11/21/2022] Open
Abstract
UNLABELLED Autism spectrum disorder (ASD) is a neurodevelopmental disorder caused by genetic variants, susceptibility alleles, and environmental perturbations. The autism associated geneMETtyrosine kinase has been implicated in many behavioral domains and endophenotypes of autism, including abnormal neural signaling in human sensory cortex. We investigated somatosensory thalamocortical synaptic communication in mice deficient in Met activity in cortical excitatory neurons to gain insights into aberrant somatosensation characteristic of ASD. The ratio of excitation to inhibition is dramatically increased due to decreased postsynaptic GABAAreceptor-mediated inhibition in the trigeminal thalamocortical pathway of mice lacking active Met in the cerebral cortex. Furthermore, in contrast to wild-type mice, insulin failed to increase GABAAreceptor-mediated response in the barrel cortex of mice with compromised Met signaling. Thus, lacking insulin effects may be a risk factor in ASD pathogenesis. SIGNIFICANCE STATEMENT A proposed common cause of neurodevelopmental disorders is an imbalance in excitatory neural transmission, provided by the glutamatergic neurons, and the inhibitory signals from the GABAergic interneurons. Many genes associated with autism spectrum disorders impair synaptic transmission in the expected cell type. Previously, inactivation of the autism-associated Met tyrosine kinase receptor in GABAergic interneurons led to decreased inhibition. In thus report, decreased Met signaling in glutamatergic neurons had no effect on excitation, but decimated inhibition. Further experiments indicate that loss of Met activity downregulates GABAAreceptors on glutamatergic neurons in an insulin independent manner. These data provide a new mechanism for the loss of inhibition and subsequent abnormal excitation/inhibition balance and potential molecular candidates for treatment or prevention.
Collapse
|
|
15
|
Simonyan KV, Avetisyan LG, Chavushyan VA. Goji fruit (Lycium barbarum) protects sciatic nerve function against crush injury in a model of diabetic stress. PATHOPHYSIOLOGY 2016; 23:169-79. [PMID: 27424529 DOI: 10.1016/j.pathophys.2016.05.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 05/25/2016] [Accepted: 05/25/2016] [Indexed: 01/10/2023] Open
Abstract
Excess fructose consumption causes changes in functioning of the central and peripheral nervous systems, which increase the vulnerability of peripheral nerves to traumatic injury. The aim of this study was to evaluate the electrophysiological parameters of responses of motoneurons of the spinal cord at high-frequency stimulation of the distal part of the injured sciatic nerve in a model of diabetic stress under action of Lycium barbarum (LB). Male albino rats were given with drinking water with 50% concentration of dietary fructose for 6 weeks. Starting on the 7th week a crush injury of the left sciatic nerve was carried out. Some of the animals received fructose post-injury for 3 weeks and some of the animals received fructose+dry LB fruits for 3 weeks. In the fructose+crush+LВ group a relatively proportional division of tetanic and posttetanic potentiation and depression in responses of ipsilateral and contralateral motoneurons was observed, which would suggest the modulatory role of LB in short-term synaptic plasticity formation. Generally, LB fruit is able to modulate central nervous system reorganization, amplifying positive adaptive changes that improve functional recovery and promote selective target reinnervation in high fructose-diet rats with sciatic nerve crush-injury.
Collapse
Affiliation(s)
- K V Simonyan
- Orbeli Institute of Physiology NAS RA, Laboratory of Neuroendocrine Relationships, 22 Orbeli Bros Street, 0028 Yerevam, Armenia.
| | - L G Avetisyan
- Orbeli Institute of Physiology NAS RA, Laboratory of Neuroendocrine Relationships, 22 Orbeli Bros Street, 0028 Yerevam, Armenia
| | - V A Chavushyan
- Orbeli Institute of Physiology NAS RA, Laboratory of Neuroendocrine Relationships, 22 Orbeli Bros Street, 0028 Yerevam, Armenia
| |
Collapse
|
|
16
|
Lin KW, Wroolie TE, Robakis T, Rasgon NL. Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response. Psychiatry Res 2015; 230:846-52. [PMID: 26602230 PMCID: PMC4978223 DOI: 10.1016/j.psychres.2015.10.013] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Revised: 09/23/2015] [Accepted: 10/09/2015] [Indexed: 10/22/2022]
Abstract
Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented insulin resistance or those who are resistant to standard psychopharmacological approaches. This study aimed to assess the effects on depressive symptoms with adjuvant treatment with the PPARγ-agonist pioglitazone. Patients (N=37) with non-psychotic, non-remitting depression receiving standard psychiatric regimens for depression were randomized across an insulin sensitivity spectrum in a 12-week double blind, randomized controlled trial of pioglitazone or placebo. Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance. An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients. Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline. A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction.
