从“治脑病”角度探讨糖尿病及其阿尔茨海默病的防治
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摘要
阿尔茨海默病(AD)目前已成为糖尿病的一大并发症,给家庭与社会均带来了严重的负担。近年来,国内外大量研究表明AD与糖尿病之间关系紧密,且具有一定共病基础。本综述将从流行病学、形态病理学、临床特征3个层面阐述AD与糖尿病之间相伴相生的联系;归纳总结两疾病间主要的共病机制;并在此基础上,笔者提出了通过"治脑病"辅助防治糖尿病及其AD并发症的新思路,以期为糖尿病及其AD并发症的临床治疗提供新的途径与方法。
Nowadays Alzheimer's disease has become another major complication of diabetes,which has brought a heavy burden to the family and society. In recent years,abundant studies at home and abroad have shown that there are closely connection between Alzheimer's disease and diabetes. The two diseases have certain comorbid foundation. This article reviewed from three levels,including epidemiological,morphological pathology,clinical features to elaborate the concomitant link between Alzheimer's disease and diabetes,and summarize the comorbid mechanisms between the two diseases. On this basis,a new thought for auxiliary preventing and treating diabetes and its complication of AD through "treating encephalopathy"was proposed,in order to provide a new way for the clinical treatment of diabetes and its complications of AD.
Nowadays Alzheimer's disease has become another major complication of diabetes,which has brought a heavy burden to the family and society. In recent years,abundant studies at home and abroad have shown that there are closely connection between Alzheimer's disease and diabetes. The two diseases have certain comorbid foundation. This article reviewed from three levels,including epidemiological,morphological pathology,clinical features to elaborate the concomitant link between Alzheimer's disease and diabetes,and summarize the comorbid mechanisms between the two diseases. On this basis,a new thought for auxiliary preventing and treating diabetes and its complication of AD through "treating encephalopathy"was proposed,in order to provide a new way for the clinical treatment of diabetes and its complications of AD.
引文
[1]OKABAYASHI SACHI,SHIMOZAWA NOBUHIRO,YASUTOMI YASUHIRO,et al.Diabetes mellitus accelerates Aβpathology in brain accompanied by enhanced GAβgeneration in nonhuman primates[J].PLo S ONE,2015,10(2):1-19.
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[3]NOBUYUKI,KIMURA.Diabetes mellitus induces Alzheimer's disease pathology:histopathological evidence from animal models[J].Int J Mol Sci,2016,17(4):45-67.
[4]KAWSER A,EMILY AL,STEPHEN AM,et al.Diabetes mellitus and Alzheimer's disease:shared pathology and treatment?[J].Br J Clin Pharmacol,2011,71(3):365-376.
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[6]CRANE PK,WALKER R,HUBBARD RA,et al.Glucose levels and risk of dementia[J].N Engl J Med,2013,369(23):540-548.
[7]WALKER JM,HARRISON FE.Shared neuropathological characteristics of obesity,type 2 diabetes and Alzheimer's disease:impacts on cognitive decline[J].Nutrients,2015,7(9):7332-7357.
[8]MATSUDA T,SHIBAHARA M,YAO I,et al.A type of cholinergic dysfunction involves cognitive deficit in a mouse model of type 2 diabetes mellitus/Alzheimer's disease[J].Alzheimers Dement,2014,10(4):342-360.
[9]BRANDS AM,BIESSELS GJ,DE HAAN EH.The effects of type 1 diabetes on cognitive performance:a meta analysis[J].Diabetes Care,2005,28(3):726-735.
[10]CUKIERMAN T,GERSTEIN HC,WILLIAMSON JD.Cognitive decline and dementia in diabetes-systematic overview of prospective observational studies[J].Diabetologia,2005,48(12):2460-2469.
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[12]CUKIERMAN T,GERSTEIN HC,WILLIAMSON JD.Cognitive decline and dementia in diabetes-systematic overview of prospective observational studies[J].Diabetologia,2005,48(12):2460-2469.
[13]ANDRS NORAMBUENA,HORST WALLRABE,LLOYD MCMAHON,et al.Mtor and rac1 control-induced,tau-dependent cell cycle re-entry in Alzheimer's disease neurons:a mechanistic explanation for classifying Alzheimer's disease as type 3 diabetes[J].Alzheimers Dement,2015,11(7):632-651.
[14]KNEBEL B,STRASSBURGER K,SZENDROEDI J,et al.Specific metabolic profiles and their relationship to insulin resistance in recent-onset type-1 and type-2 diabetes[J].J Clin Endocrinol Metab,2016,101(5):2130-2140.
