Type 2 Diabetes Mellitus Easily Develops into Alzheimer’s Disease via Hyperglycemia and Insulin Resistance

Abstract

With the acceleration of population aging, the incidence of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) is progressively increasing due to the age-relatedness of these two diseases. The association between T2DM and AD-like dementia is receiving much attention, and T2DM is reported to be a significant risk factor for AD. The aims of this review were to reveal the brain changes caused by T2DM as well as to explore the roles of hyperglycemia and insulin resistance in the development of AD.

Keywords

type 2 diabetes mellitus / Alzheimer’s disease / hyperglycemia / insulin resistance / cognition

References

[1] BiesselsGJ, DearyIJ, RyanCM. Cognition and diabetes: a lifespan perspective. Lancet Neurol, 2008, 7(2): 184-190

[2] ExaltoLG, WhitmerRA, KappeleLJ, et al.. An update on type 2 diabetes, vascular dementia and Alzheimer’s disease. Exp Gerontol, 2012, 47(11): 858-864

[3] StumvollM, GoldsteinBJ, van HaeftenTW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet, 2005, 365(9467): 1333-1346

[4] UmegakiH. Type 2 diabetes as a risk factor for cognitive impairment: current insights. Clin Interv Aging, 2014, 9: 1011-1019

[5] OgurtsovaK, da Rocha FernandesJD, HuangY, et al.. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract, 2017, 128: 40-50

[6] Collaboration NCDRF. Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet, 2016, 387(10027): 1513-1530

[7] ChatterjeeS, KhuntiK, DaviesMJ. Type 2 diabetes. Lancet, 2017, 389(10085): 2239-2251

[8] KellarD, CraftS. Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol, 2020, 19(9): 758-766

[9] McCrimmonRJ, RyanCM, FrierBM. Diabetes and cognitive dysfunction. Lancet, 2012, 379(9833): 2291-2299

[10] KahnSE, CooperME, Del PratoS. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet, 2014, 383(9922): 1068-1083

[11] WangJZ, LiuF. Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol, 2008, 85(2): 148-175

[12] CoxDJ, KovatchevBP, Gonder-FrederickLA, et al.. Relationships between hyperglycemia and cognitive performance among adults with type 1 and type 2 diabetes. Diabetes Care, 2005, 28(1): 71-77

[13] HossainMS, OomuraY, FujinoT, et al.. Glucose signaling in the brain and periphery to memory. Neurosci Biobehav Rev, 2020, 110: 100-113

[14] PeilaR, RodriguezBL, LaunerLJ, et al.. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes, 2002, 51(4): 1256-1262

[15] ArvanitakisZ, WilsonRS, BieniasJL, et al.. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol, 2004, 61(5): 661-666

[16] XuWL, QiuCX, WahlinA, et al.. Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology, 2004, 63(7): 1181-1186

[17] OharaT, DoiY, NinomiyaT, et al.. Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology, 2011, 77(12): 1126-1134

[18] HuangCC, ChungCM, LeuHB, et al.. Diabetes mellitus and the risk of Alzheimer’s disease: a nationwide population-based study. PLoS One, 2014, 9(1): e87095

[19] JansonJ, LaedtkeT, ParisiJE, et al.. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes, 2004, 53(2): 474-481

[20] BiesselsGJ, ReijmerYD. Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI?. Diabetes, 2014, 63(7): 2244-2252

[21] GoldSM, DziobekI, SweatV, et al.. Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia, 2007, 50(4): 711-719

[22] den HeijerT, VermeerSE, van DijkEJ, et al.. Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia, 2003, 46(12): 1604-1610

[23] MoheetA, MangiaS, SeaquistER. Impact of diabetes on cognitive function and brain structure. Ann N Y Acad Sci, 2015, 1353: 60-71

[24] PantoniL, GarciaJH. Pathogenesis of leukoaraiosis: a review. Stroke, 1997, 28(3): 652-659