Collapse
Affiliation(s)
| | | | | | - Natalie L. Rasgon
- Corresponding author: Natalie Rasgon M.D Ph.D., Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305-5723, Phone: (650) 724-6689, Fax: (650) 724-3144,
| |
Collapse
|
|
17
|
Sandhir R, Gupta S. Molecular and biochemical trajectories from diabetes to Alzheimer’s disease: A critical appraisal. World J Diabetes 2015; 6:1223-1242. [PMID: 26464760 PMCID: PMC4598605 DOI: 10.4239/wjd.v6.i12.1223] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/25/2015] [Accepted: 09/08/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus (DM), a metabolic disorder is a major orchestra influencing brain and behavioral responses via direct or indirect mechanisms. Many lines of evidence suggest that diabetic patients apparently face severe brain complications, but the story is far from being fully understood. Type 2 diabetes, an ever increasing epidemic and its chronic brain complications are implicated in the development of Alzheimer’s disease (AD). Evidences from clinical and experimental studies suggest that insulin draws a clear trajectory from the peripheral system to the central nervous system. This review is a spot light on striking pathological, biochemical, molecular and behavioral commonalities of AD and DM. Incidence of cognitive decline in diabetic patients and diabetic symptoms in AD patients has brought the concept of brain diabetes to attention. Brain diabetes reflects insulin resistant brain state with oxidative stress, cognitive impairment, activation of various inflammatory cascade and mitochondrial vulnerability as a shared footprint of AD and DM. It has become extremely important for the investigators to understand the patho-physiology of brain complications in diabetes and put intensive pursuits for therapeutic interventions. Although, decades of research have yielded a range of molecules with potential beneficial effects, but they are yet to meet the expectations.
Collapse
|
|
18
|
Najem D, Bamji-Mirza M, Chang N, Liu QY, Zhang W. Insulin resistance, neuroinflammation, and Alzheimer's disease. Rev Neurosci 2015; 25:509-25. [PMID: 24622783 DOI: 10.1515/revneuro-2013-0050] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 02/13/2014] [Indexed: 01/02/2023]
Abstract
Alzheimer's disease (AD) is the most common form of dementia. Pathologically, it is characterized by degeneration of neurons and synapses, the deposition of extracellular plaques consisting of aggregated amyloid-β (Aβ) peptides, and intracellular neurofibrillary tangles made up of hyperphosphorylated tau protein. Recently, the spotlights have been centered on two characteristics of AD, neuroinflammation and insulin resistance. Because both of these pathways play roles in synaptic dysfunction and neurodegeneration, they become potential targets for therapeutic intervention that could impede the progression of the disease. Here, we present an overview of the traditional amyloid hypothesis, as well as emerging data on both inflammatory and impaired insulin signaling pathways in AD. It becomes evident that more than one concurrent treatment can be synergistic and various combinations should be discussed as a potential therapeutic strategy to correct the anomalies in AD. Insulin resistance, Aβ/tau pathologies, neuroinflammation, and dysregulation of central nervous system homeostasis are intertwined processes that together create the complex pathology of AD and should be considered as a whole picture.
Collapse
|
|
19
|
Che F, Fu Q, Li X, Gao N, Qi F, Sun Z, Du Y, Li M. Association of insulin receptor H1085H C>T, insulin receptor substrate 1 G972R and insulin receptor substrate 2 1057G/A polymorphisms with refractory temporal lobe epilepsy in Han Chinese. Seizure 2014; 25:178-80. [PMID: 25458098 DOI: 10.1016/j.seizure.2014.09.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 09/25/2014] [Accepted: 09/29/2014] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Insulin/insulin receptor (INSR) signaling plays diverse roles in the central nervous system, including regulation of blood glucose, synaptic plasticity, dendritic growth, modulation of electrophysiological activity, proliferation of astrocytes and neuronal apoptosis. Interestingly, many of these and/or related processes represent biological mechanisms associated with temporal lobe epilepsy (TLE). Thus, insulin signaling may play a role in the development of TLE and its therapeutic responses. We hypothesized that functional polymorphisms in the insulin pathway genes INSR, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with the therapeutic responses of TLE. Therefore, in this study we analyzed the association of three single nucleotide polymorphisms (SNPs) showing a risk for TLE drug resistance using a hospital-based case-control design. METHOD Two hundred and one patients with refractory TLE and one hundred and seventy-five drug-responsive TLE patients were recruited for the study. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the genotypes of INSR His1085His, IRS1 G972R and IRS2 1057G/A. RESULTS No significant differences between refractory and drug-responsive TLE patients were observed for the IRS1 G972R and IRS2 1057G/A polymorphisms (P>0.05), but a significant association was found for the INSR His1085His polymorphism for both genotypes (P=0.035) and alleles (P=0.011). IRS2 1057G/A combined with the INSR His 1085 His polymorphism increased the odds ratio of drug resistance in TLE (P=0.011, OR=2.263, 95% CI: 1.208-4.239). CONCLUSION These results suggest that a genetic variation in the insulin signaling pathway genes may affect the therapeutic response of TLE.