[15]VIGNINI A,GIULIETTI A,NANETTI L,et al.Alzheimer's disease and diabetes:new insights and unifying therapies[J].Curr Diabetes Rev,2013,9(3):218-227.
[16]AURIEL W,ROGER JM,MAJA MC,et al.Biomarkers of brain insulin resistance and neuroimaging correlates in early Alzheimer's disease[J].Alzheimers Dement,2015,11(7):147-148.
[17]GHASEMI R,HAERI A,DARGAHI L,et al.Insulin in the brain:sources,localization and functions[J].Mol neurobiol,2013,47(1):145-171.
[18]UMEGAKI H.Insulin resistance in the brain:a new therapeutic target for Alzheimer's disease[J].JDI,2013,4(2):150-151.
[19]HOSCHEIDT SM,STARKS EJ,OH JM,et al.Insulin resistance is associated with increased Alzheimer's disease pathology and reduced memory function in at-risk healthy middle-aged adults[J].J Alzheimers Dis,2016,52(4):1373-1383.
[20]KUBOTA T,KUBOTA N,MOROI M,et al.Lack of insulin receptor substrate-2 causes progressiveneointima formation in response to vessel injury[J].Circulation,2003,107(16):3073-3080.
[21]LI SZ,WANG NN,LOU JY,et al.Expression ofβ-site APPcleaving enzyme 1 in the hippocampal tissue of an insulin-resistant rat model of Alzheimer's disease[J].Exp Ther Med,2015,9(6):2389-2393.
[22]ANAND S,ANURAG K,KANWALJIT C,et al.Development of an experimental model of insulin resistance-induced Alzheimer's disease[J].Alzheimers Dement,2013,9(4):156-157.
[23]SUBRATA KB.Soluble receptor for advanced glycation end products and insulin resistance during development of type 2 diabetes mellitus[J].J Diabetes Complications,2015,29(4):611-620.
[24]KO SY,KO HA,CHU KH,et al.The possible mechanism of advanced glycation end products(AGEs)for Alzheimer's disease[J].PLo S One,2015,10(11):345-356.
[25]ANGELA K,SOPHIE CL,BJRN K,et al.Advanced glycation end products are mitogenic signals and trigger cell cycle reentry of neurons in Alzheimer's disease brain[J].Neurobiol Aging,2015,36(2):753-761.
[26]XAVIER G,ARANTXA G,CELIA-Z C,et al.N epsilon-carboxymethyllysine in brain aging,diabetes mellitus,and Alzheimer's disease[J].Free Radic Biol Med,2004,36(10):1241-1247.
[27]SMALL GW,ERCOLI LM,SILVERMANET DHS,et al.Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease[J].Proc Natl Acad Sci USA,2000,97(11):6037-6042.
[28]LAUGE S,CHRISTIAN I,NAJA LH,et al.Early detection of Alzheimer's disease using MRI hippocampal texture[J].Human Brain Mapping,2016,37(3):1148-1161.
[29]ARRIETA-CRUZ I,GUTIRREZ-JUREZ R.The role of insulin resistance and glucose metabolism dysregulation in the development of Alzheimer's disease[J].Rev Invest Clin,2016,68(2):53-58.
[30]MUSHTAQ G,KHAN JA,KUMOSANI TA,et al.Alzheimer's disease and type 2 diabetes via chronic inflammatory mechanisms[J].Saudi J Biol Sci,2015,22(1):4-13.
[31]MUSHTAQ G,KHAN JA,KAMAL MA,et al.Biological mechanisms linking Alzheimer's disease and type-2 diabetes mellitus[J].CNS Neurol Disord Drug Targets,2014,13(7):1192-1201.
[32]STRAUB RH.Insulin resistance,selfish brain,and selfish immune system:an evolutionarily positively selected program used in chronic inflammatory diseases[J].Arthritis Res Ther,2014,16(4):45-64.
[33]SCHTT T,HELBOE L,PEDERSEN L,et al.Dogs with cognitive dysfunction as a spontaneous model for early Alzheimer's disease:a translational study of neuropathological and inflammatory markers[J].J Alzheimers Dis,2016,52(2):433-449.
[34]AZIZI G,NAVABI SS,AL-SHUKAILI A,et al.The role of inflammatory mediators in the pathogenesis of Alzheimer's disease[J].Sultan Qaboos Univ Med J,2015,15(3):305-316.
