Insulin: An Emerging Treatment for Alzheimer’s Disease Dementia?

详细信息    查看全文

• 作者：Jill K. Morris (1)
  Jeffrey M. Burns (1) (2)
  
• 关键词：Insulin ; Dementia ; Alzheimer’s disease ; Apolipoprotein E ; Amyloid ; Rosiglitazone ; Pioglitazone ; Insulin signaling ; Cognition ; Memory ; Intranasal ; Thiazolidinedione ; Diabetes
• 刊名：Current Neurology and Neuroscience Reports
• 出版年：2012
• 出版时间：October 2012
• 年：2012
• 卷：12
• 期：5
• 页码：520-527
• 全文大小：245KB
• 参考文献：1. Bjornholm M, Zierath JR. Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes. Biochem Soc Trans. 2005;33(Pt 2):354-.
  2. Clarke DW, Boyd Jr FT, Kappy MS, et al. Insulin binds to specific receptors and stimulates 2-deoxy-D-glucose uptake in cultured glial cells from rat brain. J Biol Chem. 1984;259:11672-.
  3. Raizada MK, Shemer J, Judkins JH, et al. Insulin receptors in the brain: structural and physiological characterization. Neurochem Res. 1988;13:297-03. CrossRef
  4. Smythe GA, Bradshaw JE, Nicholson MV, et al. Rapid bidirectional effects of insulin on hypothalamic noradrenergic and serotoninergic neuronal activity in the rat: role in glucose homeostasis. Endocrinology. 1985;117:1590-. CrossRef
  5. Gammeltoft S, Fehlmann M, Van Obberghen E. Insulin receptors in the mammalian central nervous system: binding characteristics and subunit structure. Biochimie. 1985;67:1147-3. CrossRef
  6. Uemura E, Greenlee HW. Insulin regulates neuronal glucose uptake by promoting translocation of glucose transporter GLUT3. Exp Neurol. 2006;198:48-3. CrossRef
  7. Skeberdis VA, Lan J, Zheng X, et al. Insulin promotes rapid delivery of N-methyl-D- aspartate receptors to the cell surface by exocytosis. Proc Natl Acad Sci U S A. 2001;98:3561-. CrossRef
  8. Jin Z, Jin Y, Kumar-Mendu S, et al. Insulin reduces neuronal excitability by turning on GABA(A) channels that generate tonic current. PLoS One. 2011;6:e16188. CrossRef
  9. Wan Q, Xiong ZG, Man HY, et al. Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature. 1997;388:686-0. CrossRef
  10. Moloney AM, Griffin RJ, Timmons S, et al. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010;31:224-3. CrossRef
  11. Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease—is this type 3 diabetes? J Alzheimers Dis. 2005;7:63-0.
  12. Lee HK, Kumar P, Fu Q, et al. The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid. Mol Biol Cell. 2009;20:1533-4. mbc.E08-07-0777">CrossRef
  13. Liu Y, Liu F, Grundke-Iqbal I, et al. / Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. J Pathol. 2011;225:54-2. CrossRef
  14. van der Heide LP, Ramakers GM, Smidt MP. Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol. 2006;79:205-1. CrossRef
  15. Ott A, Stolk RP, van Harskamp F, et al. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology. 1999;53:1937-2. CrossRef
  16. Leibson CL, Rocca WA, Hanson VA, et al. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol. 1997;145:301-. CrossRef
  17. Cheng D, Noble J, Tang MX, et al. Type 2 diabetes and late-onset Alzheimer's disease. Dement Geriatr Cogn Disord. 2011;31:424-0. CrossRef
  18. Luchsinger JA, Reitz C, Patel B, et al. Relation of diabetes to mild cognitive impairment. Arch Neurol. 2007;64:570-. CrossRef
  19. Xu W, Qiu C, Gatz M, et al. Mid- and late-life diabetes in relation to the risk of dementia: a population-based twin study. Diabetes. 2009;58:71-. CrossRef
  20. Yaffe K, Blackwell T, Kanaya AM, et al. Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology. 2004;63:658-3. CrossRef
  21. Janson J, Laedtke T, Parisi JE, et al. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes. 2004;53:474-1. CrossRef
  22. Stewart R, Liolitsa D. Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med. 1999;16:93-12. CrossRef
  23. Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu–Asia Aging Study. Diabetes. 2002;51:1256-2. CrossRef
  24. Arvanitakis Z, Wilson RS, Bienias JL, et al. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol. 2004;61:661-. CrossRef
  25. Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biol Psychiatry. 2010;67:505-2. CrossRef
  26. Ronnemaa E, Zethelius B, Sundelof J, et al. Impaired insulin secretion increases the risk of Alzheimer disease. Neurology. 2008;71:1065-1. CrossRef
  27. Zhao WQ, De Felice FG, Fernandez S, et al. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008;22:246-0. m">CrossRef
  28. De Felice FG, Vieira MN, Bomfim TR, et al. Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009;106:1971-. CrossRef
  29. Gasparini L, Gouras GK, Wang R, et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001;21:2561-0.
  30. Fishel MA, Watson GS, Montine TJ, et al. Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol. 2005;62:1539-4. CrossRef