Collapse
Affiliation(s)
- Fengyuan Che
- Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China; Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276003, PR China
| | - Qingxi Fu
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276003, PR China.
| | - Xuesong Li
- Linyi Health School, Linyi, Shandong 276003, PR China
| | - Naiyong Gao
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276003, PR China
| | - Faying Qi
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276003, PR China
| | - Zhiqing Sun
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276003, PR China
| | - Yifeng Du
- Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
| | - Ming Li
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276003, PR China
| |
Collapse
|
|
20
|
Williams DB. Inhibitory effects of insulin on GABAAcurrents modulated by the GABAAalpha subunit. J Recept Signal Transduct Res 2014; 35:516-22. [DOI: 10.3109/10799893.2014.960935] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
|
|
21
|
Blázquez E, Velázquez E, Hurtado-Carneiro V, Ruiz-Albusac JM. Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer's disease. Front Endocrinol (Lausanne) 2014; 5:161. [PMID: 25346723 PMCID: PMC4191295 DOI: 10.3389/fendo.2014.00161] [Citation(s) in RCA: 345] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 09/21/2014] [Indexed: 12/21/2022] Open
Abstract
Although the brain has been considered an insulin-insensitive organ, recent reports on the location of insulin and its receptors in the brain have introduced new ways of considering this hormone responsible for several functions. The origin of insulin in the brain has been explained from peripheral or central sources, or both. Regardless of whether insulin is of peripheral origin or produced in the brain, this hormone may act through its own receptors present in the brain. The molecular events through which insulin functions in the brain are the same as those operating in the periphery. However, certain insulin actions are different in the central nervous system, such as hormone-induced glucose uptake due to a low insulin-sensitive GLUT-4 activity, and because of the predominant presence of GLUT-1 and GLUT-3. In addition, insulin in the brain contributes to the control of nutrient homeostasis, reproduction, cognition, and memory, as well as to neurotrophic, neuromodulatory, and neuroprotective effects. Alterations of these functional activities may contribute to the manifestation of several clinical entities, such as central insulin resistance, type 2 diabetes mellitus (T2DM), and Alzheimer's disease (AD). A close association between T2DM and AD has been reported, to the extent that AD is twice more frequent in diabetic patients, and some authors have proposed the name "type 3 diabetes" for this association. There are links between AD and T2DM through mitochondrial alterations and oxidative stress, altered energy and glucose metabolism, cholesterol modifications, dysfunctional protein O-GlcNAcylation, formation of amyloid plaques, altered Aβ metabolism, and tau hyperphosphorylation. Advances in the knowledge of preclinical AD and T2DM may be a major stimulus for the development of treatment for preventing the pathogenic events of these disorders, mainly those focused on reducing brain insulin resistance, which is seems to be a common ground for both pathological entities.