[35]AVILA-MUOZ E,ARIAS C.When astrocytes become harmful:functional and inflammatory responses that contribute to Alzheimer's disease[J].Ageing Res Rev,2014,18(3):29-40.
[36]VERRI M,PASTORIS O,DOSSENA M,et al.Mitochondrial alterations,oxidative stress and neuroinflammation in Alzheimer's disease[J].Int J Immunopathol Pharmacol,2012,25(2):345-353.
[37]ZHOU X,LI Y,SHI X,et al.An overview on therapeutics attenuating amyloidβlevel in Alzheimer's disease:targeting neurotransmission,inflammation,oxidative stress and enhanced cholesterol levels[J].Am J Transl Res,2016,8(2):246-269.
[38]AHMED,OMYMA,GALAL,et al.Inflammation versus oxidative stress in pathophysiology of Alzheimer's disease in rat model[J].Ibnosina Journal of Medicine and Biomedical Sciences,2014,6(3):130-144.
[39]SANDRA J HAMILTON,GERALD F WATTS.Endothelial dysfunction in diabetes:pathogenesis,significance,and treatment[J].Rev Diabet Stud,2013,10(2-3):133-156.
[40]THOMAS T,MINERS S,LOVE S,et al.Post-mortem assessment of hypoperfusion of cerebral cortex in Alzheimer's disease and vascular dementia[J].Brain,2015,138(4):1059-1069.
[41]TIEHUIS AM,VINCKEN KL,VANDEN BERG E,et al.Cerebral perfusion in relation to cognitivefunction and type 2 diabetes[J].Diabetologia,2008,51(7):1321-1326.
[42]LESNSE,SHERMAN MA,GRANT M,et al.Brain amyloidbeta oligomers in ageing and Alzheimer's disease[J].Brain,2013,136(5):1383-1398.
[43]NAJEM D,BAMJI-MIRZA M,YANG Z,et al.Aβ-induced insulin resistance and the effects of insulin on the cholesterol synthesis pathway and Aβsecretion in neural cells[J].Neurosci Bull,2016,32(3):227-238.
[44]MIKLOSSY J,QING H,RADENOVIC A,et al.Beta amyloid and hyper phosphorylated tau deposits in the pancreas in type 2diabetes[J].Neurobiol Aging,2010,31(9):1503-1515.
[45]PEILA R,RODRIGUEZ BL,LAUNER LJ.Type 2 diabetes,APOE gene,and the risk for dementia and related pathologies:the honolulu-asia aging study[J].Diabetes,2002,51(4):1256-1262.
[46]WOLF AB,CASELL BJ,REIMAN EM,et al.APOE and neuroenergetics:an emerging paradigm in Alzheimer's disease[J].Neurobiol Aging,2013,34(4):1007-1017.
[47]NELOFAR S,MASOOD AQ,RUKHSHAN K,et al.Apo lipoprotein E4 gene APOE4:an early predictor of dementia/Alzheimer's disease[J].Scie Res Essays,2013,8(29):1374-1379.
[48]岳仁宋,王帅,陈源,等.2型糖尿病认知功能障碍的中医辨治[J].新中医,2011,43(6):137-138.
[2]MITTAL K,MANI RJ,KATARE DP,et al.Type 3 diabetes:cross talk between differentially regulated proteins of type 2 diabetes mellitus and Alzheimer's disease[J].Sci Rep,2016,6(5):55-89.
[3]NOBUYUKI,KIMURA.Diabetes mellitus induces Alzheimer's disease pathology:histopathological evidence from animal models[J].Int J Mol Sci,2016,17(4):45-67.
[4]KAWSER A,EMILY AL,STEPHEN AM,et al.Diabetes mellitus and Alzheimer's disease:shared pathology and treatment?[J].Br J Clin Pharmacol,2011,71(3):365-376.
[5]HOFMAN A,OTT A,BRETELER MM,et al.Atherosclerosis,apolipoprotein E,and prevalence of dementia and Alzheimer's disease in the rotterdam study[J].Lancet,1997,349(9046):151-154.
[6]CRANE PK,WALKER R,HUBBARD RA,et al.Glucose levels and risk of dementia[J].N Engl J Med,2013,369(23):540-548.
[7]WALKER JM,HARRISON FE.Shared neuropathological characteristics of obesity,type 2 diabetes and Alzheimer's disease:impacts on cognitive decline[J].Nutrients,2015,7(9):7332-7357.
[8]MATSUDA T,SHIBAHARA M,YAO I,et al.A type of cholinergic dysfunction involves cognitive deficit in a mouse model of type 2 diabetes mellitus/Alzheimer's disease[J].Alzheimers Dement,2014,10(4):342-360.
