Top

Current Neurology and Neuroscience Reports

Published in:

01-10-2012 | Dementia (KS Marder, Section Editor)

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

Authors: Jill K. Morris, Jeffrey M. Burns

Published in: Current Neurology and Neuroscience Reports | Issue 5/2012

Abstract

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.

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):354–7.PubMed

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;259:11672–5.PubMed

Raizada MK, Shemer J, Judkins JH, et al. Insulin receptors in the brain: structural and physiological characterization. Neurochem Res. 1988;13:297–303.PubMedCrossRef

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;117:1590–7.PubMedCrossRef

Gammeltoft S, Fehlmann M, Van Obberghen E. Insulin receptors in the mammalian central nervous system: binding characteristics and subunit structure. Biochimie. 1985;67:1147–53.PubMedCrossRef

Uemura E, Greenlee HW. Insulin regulates neuronal glucose uptake by promoting translocation of glucose transporter GLUT3. Exp Neurol. 2006;198:48–53.PubMedCrossRef

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;98:3561–6.PubMedCrossRef

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.PubMedCrossRef

Wan Q, Xiong ZG, Man HY, et al. Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature. 1997;388:686–90.PubMedCrossRef

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;31:224–43.PubMedCrossRef

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;7:63–80.PubMed

12.

Lee HK, Kumar P, Fu Q, et al. The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid. Mol Biol Cell. 2009;20:1533–44.PubMedCrossRef

13.

Liu Y, Liu F, Grundke-Iqbal I, et al. Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. J Pathol. 2011;225:54–62.PubMedCrossRef

14.

van der Heide LP, Ramakers GM, Smidt MP. Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol. 2006;79:205–21.PubMedCrossRef

15.

Ott A, Stolk RP, van Harskamp F, et al. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology. 1999;53:1937–42.PubMedCrossRef

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;145:301–8.PubMedCrossRef

17.

Cheng D, Noble J, Tang MX, et al. Type 2 diabetes and late-onset Alzheimer's disease. Dement Geriatr Cogn Disord. 2011;31:424–30.PubMedCrossRef

18.

Luchsinger JA, Reitz C, Patel B, et al. Relation of diabetes to mild cognitive impairment. Arch Neurol. 2007;64:570–5.PubMedCrossRef

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;58:71–7.PubMedCrossRef

20.

Yaffe K, Blackwell T, Kanaya AM, et al. Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology. 2004;63:658–63.PubMedCrossRef

21.

Janson J, Laedtke T, Parisi JE, et al. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes. 2004;53:474–81.PubMedCrossRef

22.

Stewart R, Liolitsa D. Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med. 1999;16:93–112.PubMedCrossRef

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;51:1256–62.PubMedCrossRef

24.

Arvanitakis Z, Wilson RS, Bienias JL, et al. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol. 2004;61:661–6.PubMedCrossRef

25.

Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biol Psychiatry. 2010;67:505–12.PubMedCrossRef

26.

Ronnemaa E, Zethelius B, Sundelof J, et al. Impaired insulin secretion increases the risk of Alzheimer disease. Neurology. 2008;71:1065–71.PubMedCrossRef

27.

Zhao WQ, De Felice FG, Fernandez S, et al. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008;22:246–60.PubMedCrossRef

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;106:1971–6.PubMedCrossRef

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;21:2561–70.PubMed

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;62:1539–44.PubMedCrossRef

31.

Watson GS, Peskind ER, Asthana S, et al. Insulin increases CSF Abeta42 levels in normal older adults. Neurology. 2003;60:1899–903.PubMedCrossRef

32.

Kulstad JJ, Green PS, Cook DG, et al. Differential modulation of plasma beta-amyloid by insulin in patients with Alzheimer disease. Neurology. 2006;66:1506–10.PubMedCrossRef

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):333–339.

34.

Bloomgarden ZT. Measures of insulin sensitivity. Clin Lab Med. 2006;26:611–33. vi.PubMedCrossRef

35.

Kern W, Peters A, Fruehwald-Schultes B, et al. Improving influence of insulin on cognitive functions in humans. Neuroendocrinology. 2001;74:270–80.PubMedCrossRef

36.

Craft S, Newcomer J, Kanne S, et al. Memory improvement following induced hyperinsulinemia in Alzheimer's disease. Neurobiol Aging. 1996;17:123–30.PubMedCrossRef

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;56:1135–40.PubMedCrossRef

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;5:514–6.PubMedCrossRef

40.