[25] MergenthalerP, LindauerU, DienelGA, et al.. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci, 2013, 36(10): 587-597

[26] YuAS, HirayamaBA, TimbolG, et al.. Regional distribution of SGLT activity in rat brain in vivo. Am J Physiol Cell Physiol, 2013, 304(3): C240-247

[27] HarrisJJ, JolivetR, AttwellD. Synaptic energy use and supply. Neuron, 2012, 75(5): 762-777

[28] HossainMS, OomuraY, KatafuchiT. Glucose Can Epigenetically Alter the Gene Expression of Neurotrophic Factors in the Murine Brain Cells. Mol Neurobiol, 2018, 55(4): 3408-3425

[29] JinL, LinL, LiGY, et al.. Monosodium glutamate exposure during the neonatal period leads to cognitive deficits in adult Sprague-Dawley rats. Neurosci Lett, 2018, 682: 39-44

[30] MoreiraPI. High-sugar diets, type 2 diabetes and Alzheimer’s disease. Curr Opin Clin Nutr Metab Care, 2013, 16(4): 440-445

[31] HwangIK, ChoiJH, NamSM, et al.. Activation of microglia and induction of pro-inflammatory cytokines in the hippocampus of type 2 diabetic rats. Neurol Res, 2014, 36(9): 824-832

[32] JiangQ, ZhangL, DingG, et al.. Impairment of the glymphatic system after diabetes. J Cereb Blood Flow Metab, 2017, 37(4): 1326-1337

[33] IliffJJ, WangM, ZeppenfeldDM, et al.. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci, 2013, 33(46): 18190-18199

[34] MosconiL, PupiA, De LeonMJ. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci, 2008, 1147: 180-195

[35] AlexanderGE, ChenK, PietriniP, et al.. Longitudinal PET Evaluation of Cerebral Metabolic Decline in Dementia: A Potential Outcome Measure in Alzheimer’s Disease Treatment Studies. Am J Psychiatry, 2002, 159(5): 738-745

[36] MerliniM, MeyerEP, Ulmann-SchulerA, et al.. Vascular beta-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAbeta mice. Acta Neuropathol, 2011, 122(3): 293-311

[37] WhitmerRA, KarterAJ, YaffeK, et al.. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA, 2009, 301(15): 1565-1572

[38] ChowersI, LavyS, HalpernL. Effect of insulin administered intracisternally on the glucose level of the blood and the cerebrospinal fluid in vagotomized dogs. Exp Neurol, 1966, 14(3): 383-389

[39] GhasemiR, HaeriA, DargahiL, et al.. Insulin in the brain: sources, localization and functions. Mol Neurobiol, 2013, 47(1): 145-171

[40] HillJM, LesniakMA, PertCB, et al.. Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience, 1986, 17(4): 1127-1138

[41] CzerneckiV, PillonB, HouetoJL, et al.. Motivation, reward, and Parkinson’s disease: influence of dopatherapy. Neuropsychologia, 2002, 40(13): 2257-2267

[42] AvilaJ, Leon-EspinosaG, GarciaE, et al.. Tau Phosphorylation by GSK3 in Different Conditions. Int J Alzheimers Dis, 2012, 2012: 578373

[43] FarrarC, HouserCR, ClarkeS. Activation of the PI3K/Akt signal transduction pathway and increased levels of insulin receptor in protein repair-deficient mice. Aging Cell, 2005, 4(1): 1-12

[44] ZhangW, ThompsonBJ, HietakangasV, et al.. MAPK/ERK signaling regulates insulin sensitivity to control glucose metabolism in Drosophila. PLoS Genet, 2011, 7(12): e1002429

[45] ThielsE, KlannE. Extracellular signal-regulated kinase, synaptic plasticity, and memory. Rev Neurosci, 2001, 12(4): 327-345

[46] ShowkatM, BeighMA, AndrabiKI. mTOR Signaling in Protein Translation Regulation: Implications in Cancer Genesis and Therapeutic Interventions. Mol Biol Int, 2014, 2014: 686984

