Neurodegeneration in Diabetes Mellitus

  • Hiroyuki Umegaki
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 724)


Diabetes mellitus is recognized as a group of heterogeneous disorders with the common elements of hyperglycaemia and glucose intolerance due to insulin deficiency, impaired effectiveness of insulin action, or both. The prevalence of Type 2 diabetes mellitus (T2DM) increases with age and dementia also increases its incidence in later life. Recent studies have revealed that T2DM is a risk factor for cognitive dysfunction or dementia, especially those related to Alzheimer's disease (AD). Insulin resistance, which is often associated with T2DM, may induce a deficiency of insulin effects in the central nervous system (CNS). Insulin may have a neuroprotective role and may have some impact on acetylcholine (ACh) synthesis. Hyperinsulinemia, induced by insulin resistance occurring in T2DM, may be associated with insulin deficiency caused by reduced insulin transport via the blood brain barrier (BBB). Insulin has multiple important functions in the brain. Some basic research, however, suggests that insulin accelerates Alzheimer-related pathology through its effects on the amyloid beta (Aβ) metabolism and tau phosphorylation.

Asymptomatic ischemic lesions in T2DM subjects may lower the threshold for the development of dementia and this may explain the inconsistency between the basic research and clinicopathological studies.

More research to elucidate the mechanism of neurodegeneration associated with T2DM is warranted.