  31. Watson GS, Peskind ER, Asthana S, et al. Insulin increases CSF Abeta42 levels in normal older adults. Neurology. 2003;60:1899-03. CrossRef
  32. Kulstad JJ, Green PS, Cook DG, et al. Differential modulation of plasma beta-amyloid by insulin in patients with Alzheimer disease. Neurology. 2006;66:1506-0. CrossRef
  33. Burns JM, Honea RA, Vidoni ED, et al. Insulin is differentially related to cognitive decline and atrophy in Alzheimer's disease and aging. Biochimica et biophysica acta. Mar 2012;1822(3):333-39.
  34. Bloomgarden ZT. Measures of insulin sensitivity. Clin Lab Med. 2006;26:611-3. vi. CrossRef
  35. Kern W, Peters A, Fruehwald-Schultes B, et al. Improving influence of insulin on cognitive functions in humans. Neuroendocrinology. 2001;74:270-0. CrossRef
  36. Craft S, Newcomer J, Kanne S, et al. Memory improvement following induced hyperinsulinemia in Alzheimer's disease. Neurobiol Aging. 1996;17:123-0. CrossRef
  37. Craft S, Asthana S, Newcomer JW, et al. Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry. 1999;56:1135-0. CrossRef
  38. Hanson LR, Frey 2nd WH. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci. 2009;9 Suppl 3:S5. CrossRef
  39. Born J, Lange T, Kern W, et al. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci. 2002;5:514-. CrossRef
  40. Benedict C, Hallschmid M, Schmitz K, et al. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology. 2007;32:239-3. CrossRef
  41. Reger MA, Watson GS, Frey 2nd WH, et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006;27:451-. CrossRef
  42. Benedict C, Hallschmid M, Hatke A, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29:1326-4. CrossRef
  43. -Reger MA, Watson GS, Green PS, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008;70:440-. / This article demonstrated that repeated dosing with intranasal insulin (2×/day) for 3?weeks improved memory (story recall) and caregiver-rated functional status in individuals with AD. CrossRef
  44. -Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69:29-8. / Authors report that 4?months of twice daily intranasal insulin preserved cognitive function and caregiver-rated functional status in individuals with AD or MCI. CrossRef
  45. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993;43:1467-2. CrossRef
  46. Watson GS, Baker LD, Cholerton BA, et al. Effects of insulin and octreotide on memory and growth hormone in Alzheimer's disease. J Alzheimers Dis. 2009;18:595-02.
  47. Craft S, Asthana S, Schellenberg G, et al. Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer's disease differ according to apolipoprotein-E genotype. Ann N Y Acad Sci. 2000;903:222-. CrossRef
  48. Reger MA, Watson GS, Green PS, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis. 2008;13:323-1.
  49. Craft S, Asthana S, Cook DG, et al. Insulin dose–response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology. 2003;28:809-2. CrossRef
  50. Hanefeld M. Pioglitazone and sulfonylureas: effectively treating type 2 diabetes. Int J Clin Pract Suppl. 2007;61 Suppl 153:20-. CrossRef
  51. Choi JH, Banks AS, Estall JL, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature. 2010;466:451-. CrossRef
  52. Landreth G, Jiang Q, Mandrekar S, et al. PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease. Neurotherapeutics. 2008;5:481-. CrossRef
  53. Escribano L, Simon AM, Gimeno E, et al. Rosiglitazone rescues memory impairment in Alzheimer's transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology. 2010;35:1593-04. CrossRef
  54. Pedersen WA, McMillan PJ, Kulstad JJ, et al. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol. 2006;199:265-3. CrossRef
  55. Watson GS, Cholerton BA, Reger MA, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry. 2005;13:950-.
  56. Abbatecola AM, Lattanzio F, Molinari AM, et al. Rosiglitazone and cognitive stability in older individuals with type 2 diabetes and mild cognitive impairment. Diabetes Care. 2010;33:1706-1. CrossRef
  57. -Gold M, Alderton C, Zvartau-Hind M, et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord. 2010;30:131-6. / This large, phase III study of rosiglitazone extended release found that 24?weeks of treatment did not elict effects on any primary outcome measures (ADAS-Cog and CIBC+), as compared with a placebo. CrossRef
  58. -Harrington C, Sawchak S, Chiang C, et al. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies. Curr Alzheimer Res. 2011;8:592-06. / This large, phase III study of rosiglitazone extended release found that 48?weeks of treatment did not alter primary outcome measures (ADAS-Cog and CDR-SB), as compared with a placebo. CrossRef
