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CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Review Article

Interlink Between Insulin Resistance and Neurodegeneration with an Update on Current Therapeutic Approaches

Author(s): Subrat Kumar Bhattamisra*, Lee Yuen Shin, Hanis Izzati Binti Mohd Saad, Vikram Rao, Mayuren Candasamy, Manisha Pandey and Hira Choudhury

Volume 19 , Issue 3 , 2020

Page: [174 - 183] Pages: 10

DOI: 10.2174/1871527319666200518102130

Price: $65


The interlink between diabetes mellitus and neurodegenerative diseases such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) has been identified by several researchers. Patients with Type-2 Diabetes Mellitus (T2DM) are found to be affected with cognitive impairments leading to learning and memory deficit, while patients with Type-1 Diabetes Mellitus (T1DM) showed less severe levels of these impairments in the brain. This review aimed to discuss the connection between insulin with the pathophysiology of neurodegenerative diseases (AD and PD) and the current therapeutic approached mediated through insulin for management of neurodegenerative diseases. An extensive literature search was conducted using keywords “insulin”; “insulin resistance”; “Alzheimer’s disease”; “Parkinson’s disease” in public domains of Google scholar, PubMed, and ScienceDirect. Selected articles were used to construct this review. Studies have shown that impaired insulin signaling contributes to the accumulation of amyloid-β, neurofibrillary tangles, tau proteins and α-synuclein in the brain. Whereas, improvement in insulin signaling slows down the progression of cognitive decline. Various therapeutic approaches for altering the insulin function in the brain have been researched. Besides intranasal insulin, other therapeutics like PPAR-γ agonists, neurotrophins, stem cell therapy and insulin-like growth factor-1 are under investigation. Research has shown that insulin insensitivity in T2DM leads to neurodegeneration through mechanisms involving a variety of extracellular, membrane receptor, and intracellular signaling pathway disruptions. Some therapeutics, such as intranasal administration of insulin and neuroactive substances have shown promise but face problems related to genetic background, accessibility to the brain, and invasiveness of the procedures.

Keywords: Insulin resistance, amyloid β, α-synuclein, tau protein, insulin, neurodegeneration.