Neurodegenerative Disease Vascular Dementia White Matter Lesion Insulin Deficiency ChAT Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Stewart R, Liolitsa D. Type 2 diabetes mellitus, cognitive impairment and dementia. Diabetic Medicine 1999; 16:93–112.PubMedCrossRefGoogle Scholar
  2. 2.
    Li L, Hölscher C. Common pathological processes in Alzheimer disease and type 2 diabetes: a review. Brain Res Rev 2007; 56:384–402.PubMedCrossRefGoogle Scholar
  3. 3.
    Ott A, Stolk RP, van Harskamp F et al. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999; 58:1937–1941.Google Scholar
  4. 4.
    Arvanitakis Z, Wilson RS, Bienias JL et al. Diabetes mellitus and risk of Alzheimer’s disease and decline in cognitive function. Arch Neurol 2004; 61:661–666.PubMedCrossRefGoogle Scholar
  5. 5.
    Peila R, Rodriguez BL, Launer LJ. Honolulu-Asia Aging Study. Type 2 diabetes, APOE gene and the risk for dementia and related pathologies. Diabetes 2002; 51:1256–1262.PubMedCrossRefGoogle Scholar
  6. 6.
    Peila R, Rodriguez BL, White LR et al. Fasting insulin and incident dementia in an elderly population of Japanese-American men. Neurology 2004; 63:228–233.PubMedGoogle Scholar
  7. 7.
    Vermeer SE, Koudstaal PJ, Oudkerk M et al. Prevalence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke 2002; 33:21–25.PubMedCrossRefGoogle Scholar
  8. 8.
    de Leeuw FE, de Groot JC, Achten E et al. Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry 2001; 70:9–14.PubMedCrossRefGoogle Scholar
  9. 9.
    den Heijer T, Vermeer SE, van Dijk EJ et al. Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 2003; 46:1604–1610.CrossRefGoogle Scholar
  10. 10.
    Korf ES, White LR, Scheltens P et al. Brain aging in very old men with type 2 diabetes: the Honolulu-Asia Aging Study. Diabetes Care 2006; 29:2268–2274.PubMedCrossRefGoogle Scholar
  11. 11.
    Korf ES, van Straaten EC, de Leeuw FE et al. LADIS Study Group. Diabetes mellitus, hypertension and medial temporal lobe atrophy: the LADIS study. Diabet Med 2007; 24:166–171.PubMedCrossRefGoogle Scholar
  12. 12.
    Yamagishi S, Ueda S, Okuda S. Food-derived advanced glycation end products (AGEs): a novel therapeutic target for various disorders. Curr Pharm Des 2007; 13:2832–2836.PubMedCrossRefGoogle Scholar
  13. 13.
    Valente T, Gella A, Fernàndez-Busquets X et al. Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol Dis 2010; 37:67–76.PubMedCrossRefGoogle Scholar
  14. 14.
    Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007; 8:57–69.PubMedCrossRefGoogle Scholar
  15. 15.
    Evans JL, Goldfine ID, Maddux BA et al. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 2002; 23:599–622.PubMedCrossRefGoogle Scholar
  16. 16.
    Moreira PI, Santos MS, Seiça R et al. Brain mitochondrial dysfunction as a link between Alzheimer’s disease and diabetes. J Neurol Sci 2007; 257:206–214.PubMedCrossRefGoogle Scholar
  17. 17.
    Watson GS, Craft S. The role of insulin resistance in the pathogenesis of Alzheimer’s disease: implications for treatment. CNS Drugs 2003; 17:27–45.PubMedCrossRefGoogle Scholar
  18. 18.
    Davis SN, Granner DK. Insulin, oral hypoglycemic agents and the pharmacology of the endocrine pancreas. In: Hardman JG, Gilman AG, Limbird LE, eds. Gilman and Goodman’s the Pharmacological Basis of Ttherapeutics, 9th. New York: McGraw-Hill, 1996:1487–1517.Google Scholar
  19. 19.
    Woods SC, Seeley RJ, Baskin DG et al. Insulin and the blood-brain barrier (BBB). Curr Pharm Des 2003; 9:795–800.PubMedCrossRefGoogle Scholar
  20. 20.
    Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature 1978; 272:827–829.PubMedCrossRefGoogle Scholar
  21. 21.
    Freychet P. Insulin receptors and insulin action in the nervous system. Diab Metab Res Rev 2000; 16:390–392.CrossRefGoogle Scholar
  22. 22.
    Rivera EJ, Goldin A, Fulmer N et al. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis 2005; 8:247–268.PubMedGoogle Scholar
  23. 23.
    Lacor PN, Buniel MC, Chang L et al. Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 2004; 24:10191–10200.PubMedCrossRefGoogle Scholar
  24. 24.
    Walsh DM, Klyubin I, Fadeeva JV et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416:535–539.PubMedCrossRefGoogle Scholar
  25. 25.
    Sato T, Hanyu H, Hirao K et al. Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging 2009. [Epub ahead of print]Google Scholar
  26. 26.
    Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease. Biochim Biophys Acta 2009; 1792:482–496.PubMedGoogle Scholar
  27. 27.
    Craft S, Peskind E, Schwartz MW et al. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 1998; 50:164–168.PubMedGoogle Scholar
  28. 28.
    Reger MA, Watson GS, Green PS et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008; 70:440–448.PubMedCrossRefGoogle Scholar