[47] BoucherJ, KleinriddersA, KahnCR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol, 2014, 6(1): a009191

[48] Martinez-ValbuenaI, Valenti-AzcarateR, Amat-VillegasI, et al.. Amylin as a potential link between type 2 diabetes and alzheimer disease. Ann Neurol, 2019, 86(4): 539-551

[49] AkhtarA, DhaliwalJ, SahSP. 7,8-Dihydroxyflavone improves cognitive functions in ICV-STZ rat model of sporadic Alzheimer’s disease by reversing oxidative stress, mitochondrial dysfunction, and insulin resistance. Psychopharmacology (Berl), 2021, 238(7): 1991-2009

[50] XuJ, GaoH, ZhangL, et al.. Melatonin alleviates cognition impairment by antagonizing brain insulin resistance in aged rats fed a high-fat diet. J Pineal Res, 2019, 67(2): e12584

[51] BoccardiV, MuraseccoI, MecocciP. Diabetes drugs in the fight against Alzheimer’s disease. Ageing Res Rev, 2019, 54: 100936

[52] BaoH, LiuY, ZhangM, et al.. Increased beta-site APP cleaving enzyme 1-mediated insulin receptor cleavage in type 2 diabetes mellitus with cognitive impairment. Alzheimers Dement, 2021, 238(7): 1991-2009

[53] QiuWQ, FolsteinMF. Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer’s disease: review and hypothesis. Neurobiol Aging, 2006, 27(2): 190-198

[54] GaspariniL, GourasGK, WangR, 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(8): 2561-2570

[55] MatosM, AugustoE, OliveiraCR, et al.. Amyloid-beta peptide decreases glutamate uptake in cultured astrocytes: involvement of oxidative stress and mitogen-activated protein kinase cascades. Neuroscience, 2008, 156(4): 898-910

[56] AvilaJ. Tau kinases and phosphatases. J Cell Mol Med, 2008, 12(1): 258-259

[57] Gomez-SintesR, HernandezF, LucasJJ, et al.. GSK-3 Mouse Models to Study Neuronal Apoptosis and Neurodegeneration. Front Mol Neurosci, 2011, 4: 45

[58] YoonMS. The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling. Nutrients, 2017, 9(11): 1176

[59] QuZ, JiaoZ, SunX, et al.. Effects of streptozotocin-induced diabetes on tau phosphorylation in the rat brain. Brain Res, 2011, 1383: 300-306

[60] JungHJ, KimYJ, EggertS, et al.. Age-dependent increases in tau phosphorylation in the brains of type 2 diabetic rats correlate with a reduced expression of p62. Exp Neurol, 2013, 248: 441-450

[61] KarstenSL, SangTK, GehmanLT, et al.. A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration. Neuron, 2006, 51(5): 549-560

[62] ZilkaN, FilipcikP, KosonP, et al.. Truncated tau from sporadic Alzheimer’s disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett, 2006, 580(15): 3582-3588

[63] SavuO, BradescuOM, SerafinceanuC, et al.. Erythrocyte caspase-3 and antioxidant defense is activated in red blood cells and plasma of type 2 diabetes patients at first clinical onset. Redox Rep, 2013, 18(2): 56-62

[64] KimB, BackusC, OhS, et al.. Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology, 2009, 150(12): 5294-5301

[65] HansonAJ, RubinowKB. Optimizing clinical phenotyping to better delineate the complex relationship between type 2 diabetes and Alzheimer’s disease. Clin Transl Sci, 2021, 14(5): 1681-1688

[66] KshirsagarV, ThingoreC, JuvekarA. Insulin resistance: a connecting link between Alzheimer’s disease and metabolic disorder. Metab Brain Dis, 2021, 36(1): 67-83

[67] RojasM, Chavez-CastilloM, BautistaJ, et al.. Alzheimer’s disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links. World J Diabetes, 2021, 12(6): 745-766