Graphical Abstract
Morris JK, Burns JM. Insulin: an emerging treatment for Alzheimer’s disease dementia? Curr Neurol Neurosci Rep 2012; 12(5): 520-7.
[] [PMID: 22791280]
Lee CC, Huang CC, Wu MY, Hsu KS. Insulin stimulates postsynaptic density-95 protein translation via the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway. J Biol Chem 2005; 280(18): 18543-50.
[] [PMID: 15755733]
Park CR, Seeley RJ, Craft S, Woods SC. Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav 2000; 68(4): 509-14.
[] [PMID: 10713291]
Gupta S, Singhal NK, Ganesh S, Sandhir R. Extending arms of insulin resistance from diabetes to Alzheimer’s disease: identification of potential therapeutic targets. CNS Neurol Disord Drug Targets 2019; 18(3): 172-84.
[] [PMID: 30430949]
Werther GA, Abate M, Hogg A, et al. Localization of insulin-like growth factor-I mRNA in rat brain by in situ hybridization--relationship to IGF-I receptors. Mol Endocrinol 1990; 4(5): 773-8.
[] [PMID: 2177145]
Yang L, Wang H, Liu L, Xie A. The role of insulin/IGF-1/PI3K/Akt/GSK3β signaling in Parkinson’s disease dementia. Front Neurosci 2018; 12: 73.
[] [PMID: 29515352]
Fadool DA, Tucker K, Phillips JJ, Simmen JA. Brain insulin receptor causes activity-dependent current suppression in the olfactory bulb through multiple phosphorylation of Kv1.3. J Neurophysiol 2000; 83(4): 2332-48.
[] [PMID: 10758137]
Wada A, Yokoo H, Yanagita T, Kobayashi H. New twist on neuronal insulin receptor signaling in health, disease, and therapeutics. J Pharmacol Sci 2005; 99(2): 128-43.
[] [PMID: 16210778]
Arshad N, Lin TS, Yahaya MF. Metabolic syndrome and its effect on the brain: possible mechanism. CNS Neurol Disord Drug Targets 2018; 17(8): 595-603.
[PMID: 30047340]
Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 1998; 50(1): 164-8.
[] [PMID: 9443474]
de la Monte SM. Brain insulin resistance and deficiency as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res 2012; 9(1): 35-66.
[] [PMID: 22329651]
Gratwicke J, Jahanshahi M, Foltynie T. Parkinson’s disease dementia: a neural networks perspective. Brain 2015; 138(Pt 6): 1454-76.
[] [PMID: 25888551]
Rosales-Corral S, Tan DX, Manchester L, Reiter RJ. Diabetes and Alzheimer disease, two overlapping pathologies with the same background: oxidative stress. Oxid Med Cell Longev 2015; 2015985845
[] [PMID: 25815110]
Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C. 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(2): 224-43.
[] [PMID: 18479783]
Hölscher C, Li L. New roles for insulin-like hormones in neuronal signalling and protection: new hopes for novel treatments of Alzheimer’s disease? Neurobiol Aging 2010; 31(9): 1495-502.
[] [PMID: 18930564]
Correia SC, Santos RX, Perry G, Zhu X, Moreira PI, Smith MA. Insulin-resistant brain state: the culprit in sporadic Alzheimer’s disease? Ageing Res Rev 2011; 10(2): 264-73.
[] [PMID: 21262392]
Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 2011; 68(1): 51-7.
[] [PMID: 20837822]
Benedict C, Brooks SJ, Kullberg J, et al. Impaired insulin sensitivity as indexed by the HOMA score is associated with deficits in verbal fluency and temporal lobe gray matter volume in the elderly. Diabetes Care 2012; 35(3): 488-94.
[] [PMID: 22301128]
Tan ZS, Beiser AS, Fox CS, et al. Association of metabolic dysregulation with volumetric brain magnetic resonance imaging and cognitive markers of subclinical brain aging in middle-aged adults: the Framingham Offspring Study. Diabetes Care 2011; 34(8): 1766-70.
[] [PMID: 21680719]
Athauda D, Foltynie T. Insulin resistance and Parkinson’s disease: a new target for disease modification? Prog Neurobiol 2016; 145-146: 98-120.
[] [PMID: 27713036]
Esparza TJ, Wildburger NC, Jiang H, et al. Soluble amyloid-beta aggregates from human Alzheimer’s disease brains. Sci Rep 2016; 6: 38187.
[] [PMID: 27917876]
Nussbaum JM, Schilling S, Cynis H, et al. Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β. Nature 2012; 485(7400): 651-5.
[] [PMID: 22660329]
Ashpole NM, Sanders JE, Hodges EL, Yan H, Sonntag WE. Growth hormone, insulin-like growth factor-1 and the aging brain. Exp Gerontol 2015; 68: 76-81.
[] [PMID: 25300732]
De Felice FG, Benedict C. A key role of insulin receptors in memory. Diabetes 2015; 64(11): 3653-5.
[] [PMID: 26494219]
McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem 2010; 93(4): 546-53.
[] [PMID: 20176121]
Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol 2018; 14: 450-64.
[] [PMID: 29080524]
de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2008; 2(6): 1101-13.
[] [PMID: 19885299]
Butterfield DA, Di Domenico F, Barone E. Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain. Biochim Biophys Acta 2014; 1842(9): 1693-706.
[] [PMID: 24949886]
Candasamy M, Elhassan SA, Bhattamisra SK, et al. Type 3 diabetes (Alzheimer’s disease): new insight for promising therapeutic avenues. Panminerva Med 2020.
[] [PMID: 32208408]