  29. 29.
    Thorne RG, Pronk GJ, Padmanabhan V et al. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 2004; 127:481–496.PubMedCrossRefGoogle Scholar
  30. 30.
    Benedict C, Hallschmid M, Hatke A et al. Intranasal insulin reportedly improves memory and attention in humans. Psychoneuroendocrinology 2004; 29:1326–1334.PubMedCrossRefGoogle Scholar
  31. 31.
    Beeri MS, Silverman JM, Davis KL et al. Type 2 diabetes is negatively associated with Alzheimer’s disease neuropathology. J Gerontol A Biol Sci Med Sci 2005; 60:471–475.PubMedCrossRefGoogle Scholar
  32. 32.
    Arvanitakis Z, Schneider JA, Wilson RS et al. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 2006; 7:960–1965.Google Scholar
  33. 33.
    de la Torre JC. Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma and dialectics. Lancet Neurol 2004; 3:184–190.PubMedCrossRefGoogle Scholar
  34. 34.
    Riekse RG, Leverenz JB, McCormick W et al. Effect of vascular lesions on cognition in Alzheimer’s disease: a community-based study. J Am Geriatr Soc 2004; 52:1442–1448.PubMedCrossRefGoogle Scholar
  35. 35.
    Akisaki T, Sakurai T, Takata T et al. Cognitive dysfunction associates with white matter hyperintensities and subcortical atrophy on magnetic resonance imaging of the elderly diabetes mellitus. Japanese elderly diabetes intervention trial (J-EDIT). Diabetes Metab Res Rev 2006; 22:376–384.PubMedCrossRefGoogle Scholar
  36. 36.
    Umegaki H, Kawamura T, Mogi N et al. Glucose control levels, ischaemic brain lesions and hyperinsulinaemia were associated with cognitive dysfunction in diabetic elderly. Age Ageing 2008; 37:458–461.PubMedCrossRefGoogle Scholar
  37. 37.
    Suzuki M, Umegaki H, Ieda S et al. Factors associated with cognitive impairment in elderly patients with diabetes mellitus. J Am Geriatr Soc 2006; 54:558–559.PubMedCrossRefGoogle Scholar
  38. 38.
    Sonnen JA, Larson EB, Brickell K et al. Different patterns of cerebral injury in dementia with or without diabetes. Arch Neurol 2009; 66:315–322.PubMedCrossRefGoogle Scholar
  39. 39.
    Arvanitakis Z, Wilson RS, Bienias JL et al. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 2004; 61:661–666.PubMedCrossRefGoogle Scholar
  40. 40.
    Schneider JA, Wilson RS, Cochran EJ et al. Relation of cerebral infarctions to dementia and cognitive function in older persons. Neurology 2003; 60:1082–1088.PubMedGoogle Scholar
  41. 41.
    Peters R, Beckett N, Forette F et al. Incident dementia and blood pressure lowering in the hypertension in the very elderly trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. Lancet Neurol 2008; 7:683–689.PubMedCrossRefGoogle Scholar
  42. 42.
    Cukierman-Yaffe T, Gerstein HC, Williamson JD et al. Relationship between baseline glycemic control and cognitive function in individuals with type 2 diabetes and other cardiovascular risk factors: the action to control cardiovascular risk in diabetes-memory in diabetes (ACCORD-MIND) trial; Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) Investigators. Diabetes Care 2009; 32:221–226.PubMedCrossRefGoogle Scholar
  43. 43.
    Maggi S, Limongi F, Noale M et al. LSA Study Group. Diabetes as a risk factor for cognitive decline in older patients. Dement Geriatr Cogn Disord 2009; 27:24–33.PubMedCrossRefGoogle Scholar
  44. 44.
    Ikonomovic MD, Klunk WE, Abrahamson EE et al. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain 2008; 131:1630–1645.PubMedCrossRefGoogle Scholar
  45. 46.
    Novak V, Abduljalil AM, Novak P et al. High-resolution ultrahigh-field MRI of stroke. Magn Reson Imaging 2005; 23:539–548.PubMedCrossRefGoogle Scholar
  46. 47.
    Kodl CT, Franc DT, Rao JP et al. Diffusion tensor imaging identifies deficits in white matter microstructure in subjects with type 1 diabetes that correlate with reduced neurocognitive function. Diabetes 2008; 57:3083–3089.PubMedCrossRefGoogle Scholar
  47. 48.
    Zetterberg LO, Wahlund K, Blennow. Cerebrospinal fluid markers for prediction of Alzheimer’s disease. Neurosci Lett 2003; 352:67–69.PubMedCrossRefGoogle Scholar
  48. 49.
    Hansson H, Zetterberg P, Buchhave E et al. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006; 5:228–234.PubMedCrossRefGoogle Scholar
  49. 50.
    Ewers M, Buerger K, Teipel SJ et al. Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI. Neurology 2007; 69:2205–2212.PubMedCrossRefGoogle Scholar
  50. 51.
    Gouw AA, van der Flier WM, Fazekas F et al. Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period: the Leukoaraiosis and Disability study. Stroke 2008; 39:1414–1420.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Hiroyuki Umegaki
    • 1
  1. 1.Department of GeriatricsNagoya University Graduate School of MedicineNagoya, AichiJapan

Personalised recommendations