Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close rel...Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.展开更多
Icariin,a major prenylated flavonoid found in Epimedium spp.,is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer’s disease.In this stud...Icariin,a major prenylated flavonoid found in Epimedium spp.,is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer’s disease.In this study,we investigated the neuroprotective mechanism of icariin in an APP/PS1/Tau triple-transgenic mouse model of Alzheimer’s disease.We performed behavioral tests,pathological examination,and western blot assay,and found that memory deficits of the model mice were obviously improved,neuronal and synaptic damage in the cerebral cortex was substantially mitigated,and amyloid-βaccumulation and tau hyperphosphorylation were considerably reduced after 5 months of intragastric administration of icariin at a dose of 60 mg/kg body weight per day.Furthermore,deficits of proteins in the insulin signaling pathway and their phosphorylation levels were significantly reversed,including the insulin receptor,insulin receptor substrate 1,phosphatidylinositol-3-kinase,protein kinase B,and glycogen synthase kinase 3β,and the levels of glucose transporter 1 and 3 were markedly increased.These findings suggest that icariin can improve learning and memory impairments in the mouse model of Alzheimer’s disease by regulating brain insulin signaling and glucose transporters,which lays the foundation for potential clinical application of icariin in the prevention and treatment of Alzheimer’s disease.展开更多
Contrary to the previous belief that insulin does not act in the brain, studies in the last three decades have demonstrated important roles of insulin and insulin signal transduction in various functions of the centra...Contrary to the previous belief that insulin does not act in the brain, studies in the last three decades have demonstrated important roles of insulin and insulin signal transduction in various functions of the central nervous system. Deregulated brain insulin signaling and its role in molecular pathogenesis have recently been reported in Alzheimer＇s disease （AD）. In this article, we review the roles of brain insulin signaling in memory and cognition, the metabolism of amyloid 13 precursor protein, and tau phosphorylation. We further discuss deficiencies of brain insulin signaling and glucose metabolism, their roles in the development of AD, and recent studies that target the brain insulin signaling pathway for the treatment of AD. It is clear now that deregulation of brain insulin signaling plays an important role in the development of sporadic AD. The brain insulin signaling pathway also offers a promising therapeutic target for treating AD and probably other neurodegenerative disorders.展开更多
There is relatively limited knowledge concerning our understanding of how our immune system and brain take most of the available energy in a selfish manner to compensate for their own needs on priority in high energy ...There is relatively limited knowledge concerning our understanding of how our immune system and brain take most of the available energy in a selfish manner to compensate for their own needs on priority in high energy demanding situations. The main objective of this review is to understand the energy allocation to immune system and brain in infections and/or fight or flight situations. The immune system and brain behave in a selfish manner as they allocate themselves majority of the total available energy. Insulin resistance (IR) is used as a tool for energy allocation by these systems. The immune system is activated as a response to stress and infection. Similarly, the brain gets activated as a response to any external environmental impulse, anxiety, and/or mental factor. These situations need to be dealt in a way to minimize their adverse health effects. The immune system and the brain in such situations need enormous energy for activation which is derived from the energy quota otherwise allocated to other organs. This maximum flux of energy towards these systems is achieved by making rest of the organs less responsive to insulin, a condition known as IR. As immune system and brain do not depend upon insulin for uptake of glucose, these systems are benefited from IR. IR is indicated as a beneficial role ensuring maximum energy allocation to these systems for improving health and well-being.展开更多
Acupuncture has recently gained popularity in many countries as an alternative and complementary therapeutic intervention. Previous studies have shown that changes in genes, proteins, and their metabolites were measur...Acupuncture has recently gained popularity in many countries as an alternative and complementary therapeutic intervention. Previous studies have shown that changes in genes, proteins, and their metabolites were measureable during acupuncture for treatment of cerebral ischemia. Through the use of in situ hybridization and immunohistochemistry, the present study confirmed that electroacupuncture increased insulin-like growth factor-1 mRNA and protein expression in the corpus stfiatum following cerebral ischemia, reduced brain edema following middle cerebral artery occlusion reperfusion, and decreased infarct volume. Results suggested that electroacupuncture is effective in the relief of cerebral ischemia by increasing endogenous insulin-like growth factor-1 expression.展开更多
Long-acting glucagon-like peptide-1(GLP-1) analogues marketed for type 2 diabetes(T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain....Long-acting glucagon-like peptide-1(GLP-1) analogues marketed for type 2 diabetes(T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2 D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors(GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions(e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2 D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation(thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2 D, stroke and Alzheimer disease(AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biomarkers. Herein, we discuss the GLP-1 action through the gut-brain axis, the hormone's regulation of some autonomic functions and liraglutide's neuroprotective potential.展开更多