Talbot K, Wang HY, Kazi H, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 2012; 122(4): 1316-38.
[] [PMID: 22476197]
Bedse G, Di Domenico F, Serviddio G, Cassano T. Aberrant insulin signaling in Alzheimer’s disease: current knowledge. Front Neurosci 2015; 9: 204.
[] [PMID: 26136647]
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]
Qiu WQ, Folstein MF. Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer’s disease: review and hypothesis. Neurobiol Aging 2006; 27(2): 190-8.
[] [PMID: 16399206]
Ahmad SS, Khan S, Kamal MA, Wasi U. The structure and function of α, β and γ-secretase as therapeutic target enzymes in the development of Alzheimer’s disease: A review. CNS Neurol Disord Drug Targets 2019; 18(9): 657-67.
[] [PMID: 31608840]
Cardoso S, Correia S, Santos RX, et al. Insulin is a two-edged knife on the brain. J Alzheimers Dis 2009; 18(3): 483-507.
[] [PMID: 19542630]
Yarchoan M, Toledo JB, Lee EB, et al. Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies. Acta Neuropathol 2014; 128(5): 679-89.
[] [PMID: 25107476]
Perluigi M, Pupo G, Tramutola A, et al. Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain. Biochim Biophys Acta 2014; 1842(7): 1144-53.
[] [PMID: 24735980]
Rohn TT. The role of caspases in Alzheimer’s disease; potential novel therapeutic opportunities. Apoptosis 2010; 15(11): 1403-9.
[] [PMID: 20127416]
Fang F, Gao Y, Wang T, et al. Insulin signaling disruption in male mice due to perinatal bisphenol A exposure: Role of insulin signaling in the brain. Toxicol Lett 2016; 245: 59-67.
[] [PMID: 26779933]
Bosco D, Plastino M, Cristiano D, et al. Dementia is associated with insulin resistance in patients with Parkinson’s disease. J Neurol Sci 2012; 315(1-2): 39-43.
[] [PMID: 22265943]
Yuan YH, Yan WF, Sun JD, Huang JY, Mu Z, Chen NH. The molecular mechanism of rotenone-induced α-synuclein aggregation: emphasizing the role of the calcium/GSK3β pathway. Toxicol Lett 2015; 233(2): 163-71.
[] [PMID: 25433145]
Askar MH, Hussein AM, Al-Basiony SF, et al. Effects of exercise and ferulic acid on alpha synuclein and neuroprotective heat shock protein 70 in an experimental model of Parkinsonism disease. CNS Neurol Disord Drug Targets 2019; 18(2): 156-69.
[] [PMID: 30113007]
Majd S, Chegini F, Chataway T, Zhou XF, Gai W. Reciprocal induction between α-synuclein and β-amyloid in adult rat neurons. Neurotox Res 2013; 23(1): 69-78.
[] [PMID: 22610785]
Kumar A, Dhawan A, Kadam A, Shinde A. Autophagy and mitochondria: targets in neurodegenerative disorders. CNS Neurol Disord Drug Targets 2018; 17(9): 696-705.
[] [PMID: 30113005]
Gąssowska M, Czapski GA, Pająk B, Cieślik M, Lenkiewicz AM, Adamczyk A. Extracellular α-synuclein leads to microtubule destabilization via GSK-3β-dependent Tau phosphorylation in PC12 cells. PLoS One 2014; 9(4)e94259
[] [PMID: 24722055]
Sharma SK, Chorell E, Steneberg P, Vernersson-Lindahl E, Edlund H, Wittung-Stafshede P. Insulin-degrading enzyme prevents α-synuclein fibril formation in a nonproteolytical manner. Sci Rep 2015; 5: 12531.
[] [PMID: 26228656]
Quesada A, Lee BYMP, Micevych PE. PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson’s disease. Dev Neurobiol 2008; 68(5): 632-44.
[] [PMID: 18278798]
Lee CC, Adler AI, Sandhu MS, et al. Association of C-reactive protein with type 2 diabetes: prospective analysis and meta-analysis. Diabetologia 2009; 52(6): 1040-7.
[] [PMID: 19326095]
Pandareesh MD, Kandikattu HK, Razack S, et al. Nutrition and nutraceuticals in neuroinflammatory and brain metabolic stress: implications for neurodegenerative disorders. CNS Neurol Disord Drug Targets 2018; 17(9): 680-8.
[] [PMID: 29938622]
Balbaa M, Abdulmalek SA, Khalil S. Oxidative stress and expression of insulin signaling proteins in the brain of diabetic rats: role of Nigella sativa oil and antidiabetic drugs. PLoS One 2017; 12(5)e0172429
[] [PMID: 28505155]
Breteler MM. Vascular risk factors for Alzheimer’s disease: an epidemiologic perspective. Neurobiol Aging 2000; 21(2): 153-60.
[] [PMID: 10867200]
Marioni RE, Strachan MWJ, Reynolds RM, et al. Association between raised inflammatory markers and cognitive decline in elderly people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes 2010; 59(3): 710-3.
[] [PMID: 19959761]
Kuga GK, Botezelli JD, Gaspar RC, Gomes RJ, Pauli JR, De Almeida Leme JAC. Hippocampal insulin signaling and neuroprotection mediated by physical exercise in Alzheimer’s disease. Motriz Rev Educ Fis 2017; 23: 1-6.
Kandimalla R, Thirumala V, Reddy PH, States U, Texas N. Is Alzheimer’s disease a type 3 diabetes? A critical appraisal. Biochim Biophys Acta Mol Basis Dis 2017; 1863(5): 1078-89.
[] [PMID: 27567931]
Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 2015; 6(3): 456-80.
[] [PMID: 25897356]
Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 2009; 7(1): 65-74.
[] [PMID: 19721819]
Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta 2014; 1842(8): 1240-7.