[9]BRANDS AM,BIESSELS GJ,DE HAAN EH.The effects of type 1 diabetes on cognitive performance:a meta analysis[J].Diabetes Care,2005,28(3):726-735.
[10]CUKIERMAN T,GERSTEIN HC,WILLIAMSON JD.Cognitive decline and dementia in diabetes-systematic overview of prospective observational studies[J].Diabetologia,2005,48(12):2460-2469.
[11]GOLD SM,DZIOBEK I,SWEAT V.Hippocampal damage and memory impairments as possible early brain complications of type2 diabetes[J].Diabetologia,2007,50(4):711-719.
[12]CUKIERMAN T,GERSTEIN HC,WILLIAMSON JD.Cognitive decline and dementia in diabetes-systematic overview of prospective observational studies[J].Diabetologia,2005,48(12):2460-2469.
[13]ANDRS NORAMBUENA,HORST WALLRABE,LLOYD MCMAHON,et al.Mtor and rac1 control-induced,tau-dependent cell cycle re-entry in Alzheimer's disease neurons:a mechanistic explanation for classifying Alzheimer's disease as type 3 diabetes[J].Alzheimers Dement,2015,11(7):632-651.
[14]KNEBEL B,STRASSBURGER K,SZENDROEDI J,et al.Specific metabolic profiles and their relationship to insulin resistance in recent-onset type-1 and type-2 diabetes[J].J Clin Endocrinol Metab,2016,101(5):2130-2140.
[15]VIGNINI A,GIULIETTI A,NANETTI L,et al.Alzheimer's disease and diabetes:new insights and unifying therapies[J].Curr Diabetes Rev,2013,9(3):218-227.
[16]AURIEL W,ROGER JM,MAJA MC,et al.Biomarkers of brain insulin resistance and neuroimaging correlates in early Alzheimer's disease[J].Alzheimers Dement,2015,11(7):147-148.
[17]GHASEMI R,HAERI A,DARGAHI L,et al.Insulin in the brain:sources,localization and functions[J].Mol neurobiol,2013,47(1):145-171.
[18]UMEGAKI H.Insulin resistance in the brain:a new therapeutic target for Alzheimer's disease[J].JDI,2013,4(2):150-151.
[19]HOSCHEIDT SM,STARKS EJ,OH JM,et al.Insulin resistance is associated with increased Alzheimer's disease pathology and reduced memory function in at-risk healthy middle-aged adults[J].J Alzheimers Dis,2016,52(4):1373-1383.
[20]KUBOTA T,KUBOTA N,MOROI M,et al.Lack of insulin receptor substrate-2 causes progressiveneointima formation in response to vessel injury[J].Circulation,2003,107(16):3073-3080.
[21]LI SZ,WANG NN,LOU JY,et al.Expression ofβ-site APPcleaving enzyme 1 in the hippocampal tissue of an insulin-resistant rat model of Alzheimer's disease[J].Exp Ther Med,2015,9(6):2389-2393.
[22]ANAND S,ANURAG K,KANWALJIT C,et al.Development of an experimental model of insulin resistance-induced Alzheimer's disease[J].Alzheimers Dement,2013,9(4):156-157.
[23]SUBRATA KB.Soluble receptor for advanced glycation end products and insulin resistance during development of type 2 diabetes mellitus[J].J Diabetes Complications,2015,29(4):611-620.
[24]KO SY,KO HA,CHU KH,et al.The possible mechanism of advanced glycation end products(AGEs)for Alzheimer's disease[J].PLo S One,2015,10(11):345-356.
[25]ANGELA K,SOPHIE CL,BJRN K,et al.Advanced glycation end products are mitogenic signals and trigger cell cycle reentry of neurons in Alzheimer's disease brain[J].Neurobiol Aging,2015,36(2):753-761.
[26]XAVIER G,ARANTXA G,CELIA-Z C,et al.N epsilon-carboxymethyllysine in brain aging,diabetes mellitus,and Alzheimer's disease[J].Free Radic Biol Med,2004,36(10):1241-1247.
[27]SMALL GW,ERCOLI LM,SILVERMANET DHS,et al.Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease[J].Proc Natl Acad Sci USA,2000,97(11):6037-6042.
[28]LAUGE S,CHRISTIAN I,NAJA LH,et al.Early detection of Alzheimer's disease using MRI hippocampal texture[J].Human Brain Mapping,2016,37(3):1148-1161.