Cerebral ageing is a complex biological process associated with progressing cerebrovascular disease and neuronal death. It does not always, however, associate with a functional decline, as the ageing mammalian brain r...Cerebral ageing is a complex biological process associated with progressing cerebrovascular disease and neuronal death. It does not always, however, associate with a functional decline, as the ageing mammalian brain retains considerable functional plasticity which supports successful cerebral ageing where age-related cognitive decline is modest. On the contrary, pathological cerebral ageing results in memory impairment and cognitive deterioration, with Alzheimer's disease(AD) being a florid example. Trophic/growth factors promote brain plasticity; among them are peptides which belong tothe insulin family. Preclinical research suggests that the evolutionarily conserved brain insulin/insulin-like growth factor-1(IGF-1) signalling system controls lifespan and protects against some features of AD such as neurodegeneration-related accumulation of toxic proteins and cognitive deficiencies, as observed in animal models. Insulin and IGF-1 activate cell signalling mechanisms which play protective and regenerative roles; abnormalities in the insulin/IGF-1 system may trigger a cascade of neurodegeneration in AD. AD patients show cerebral resistance to insulin which associates with IGF-I resistance and dysregulation of insulin/IGF-1 receptors as well as cognitive deterioration. This review is focused on the roles of the insulin/IGF-1 signalling system in cerebral ageing and its potential involvement in neurodegeneration in the human brain as seen against the background of preclinical evidence.展开更多
Abnormalities in insulin metabolism, characteristic of T2DM, are among the major factors thought to mechanistically influence the onset of AD. These abnormalities are thought to play a role in AD via their influence o...Abnormalities in insulin metabolism, characteristic of T2DM, are among the major factors thought to mechanistically influence the onset of AD. These abnormalities are thought to play a role in AD via their influence on the synthesis and degradation of Aβ and as a consequence of the cascade of neuronal alterations resulting from the effects of danger/alarm signals from oligomeric amyloid species. Additionally, recent studies have indicated that certain signal transduction pathways downstream of the InsR may also promote the generation of Aβ peptides by modulating the cleavage of the parent Aβ precursor protein (AβPP) at the γ-secretase site, a cleavage site necessary for Aβ amyloidogenicity. Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia;this condition persists for several years before becoming full blown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid (CSF) concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide (Aβ) and an increase of tau hyperphosphorylation as a result of augmented cdk5 and GSK3β activities. This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. Chronic peripheral hyperinsulinemia results in a reduction of insulin transport across the BBB and reduced insulin signaling in brain, altering all of insulin’s actions, including its anti-apoptotic effect. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognition enhancing effect on patient with AD.展开更多
Astrocytes perform many functions in the brain and spinal cord.Glucose metabolism is important for astroglial cells and astrocytes are the only cells with insulin receptors in the brain.The common antibiotic penicilli...Astrocytes perform many functions in the brain and spinal cord.Glucose metabolism is important for astroglial cells and astrocytes are the only cells with insulin receptors in the brain.The common antibiotic penicillin is also a chemical agent that causes degenerative effect on neuronal cell.The aim of this study is to show the effect of insulin and glucose at different concentrations on the astrocyte death induced by penicillin on primer astroglial cell line.It is well known that intracranial penicillin treatment causes neuronal cell death and it is used for experimental epilepsy model commonly.Previous studies showed that insulin and glucose might protect neuronal cell in case of proper concentrations.But,the present study is about the effect of insulin and glucose against astrocyte death induced by penicillin.For this purpose,newborn rat brain was extracted and then mechanically dissociated to astroglial cell suspension and finally grown in culture medium.Clutters were maintained for 2 weeks prior to being used in these experiments.Different concentrations of insulin（0,1,3 nM）and glucose（0,3,30 mM）were used in media without penicillin and with 2 500μM penicillin.Penicillin decreased the viability of astroglial cell seriously.The highest cell viability appeared in medium with 3 nM insulin and 3 mM glucose but without penicillin.However,in medium with penicillin,the best cell survival was in medium with 1 nM insulin but without glucose. We concluded that insulin and glucose show protective effects on the damage induced by penicillin to primer astroglial cell line.Interestingly,cell survival depends on concentrations of insulin and glucose strongly.The results of this study will help to explain cerebrovascular pathologies parallel to insulin and glucose conditions of patient after intracranial injuries.展开更多
基金support from Region Stockholm,ALF-project(FoUI-960041)Open Access funding is provided by Karolinska Institute(both to IM)。
文摘Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.