[] [PMID: 24189435]
Mule NK, Singh JN. Diabetes mellitus to neurodegenerative disorders: Is oxidative stress fueling the flame? CNS Neurol Disord Drug Targets 2018; 17(9): 644-53.
[] [PMID: 30091419]
Lyoo IK, Yoon S, Renshaw PF, et al. Network-level structural abnormalities of cerebral cortex in type 1 diabetes mellitus. PLoS One 2013; 8(8)e71304
[] [PMID: 24058401]
Krug R, Benedict C, Born J, Hallschmid M. Comparable sensitivity of postmenopausal and young women to the effects of intranasal insulin on food intake and working memory. J Clin Endocrinol Metab 2010; 95(12): E468-72.
[] [PMID: 20719831]
Benedict C, Kern W, Schultes B, Born J, Hallschmid M. Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J Clin Endocrinol Metab 2008; 93(4): 1339-44.
[] [PMID: 18230654]
van der Heide LP, Kamal A, Artola A, Gispen WH, Ramakers GMJ. Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner. J Neurochem 2005; 94(4): 1158-66.
[] [PMID: 16092951]
Craft S, Asthana S, Cook DG, Baker LD, Cherrier M, Purganan K, 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.
Hanson LR, Frey WH II. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci 2008; 9(Suppl. 3): S5.
[] [PMID: 19091002]
Chapman CD, Frey WH II, Craft S, et al. Intranasal treatment of central nervous system dysfunction in humans. Pharm Res 2013; 30(10): 2475-84.
[] [PMID: 23135822]
Freiherr J, Hallschmid M, Frey WH II, et al. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs 2013; 27(7): 505-14.
[] [PMID: 23719722]
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(3): 595-602.
[] [PMID: 19625744]
Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T. Effect of intranasal insulin on cognitive function: a systematic review. J Clin Endocrinol Metab 2012; 97(2): 366-76.
[] [PMID: 22162476]
Rodrigue KM, Kennedy KM, Devous MD Sr, et al. β-Amyloid burden in healthy aging: regional distribution and cognitive consequences. Neurology 2012; 78(6): 387-95.
[] [PMID: 22302550]
Scazzocchio B, Varì R, D’Archivio M, et al. Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases. J Lipid Res 2009; 50(5): 832-45.
[] [PMID: 19136667]
Guthoff M, Grichisch Y, Canova C, et al. Insulin modulates food-related activity in the central nervous system. J Clin Endocrinol Metab 2010; 95(2): 748-55.
[] [PMID: 19996309]
Moon JH, Kim HJ, Yang AH, et al. The effect of rosiglitazone on LRP1 expression and amyloid β uptake in human brain microvascular endothelial cells: a possible role of a low-dose thiazolidinedione for dementia treatment. Int J Neuropsychopharmacol 2012; 15(1): 135-42.
[] [PMID: 22040807]
Escribano L, Simón 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(7): 1593-604.
[] [PMID: 20336061]
Landreth G, Jiang Q, Mandrekar S, Heneka M. PPARgamma agonists as therapeutics for the treatment of Alzheimer’s disease. Neurotherapeutics 2008; 5(3): 481-9.
[] [PMID: 18625459]
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(2): 131-46.
[] [PMID: 20733306]
Mannucci E, Monami M, Di Bari M, et al. Cardiac safety profile of rosiglitazone: a comprehensive meta-analysis of randomized clinical trials. Int J Cardiol 2010; 143(2): 135-40.
[] [PMID: 19328563]
Babaei P, Soltani Tehrani B, Alizadeh A. Transplanted bone marrow mesenchymal stem cells improve memory in rat models of Alzheimer’s disease. Stem Cells Int 2012; 2012369417
[] [PMID: 22754576]
Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta JA. Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen Med 2010; 5(6): 933-46.
[] [PMID: 21082892]
Singh A, Hasan A, Tiwari S, Pandey LM. Therapeutic advancement in Alzheimer disease: new hopes on the horizon? CNS Neurol Disord Drug Targets 2018; 17(8): 571-89.
[] [PMID: 29952273]
Layliev J, Wilson S, Warren SM, Saadeh PB. Improving wound healing with topical gene therapy. Adv Wound Care (New Rochelle) 2012; 1(5): 218-23.
[] [PMID: 24527309]
Ikehara S, Li M. Stem cell transplantation improves aging-related diseases. Front Cell Dev Biol 2014; 2: 16.
[] [PMID: 25364723]
Amemori T, Jendelova P, Ruzicka J, Urdzikova LM, Sykova E. Alzheimer’s disease: Mechanism and approach to cell therapy. Int J Mol Sci 2015; 16(11): 26417-51.
[] [PMID: 26556341]
Poduslo JF, Curran GL, Berg CT. Macromolecular permeability across the blood-nerve and blood-brain barriers. Proc Natl Acad Sci USA 1994; 91(12): 5705-9.
[] [PMID: 8202551]
Rinne JO, Kaasinen V, Järvenpää T, et al. Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2003; 74(1): 113-5.
[] [PMID: 12486280]
Capsoni S, Marinelli S, Ceci M, et al. Intranasal “painless” human nerve growth factor [corrected] slows amyloid neurodegeneration and prevents memory deficits in App X PS1 mice. PLoS One 2012; 7(5)e37555
[] [PMID: 22666365]
Mufson EJ, Counts SE, Perez SE, Ginsberg SD. Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications. Expert Rev Neurother 2008; 8(11): 1703-18.
[] [PMID: 18986241]

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