Collapse
Affiliation(s)
- Enrique Blázquez
- Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Madrid, Spain
- The Center for Biomedical Research in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdiSSC), Madrid, Spain
- *Correspondence: Enrique Blázquez, Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, Madrid 28040, Spain e-mail:
| | - Esther Velázquez
- Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Madrid, Spain
- The Center for Biomedical Research in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdiSSC), Madrid, Spain
| | - Verónica Hurtado-Carneiro
- Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Madrid, Spain
- The Center for Biomedical Research in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdiSSC), Madrid, Spain
| | - Juan Miguel Ruiz-Albusac
- Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Madrid, Spain
- The Center for Biomedical Research in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdiSSC), Madrid, Spain
| |
Collapse
|
|
22
|
Arantes LM, Bertolini NO, de Moura RF, de Mello MAR, Luciano E. Insulin concentrations in cerebellum and body balance in diabetic male rats: aerobic training effects. Physiol Behav 2013; 118:58-62. [PMID: 23684905 DOI: 10.1016/j.physbeh.2013.05.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Revised: 01/21/2013] [Accepted: 05/06/2013] [Indexed: 01/22/2023]
Abstract
UNLABELLED Brain insulin has had widespread metabolic, neurotrophic, and neuromodulatory functions and has been involved in the central regulation of food intake and body weight, learning and memory, neuronal development, and neuronal apoptosis. PURPOSE The present study investigated the role of swimming training on cerebral metabolism on insulin concentrations in cerebellum and the body balance performance of diabetic rats. METHODS Forty Male Wistar rats were divided in four groups: sedentary control (SC), trained control (TC), sedentary diabetic (SD), and trained diabetic (TD). Diabetes was induced by alloxan (32mgkg b.w.), single dose injection. The mean blood glucose of diabetic groups was 367±40mg/dl. Training program consisted in swimming 5days/week, 1h/day, 8weeks, supporting a workload corresponding to 90% of maximal lactate steady state (MLSS). For the body balance testing rats were trained to traverse for 5min daily for 5-7days. All dependent variables were analyzed by one-way analysis of variance (ANOVA) and a significance level of p<0.05 was used for all comparisons. RESULTS The body balance testing scores were different between groups. Insulin concentrations in cerebellum were not different between groups. CONCLUSION It was concluded that in diabetic rats, aerobic training does not induce alterations on cerebellum insulin but induces important metabolic, hormonal and behavioral alterations which are associated with an improvement in glucose homeostasis, serum insulin concentrations and body balance.
Collapse
|
|
23
|
De Felice FG. Alzheimer's disease and insulin resistance: translating basic science into clinical applications. J Clin Invest 2013; 123:531-9. [PMID: 23485579 DOI: 10.1172/jci64595] [Citation(s) in RCA: 247] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Alzheimer's disease (AD) and diabetes are currently considered among the top threats to human health worldwide. Intriguingly, a connection between these diseases has been established during the past decade, since insulin resistance, a hallmark of type 2 diabetes, also develops in Alzheimer brains. In this article, the molecular and cellular mechanisms underlying defective brain insulin signaling in AD are discussed, with emphasis on evidence that Alzheimer's and diabetes share common inflammatory signaling pathways. I put forward here a hypothesis on how a cross-talk between peripheral tissues and the brain might influence the development of AD, and highlight important unanswered questions in the field. Furthermore, I discuss a rational basis for the use of antidiabetic agents as novel and potentially effective therapeutics in AD.
Collapse
Affiliation(s)
- Fernanda G De Felice
- Institute of Medical Biochemistry, CCS, Room H2-019, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil.
| |
Collapse
|
|
24
|
Ghasemi R, Dargahi L, Haeri A, Moosavi M, Mohamed Z, Ahmadiani A. Brain insulin dysregulation: implication for neurological and neuropsychiatric disorders. Mol Neurobiol 2013; 47:1045-65. [PMID: 23335160 DOI: 10.1007/s12035-013-8404-z] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2012] [Accepted: 01/03/2013] [Indexed: 12/18/2022]
Abstract
Arduous efforts have been made in the last three decades to elucidate the role of insulin in the brain. A growing number of evidences show that insulin is involved in several physiological function of the brain such as food intake and weight control, reproduction, learning and memory, neuromodulation and neuroprotection. In addition, it is now clear that insulin and insulin disturbances particularly diabetes mellitus may contribute or in some cases play the main role in development and progression of neurodegenerative and neuropsychiatric disorders. Focusing on the molecular mechanisms, this review summarizes the recent findings on the involvement of insulin dysfunction in neurological disorders like Alzheimer's disease, Parkinson's disease and Huntington's disease and also mental disorders like depression and psychosis sharing features of neuroinflammation and neurodegeneration.