  59. -Tzimopoulou S, Cunningham VJ, Nichols TE, et al. A multicenter randomized proof-of-concept clinical trial applying [(1)F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease. J Alzheimers Dis. 2010;22:1241-6. / This multicenter trial tested rosiglitazone extended release dosing for 1?year and found no significant differences in the primary outcome measure of brain glucose metabolism using 18F FDG-PET. Moreover, no significant differences were evident in secondary outcome measures (ADAS-cog and CIBIC+).
  60. Kaur B, Singh N, Jaggi AS. Exploring mechanism of pioglitazone-induced memory restorative effect in experimental dementia. Fundam Clin Pharmacol. 2009;23:557-6. CrossRef
  61. Kumar P, Kaundal RK, More S, et al. Beneficial effects of pioglitazone on cognitive impairment in MPTP model of Parkinson's disease. Behav Brain Res. 2009;197:398-03. CrossRef
  62. Hanyu H, Sato T, Kiuchi A, et al. Pioglitazone improved cognition in a pilot study on patients with Alzheimer's disease and mild cognitive impairment with diabetes mellitus. J Am Geriatr Soc. 2009;57:177-. CrossRef
  63. Sato T, Hanyu H, Hirao K, et al. Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011;32:1626-3. CrossRef
  64. Kim B, Feldman EL. Insulin resistance in the nervous system. Trends in endocrinology and metabolism: TEM. Mar 2012;23(3):133-41.
  65. Sykiotis GP, Papavassiliou AG. Serine phosphorylation of insulin receptor substrate-1: a novel target for the reversal of insulin resistance. Mol Endocrinol. 2001;15:1864-. me.15.11.1864">CrossRef
  66. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414:799-06. CrossRef
  67. Khan AH, Pessin JE. Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Diabetologia. 2002;45:1475-3. CrossRef
  68. Xie L, Helmerhorst E, Taddei K, et al. Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci. 2002;22:RC221.
  69. Kremer A, Louis JV, Jaworski T, et al. GSK3 and Alzheimer's disease: facts and fiction. Front Mol Neurosci. 2011;4:17. mol.2011.00017">CrossRef
  70. Li X, Lu F, Tian Q, et al. Activation of glycogen synthase kinase-3 induces Alzheimer-like tau hyperphosphorylation in rat hippocampus slices in culture. J Neural Transm. 2006;113:93-02. CrossRef
  71. Bales KR, Liu F, Wu S, et al. Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. J Neurosci. 2009;29:6771-. CrossRef
  72. Rodrigue KM, Kennedy KM, Devous Sr MD, et al. Beta-amyloid burden in healthy aging: regional distribution and cognitive consequences. Neurology. 2012;78:387-5. CrossRef
  73. Srinivasan SR, Ehnholm C, Elkasabany A, et al. Apolipoprotein E polymorphism modulates the association between obesity and dyslipidemias during young adulthood: the Bogalusa Heart Study. Metabolism. 2001;50:696-02. meta.2001.23299">CrossRef
  74. Maziere C, Morliere P, Santus R, et al. Inhibition of insulin signaling by oxidized low density lipoprotein: protective effect of the antioxidant Vitamin E. Atherosclerosis. 2004;175:23-0. CrossRef
  75. Scazzocchio B, Vari R, D'Archivio M, et al. Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases. J Lipid Res. 2009;50:832-5. CrossRef
  76. Sanz C, Andrieu S, Sinclair A, et al. Diabetes is associated with a slower rate of cognitive decline in Alzheimer disease. Neurology. 2009;73:1359-6. CrossRef
  77. Gradman TJ, Laws A, Thompson LW, et al. Verbal learning and/or memory improves with glycemic control in older subjects with non-insulin-dependent diabetes mellitus. J Am Geriatr Soc. 1993;41:1305-2.
  78. Ryan CM, Freed MI, Rood JA, et al. Improving metabolic control leads to better working memory in adults with type 2 diabetes. Diabetes Care. 2006;29:345-1. CrossRef
  
• 作者单位：Jill K. Morris (1)
  Jeffrey M. Burns (1) (2)
  
  1. Department of Neurology and Alzheimer’s Disease Center, University of Kansas Medical Center, Fairway, KS, 66205, USA
  2. KU Medical Center Clinical Research Center, Alzheimer’s Disease Center, Mail Stop 6002, 4350 Shawnee Mission Parkway, Fairway, KS, 66205, USA
  

文摘

Accumulating evidence indicates a role for metabolic dysfunction in the pathogenesis of Alzheimer’s disease (AD). It is widely reported that Type 2 diabetes (T2D) increases the risk of developing AD, and several postmortem analyses have found evidence of insulin resistance in the AD brain. Thus, insulin-based therapies have emerged as potential strategies to slow cognitive decline in AD. The main methods for targeting insulin to date have been intravenous insulin infusion, intranasal insulin administration, and use of insulin sensitizers. These methods have elicited variable results regarding improvement in cognitive function. This review will discuss the rationale for targeting insulin signaling to improve cognitive function in AD, the results of clinical studies that have targeted insulin signaling, and what these results mean for future studies of the role of insulin-based therapies for AD.