基金supported by the National Natural Science Foundation of China, Nos. 82060727 (to FJ), 81660599 (to FJ)the National Innovation Training Project for College Students, No. 201910661009 (to FJ)the Science and Technology Cooperation Project of Zunyi Science and Technology Bureau and Zunyi Medical University, No. (2019) 47 (to XLF)
文摘Icariin,a major prenylated flavonoid found in Epimedium spp.,is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer’s disease.In this study,we investigated the neuroprotective mechanism of icariin in an APP/PS1/Tau triple-transgenic mouse model of Alzheimer’s disease.We performed behavioral tests,pathological examination,and western blot assay,and found that memory deficits of the model mice were obviously improved,neuronal and synaptic damage in the cerebral cortex was substantially mitigated,and amyloid-βaccumulation and tau hyperphosphorylation were considerably reduced after 5 months of intragastric administration of icariin at a dose of 60 mg/kg body weight per day.Furthermore,deficits of proteins in the insulin signaling pathway and their phosphorylation levels were significantly reversed,including the insulin receptor,insulin receptor substrate 1,phosphatidylinositol-3-kinase,protein kinase B,and glycogen synthase kinase 3β,and the levels of glucose transporter 1 and 3 were markedly increased.These findings suggest that icariin can improve learning and memory impairments in the mouse model of Alzheimer’s disease by regulating brain insulin signaling and glucose transporters,which lays the foundation for potential clinical application of icariin in the prevention and treatment of Alzheimer’s disease.
基金supported in part by the New York State Office for People with Developmental Disabilitiesthe Second Affiliated Hospital of the School of Medicine,Zhejiang Universitya grant from the U.S.Alzheimer’s Association(IIRG-10-170405)
文摘Contrary to the previous belief that insulin does not act in the brain, studies in the last three decades have demonstrated important roles of insulin and insulin signal transduction in various functions of the central nervous system. Deregulated brain insulin signaling and its role in molecular pathogenesis have recently been reported in Alzheimer＇s disease （AD）. In this article, we review the roles of brain insulin signaling in memory and cognition, the metabolism of amyloid 13 precursor protein, and tau phosphorylation. We further discuss deficiencies of brain insulin signaling and glucose metabolism, their roles in the development of AD, and recent studies that target the brain insulin signaling pathway for the treatment of AD. It is clear now that deregulation of brain insulin signaling plays an important role in the development of sporadic AD. The brain insulin signaling pathway also offers a promising therapeutic target for treating AD and probably other neurodegenerative disorders.
文摘There is relatively limited knowledge concerning our understanding of how our immune system and brain take most of the available energy in a selfish manner to compensate for their own needs on priority in high energy demanding situations. The main objective of this review is to understand the energy allocation to immune system and brain in infections and/or fight or flight situations. The immune system and brain behave in a selfish manner as they allocate themselves majority of the total available energy. Insulin resistance (IR) is used as a tool for energy allocation by these systems. The immune system is activated as a response to stress and infection. Similarly, the brain gets activated as a response to any external environmental impulse, anxiety, and/or mental factor. These situations need to be dealt in a way to minimize their adverse health effects. The immune system and the brain in such situations need enormous energy for activation which is derived from the energy quota otherwise allocated to other organs. This maximum flux of energy towards these systems is achieved by making rest of the organs less responsive to insulin, a condition known as IR. As immune system and brain do not depend upon insulin for uptake of glucose, these systems are benefited from IR. IR is indicated as a beneficial role ensuring maximum energy allocation to these systems for improving health and well-being.
文摘Acupuncture has recently gained popularity in many countries as an alternative and complementary therapeutic intervention. Previous studies have shown that changes in genes, proteins, and their metabolites were measureable during acupuncture for treatment of cerebral ischemia. Through the use of in situ hybridization and immunohistochemistry, the present study confirmed that electroacupuncture increased insulin-like growth factor-1 mRNA and protein expression in the corpus stfiatum following cerebral ischemia, reduced brain edema following middle cerebral artery occlusion reperfusion, and decreased infarct volume. Results suggested that electroacupuncture is effective in the relief of cerebral ischemia by increasing endogenous insulin-like growth factor-1 expression.