Collapse
Affiliation(s)
- Rasoul Ghasemi
- Neuroscience Research Center and Department of Physiology, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | | | | | | | | |
Collapse
|
|
25
|
Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol 2012; 47:145-71. [PMID: 22956272 DOI: 10.1007/s12035-012-8339-9] [Citation(s) in RCA: 215] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2012] [Accepted: 08/20/2012] [Indexed: 02/07/2023]
Abstract
Historically, insulin is best known for its role in peripheral glucose homeostasis, and insulin signaling in the brain has received less attention. Insulin-independent brain glucose uptake has been the main reason for considering the brain as an insulin-insensitive organ. However, recent findings showing a high concentration of insulin in brain extracts, and expression of insulin receptors (IRs) in central nervous system tissues have gathered considerable attention over the sources, localization, and functions of insulin in the brain. This review summarizes the current status of knowledge of the peripheral and central sources of insulin in the brain, site-specific expression of IRs, and also neurophysiological functions of insulin including the regulation of food intake, weight control, reproduction, and cognition and memory formation. This review also considers the neuromodulatory and neurotrophic effects of insulin, resulting in proliferation, differentiation, and neurite outgrowth, introducing insulin as an attractive tool for neuroprotection against apoptosis, oxidative stress, beta amyloid toxicity, and brain ischemia.
Collapse
Affiliation(s)
- Rasoul Ghasemi
- Department of Physiology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | | | | | | |
Collapse
|
|
26
|
Paranjape SA, Chan O, Zhu W, Horblitt AM, McNay EC, Cresswell JA, Bogan JS, McCrimmon RJ, Sherwin RS. Influence of insulin in the ventromedial hypothalamus on pancreatic glucagon secretion in vivo. Diabetes 2010; 59:1521-7. [PMID: 20299468 PMCID: PMC2874714 DOI: 10.2337/db10-0014] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Insulin released by the beta-cell is thought to act locally to regulate glucagon secretion. The possibility that insulin might also act centrally to modulate islet glucagon secretion has received little attention. RESEARCH DESIGN AND METHODS Initially the counterregulatory response to identical hypoglycemia was compared during intravenous insulin and phloridzin infusion in awake chronically catheterized nondiabetic rats. To explore whether the disparate glucagon responses seen were in part due to changes in ventromedial hypothalamus (VMH) exposure to insulin, bilateral guide cannulas were inserted to the level of the VMH and 8 days later rats received a VMH microinjection of either 1) anti-insulin affibody, 2) control affibody, 3) artificial extracellular fluid, 4) insulin (50 microU), 5) insulin receptor antagonist (S961), or 6) anti-insulin affibody plus a gamma-aminobutyric acid A (GABA(A)) receptor agonist muscimol, prior to a hypoglycemic clamp or under baseline conditions. RESULTS As expected, insulin-induced hypoglycemia produced a threefold increase in plasma glucagon. However, the glucagon response was fourfold to fivefold greater when circulating insulin did not increase, despite equivalent hypoglycemia and C-peptide suppression. In contrast, epinephrine responses were not altered. The phloridzin-hypoglycemia induced glucagon increase was attenuated (40%) by VMH insulin microinjection. Conversely, local VMH blockade of insulin amplified glucagon twofold to threefold during insulin-induced hypoglycemia. Furthermore, local blockade of basal insulin levels or insulin receptors within the VMH caused an immediate twofold increase in fasting glucagon levels that was prevented by coinjection to the VMH of a GABA(A) receptor agonist. CONCLUSIONS Together, these data suggest that insulin's inhibitory effect on alpha-cell glucagon release is in part mediated at the level of the VMH under both normoglycemic and hypoglycemic conditions.
Collapse
Affiliation(s)
- Sachin A Paranjape
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Cardoso S, Santos R, Correia S, Carvalho C, Zhu X, Lee HG, Casadesus G, Smith MA, Perry G, Moreira PI. Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets. Pharmaceuticals (Basel) 2009; 2:250-286. [PMID: 27713238 PMCID: PMC3978547 DOI: 10.3390/ph2030250] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2009] [Revised: 12/21/2009] [Accepted: 12/22/2009] [Indexed: 12/13/2022] Open
Abstract
Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ). Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.
Collapse
Affiliation(s)
- Susana Cardoso
- Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal
- Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000- 354 Coimbra, Portugal
| | - Renato Santos
- Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal
- Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000- 354 Coimbra, Portugal
| | - Sonia Correia
- Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal
- Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000- 354 Coimbra, Portugal
| | - Cristina Carvalho
- Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal
- Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000- 354 Coimbra, Portugal
| | - Xiongwei Zhu
- School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Hyoung-Gon Lee
- School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Gemma Casadesus
- School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Mark A Smith
- School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - George Perry
- College of Sciences, The University of Texas at San Antonio, TX 78249, USA
| | - Paula I Moreira
- Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal.
- Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal.
| |
Collapse
|