Benedict C, Hallschmid M, Schmitz K, et al. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology. 2007;32:239–43.PubMedCrossRef

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;27:451–8.PubMedCrossRef

42.

Benedict C, Hallschmid M, Hatke A, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29:1326–34.PubMedCrossRef

43.

• Reger MA, Watson GS, Green PS, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008;70:440–8. 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.PubMedCrossRef

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;69:29–38. Authors report that 4 months of twice daily intranasal insulin preserved cognitive function and caregiver-rated functional status in individuals with AD or MCI.PubMedCrossRef

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;43:1467–72.PubMedCrossRef

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;18:595–602.PubMed

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;903:222–8.PubMedCrossRef

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;13:323–31.PubMed

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;28:809–22.PubMedCrossRef

50.

Hanefeld M. Pioglitazone and sulfonylureas: effectively treating type 2 diabetes. Int J Clin Pract Suppl. 2007;61 Suppl 153:20–7.CrossRef

51.

Choi JH, Banks AS, Estall JL, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature. 2010;466:451–6.PubMedCrossRef

52.

Landreth G, Jiang Q, Mandrekar S, et al. PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease. Neurotherapeutics. 2008;5:481–9.PubMedCrossRef

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;35:1593–604.PubMedCrossRef

54.

Pedersen WA, McMillan PJ, Kulstad JJ, et al. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol. 2006;199:265–73.PubMedCrossRef

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;13:950–8.PubMed

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;33:1706–11.PubMedCrossRef

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;30:131–46. 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.PubMedCrossRef

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;8:592–606. 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.PubMedCrossRef

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;22:1241–56. 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+).PubMed

60.

Kaur B, Singh N, Jaggi AS. Exploring mechanism of pioglitazone-induced memory restorative effect in experimental dementia. Fundam Clin Pharmacol. 2009;23:557–66.PubMedCrossRef

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;197:398–403.PubMedCrossRef

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;57:177–9.PubMedCrossRef

63.

Sato T, Hanyu H, Hirao K, et al. Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011;32:1626–33.PubMedCrossRef

64.

Kim B, Feldman EL. Insulin resistance in the nervous system. Trends in endocrinology and metabolism: TEM. Mar 2012;23(3):133–141.

65.

Sykiotis GP, Papavassiliou AG. Serine phosphorylation of insulin receptor substrate-1: a novel target for the reversal of insulin resistance. Mol Endocrinol. 2001;15:1864–9.PubMedCrossRef

66.

Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414:799–806.PubMedCrossRef

67.

Khan AH, Pessin JE. Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Diabetologia. 2002;45:1475–83.PubMedCrossRef

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.PubMed

69.

Kremer A, Louis JV, Jaworski T, et al. GSK3 and Alzheimer's disease: facts and fiction. Front Mol Neurosci. 2011;4:17.PubMedCrossRef

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;113:93–102.PubMedCrossRef

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;29:6771–9.PubMedCrossRef

72.

Rodrigue KM, Kennedy KM, Devous Sr MD, et al. Beta-amyloid burden in healthy aging: regional distribution and cognitive consequences. Neurology. 2012;78:387–95.PubMedCrossRef

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;50:696–702.PubMedCrossRef

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;175:23–30.PubMedCrossRef

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;50:832–45.PubMedCrossRef

76.

Sanz C, Andrieu S, Sinclair A, et al. Diabetes is associated with a slower rate of cognitive decline in Alzheimer disease. Neurology. 2009;73:1359–66.PubMedCrossRef

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;41:1305–12.PubMed

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;29:345–51.PubMedCrossRef

Title: Insulin: An Emerging Treatment for Alzheimer’s Disease Dementia?
Authors: Jill K. Morris
Jeffrey M. Burns
Publication date: 01-10-2012
Publisher: Current Science Inc.
Published in: Current Neurology and Neuroscience Reports / Issue 5/2012
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI: https://doi.org/10.1007/s11910-012-0297-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2012

Benign Multiple Sclerosis: Does it exist?

Modifiable Comorbidities and Disability in Multiple Sclerosis

Sleep-Disordered Breathing and Cognition in Older Adults

New Disease-Modifying Therapies and New Challenges for MS

Biomarkers in Traumatic Brain Injury

Assessing Dementia in Resource-Poor Regions