基金Supported by FEDER(Programa Operacional Factores de Competitividade-COMPETE)Portuguese funds via Portuguese Science Foundation(FCT)(Projects:PTDC/SAUNMC/110990/2009,PTDC/SAU-TOX/117481/2010 and Pest/SAU/LA0001/2011fellowships:SFRH/BD/90036/2012,PTDC/SAU-TOX/117481/2010,SFRH/BPD/95770/2013,SFRH/BPD/84163/2012,QREN Do IT,"DIAMARKER PROJECT",n.o 13853,SFRH/BD/73388/2010,SFRH/BPD/84473/2012)
文摘Long-acting glucagon-like peptide-1(GLP-1) analogues marketed for type 2 diabetes(T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2 D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors(GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions(e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2 D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation(thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2 D, stroke and Alzheimer disease(AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biomarkers. Herein, we discuss the GLP-1 action through the gut-brain axis, the hormone's regulation of some autonomic functions and liraglutide's neuroprotective potential.
文摘Cerebral ageing is a complex biological process associated with progressing cerebrovascular disease and neuronal death. It does not always, however, associate with a functional decline, as the ageing mammalian brain retains considerable functional plasticity which supports successful cerebral ageing where age-related cognitive decline is modest. On the contrary, pathological cerebral ageing results in memory impairment and cognitive deterioration, with Alzheimer's disease(AD) being a florid example. Trophic/growth factors promote brain plasticity; among them are peptides which belong tothe insulin family. Preclinical research suggests that the evolutionarily conserved brain insulin/insulin-like growth factor-1(IGF-1) signalling system controls lifespan and protects against some features of AD such as neurodegeneration-related accumulation of toxic proteins and cognitive deficiencies, as observed in animal models. Insulin and IGF-1 activate cell signalling mechanisms which play protective and regenerative roles; abnormalities in the insulin/IGF-1 system may trigger a cascade of neurodegeneration in AD. AD patients show cerebral resistance to insulin which associates with IGF-I resistance and dysregulation of insulin/IGF-1 receptors as well as cognitive deterioration. This review is focused on the roles of the insulin/IGF-1 signalling system in cerebral ageing and its potential involvement in neurodegeneration in the human brain as seen against the background of preclinical evidence.
文摘Abnormalities in insulin metabolism, characteristic of T2DM, are among the major factors thought to mechanistically influence the onset of AD. These abnormalities are thought to play a role in AD via their influence on the synthesis and degradation of Aβ and as a consequence of the cascade of neuronal alterations resulting from the effects of danger/alarm signals from oligomeric amyloid species. Additionally, recent studies have indicated that certain signal transduction pathways downstream of the InsR may also promote the generation of Aβ peptides by modulating the cleavage of the parent Aβ precursor protein (AβPP) at the γ-secretase site, a cleavage site necessary for Aβ amyloidogenicity. Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia;this condition persists for several years before becoming full blown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid (CSF) concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide (Aβ) and an increase of tau hyperphosphorylation as a result of augmented cdk5 and GSK3β activities. This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. Chronic peripheral hyperinsulinemia results in a reduction of insulin transport across the BBB and reduced insulin signaling in brain, altering all of insulin’s actions, including its anti-apoptotic effect. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognition enhancing effect on patient with AD.
文摘Astrocytes perform many functions in the brain and spinal cord.Glucose metabolism is important for astroglial cells and astrocytes are the only cells with insulin receptors in the brain.The common antibiotic penicillin is also a chemical agent that causes degenerative effect on neuronal cell.The aim of this study is to show the effect of insulin and glucose at different concentrations on the astrocyte death induced by penicillin on primer astroglial cell line.It is well known that intracranial penicillin treatment causes neuronal cell death and it is used for experimental epilepsy model commonly.Previous studies showed that insulin and glucose might protect neuronal cell in case of proper concentrations.But,the present study is about the effect of insulin and glucose against astrocyte death induced by penicillin.For this purpose,newborn rat brain was extracted and then mechanically dissociated to astroglial cell suspension and finally grown in culture medium.Clutters were maintained for 2 weeks prior to being used in these experiments.Different concentrations of insulin（0,1,3 nM）and glucose（0,3,30 mM）were used in media without penicillin and with 2 500μM penicillin.Penicillin decreased the viability of astroglial cell seriously.The highest cell viability appeared in medium with 3 nM insulin and 3 mM glucose but without penicillin.However,in medium with penicillin,the best cell survival was in medium with 1 nM insulin but without glucose. We concluded that insulin and glucose show protective effects on the damage induced by penicillin to primer astroglial cell line.Interestingly,cell survival depends on concentrations of insulin and glucose strongly.The results of this study will help to explain cerebrovascular pathologies parallel to insulin and glucose conditions of patient after intracranial injuries.