[29]ARRIETA-CRUZ I,GUTIRREZ-JUREZ R.The role of insulin resistance and glucose metabolism dysregulation in the development of Alzheimer's disease[J].Rev Invest Clin,2016,68(2):53-58.
[30]MUSHTAQ G,KHAN JA,KUMOSANI TA,et al.Alzheimer's disease and type 2 diabetes via chronic inflammatory mechanisms[J].Saudi J Biol Sci,2015,22(1):4-13.
[31]MUSHTAQ G,KHAN JA,KAMAL MA,et al.Biological mechanisms linking Alzheimer's disease and type-2 diabetes mellitus[J].CNS Neurol Disord Drug Targets,2014,13(7):1192-1201.
[32]STRAUB RH.Insulin resistance,selfish brain,and selfish immune system:an evolutionarily positively selected program used in chronic inflammatory diseases[J].Arthritis Res Ther,2014,16(4):45-64.
[33]SCHTT T,HELBOE L,PEDERSEN L,et al.Dogs with cognitive dysfunction as a spontaneous model for early Alzheimer's disease:a translational study of neuropathological and inflammatory markers[J].J Alzheimers Dis,2016,52(2):433-449.
[34]AZIZI G,NAVABI SS,AL-SHUKAILI A,et al.The role of inflammatory mediators in the pathogenesis of Alzheimer's disease[J].Sultan Qaboos Univ Med J,2015,15(3):305-316.
[35]AVILA-MUOZ E,ARIAS C.When astrocytes become harmful:functional and inflammatory responses that contribute to Alzheimer's disease[J].Ageing Res Rev,2014,18(3):29-40.
[36]VERRI M,PASTORIS O,DOSSENA M,et al.Mitochondrial alterations,oxidative stress and neuroinflammation in Alzheimer's disease[J].Int J Immunopathol Pharmacol,2012,25(2):345-353.
[37]ZHOU X,LI Y,SHI X,et al.An overview on therapeutics attenuating amyloidβlevel in Alzheimer's disease:targeting neurotransmission,inflammation,oxidative stress and enhanced cholesterol levels[J].Am J Transl Res,2016,8(2):246-269.
[38]AHMED,OMYMA,GALAL,et al.Inflammation versus oxidative stress in pathophysiology of Alzheimer's disease in rat model[J].Ibnosina Journal of Medicine and Biomedical Sciences,2014,6(3):130-144.
[39]SANDRA J HAMILTON,GERALD F WATTS.Endothelial dysfunction in diabetes:pathogenesis,significance,and treatment[J].Rev Diabet Stud,2013,10(2-3):133-156.
[40]THOMAS T,MINERS S,LOVE S,et al.Post-mortem assessment of hypoperfusion of cerebral cortex in Alzheimer's disease and vascular dementia[J].Brain,2015,138(4):1059-1069.
[41]TIEHUIS AM,VINCKEN KL,VANDEN BERG E,et al.Cerebral perfusion in relation to cognitivefunction and type 2 diabetes[J].Diabetologia,2008,51(7):1321-1326.
[42]LESNSE,SHERMAN MA,GRANT M,et al.Brain amyloidbeta oligomers in ageing and Alzheimer's disease[J].Brain,2013,136(5):1383-1398.
[43]NAJEM D,BAMJI-MIRZA M,YANG Z,et al.Aβ-induced insulin resistance and the effects of insulin on the cholesterol synthesis pathway and Aβsecretion in neural cells[J].Neurosci Bull,2016,32(3):227-238.
[44]MIKLOSSY J,QING H,RADENOVIC A,et al.Beta amyloid and hyper phosphorylated tau deposits in the pancreas in type 2diabetes[J].Neurobiol Aging,2010,31(9):1503-1515.
[45]PEILA R,RODRIGUEZ BL,LAUNER LJ.Type 2 diabetes,APOE gene,and the risk for dementia and related pathologies:the honolulu-asia aging study[J].Diabetes,2002,51(4):1256-1262.
[46]WOLF AB,CASELL BJ,REIMAN EM,et al.APOE and neuroenergetics:an emerging paradigm in Alzheimer's disease[J].Neurobiol Aging,2013,34(4):1007-1017.
[47]NELOFAR S,MASOOD AQ,RUKHSHAN K,et al.Apo lipoprotein E4 gene APOE4:an early predictor of dementia/Alzheimer's disease[J].Scie Res Essays,2013,8(29):1374-1379.
[48]岳仁宋,王帅,陈源,等.2型糖尿病认知功能障碍的中医辨治[J].新中医,2011,43(6):137-138.