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Central nervous system involvement in diabetes mellitus

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Abstract

Diabetic complications result in much morbidity and mortality and considerable consumption of scarce medical resources. Thus, elucidation of the risk factors and pathophysiologic mechanisms underlying diabetic complications is important. The effects of diabetes on the central nervous system (CNS) result in cognitive dysfunction and cerebrovascular disease. Treatmentrelated hypoglycemia also has CNS consequences. Advances in neuroimaging now provide greater insights into the structural and functional impact of diabetes on the CNS. Greater understanding of CNS involvement could lead to new strategies to prevent or reverse the damage caused by diabetes mellitus.

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References and Recommended Reading

  1. Mijnhout GS, Scheltens P, Diamant M, et al.: Diabetic encephalopathy: a concept in need of a de.nition. Diabetologia 2006, 49:1447–1448.

    Article  PubMed  CAS  Google Scholar 

  2. van den Berg E, de Craen AJ, Biessels GJ, et al.: The impact of diabetes mellitus on cognitive decline in the oldest of the old: a prospective population-based study. Diabetologia 2006, 28:2015–2023.

    Article  Google Scholar 

  3. Allen KV, Frier BM, Strachan MW: The relationship between type 2 diabetes and cognitive dysfunction: longitudinal studies and their methodological limitations. Eur J Pharmacol 2004, 19:169–175.

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Ott A, Stolk RP, Hofman A, et al.: Association of diabetes mellitus and dementia: the Rotterdam Study. Diabetologia 1996, 39:1392–1397.

    Article  PubMed  CAS  Google Scholar 

  6. Lindsay J, Hebert R, Rockwood K: The Canadian Study of Health and Aging: risk factors for vascular dementia. Stroke 1997, 28:526–530.

    PubMed  CAS  Google Scholar 

  7. Yoshitake T, Kiyohara Y, Kato I, et al.: Incidence and risk factors of vascular dementia and Alzheimer’s disease in a de.ned elderly Japanese population: the Hisayama Study. Neurology 1995, 45:1161–1168.

    PubMed  CAS  Google Scholar 

  8. Elias PK, Elias MF, D’Agostino RB, et al.: NIDDM and blood pressure as risk factors for poor cognitive performance. The Framingham Study. Diabetes Care 1997, 20:1388–1395.

    Article  PubMed  CAS  Google Scholar 

  9. Walker PM, Ben Salem D, Giroud M, et al.: Is NAA reduction in normal contralateral cerebral tissue in stroke patients dependent on underlying risk factors? J Neurol Neurosurg Psychiatry 2006, 77:596–600.

    Article  PubMed  CAS  Google Scholar 

  10. Sabri O, Ringelstein EB, Hellwig D, et al.: Neuropsychological impairment correlates with hypoperfusion and hypometabolism but not with severity of white matter lesions on MRI in patients with cerebral microangiopathy. Stroke 1999, 30:556–566.

    PubMed  CAS  Google Scholar 

  11. Mathews VP, Barker PB, Blackband SJ, et al.: Cerebral metabolites in patients with acute and subacute strokes: concentrations determined by quantitative proton MR spectroscopy. AJR Am J Roentgenol 1995, 165:633–638.

    PubMed  CAS  Google Scholar 

  12. Perlmuter LC, Nathan DM, Goldfinger SH, et al.: Triglyceride levels affect cognitive function in noninsulin-dependent diabetics. J Diabetes Complications 1988, 2:210–213.

    Article  CAS  Google Scholar 

  13. Gustafson D: Adiposity indices and dementia. Lancet Neurol 2006, 5:713–720. A recent review that provides a unique insight into the etiology of dementia. Suggests potential interventions that may reduce the incidence of dementia.

    Article  PubMed  Google Scholar 

  14. Kalmijn S, Feskens EJ, Launer LJ, et al.: Glucose intolerance, hyperinsulinaemia and cognitive function in a general population of elderly men. Diabetologia 1995, 38:1096–1102.

    PubMed  CAS  Google Scholar 

  15. Enzinger C, Fazekas F, Matthews PM, et al.: Risk factors for progression of brain atrophy in aging: six-year followup of normal subjects. Neurology 2005, 64:1704–1711.

    Article  PubMed  CAS  Google Scholar 

  16. Knopman DS, Mosley TH, Catellier DJ, Sharrett AR: Cardiovascular risk factors and cerebral atrophy in a middle-aged cohort. Atherosclerosis Risk in Communities (ARIC) Study. Neurology 2005, 65:876–881.

    Article  PubMed  Google Scholar 

  17. Seshadri S, Wolf PA, Beiser A, et al.: Stroke risk profile, brain volume, and cognitive function: the Framingham Offspring Study. Neurology 2004, 63:1591–1599.

    PubMed  CAS  Google Scholar 

  18. Schmidt R, Launer LJ, Nilsson LG, et al.: CASCADE Consortium. Magnetic resonance imaging of the brain in diabetes: the Cardiovascular Determinants of Dementia (CASCADE) Study. Diabetes 2004, 53:687–692.

    Article  PubMed  CAS  Google Scholar 

  19. Cooper GJ, Leighton B, Dimitriadis GD, et al.: Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen metabolism in skeletal muscle. Proc Natl Acad Sci U S A 1988, 85:7763–7766.

    Article  PubMed  CAS  Google Scholar 

  20. Dore S, Kar S, Quirion R: Insulin-like growth factor I protects and rescues hippocampal neurons against betaamyloid-and human amylin-induced toxicity. Proc Natl Acad Sci U S A 1997, 94:4772–4777.

    Article  PubMed  CAS  Google Scholar 

  21. Takeda A, Wakai M, Niwa H, et al.: Neuronal and glial advanced glycation end product [Nepsilon-(carboxymethyl)lysine)] in Alzheimer’s disease brains. Acta Neuropathol 2001, 101:27–35.

    PubMed  CAS  Google Scholar 

  22. Finch CE, Cohen DM: Aging, metabolism, and Alzheimer disease: review and hypotheses. Exp Neurol 1997, 143:82–102.

    Article  PubMed  CAS  Google Scholar 

  23. Renard C, Chappey O, Wautier MP, et al.: Recombinant advanced glycation end product receptor pharmacokinetics in normal and diabetic rats. Mol Pharmacol 1997, 52:54–62.

    PubMed  CAS  Google Scholar 

  24. Yan SD, Fu J, Soto C, et al.: An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer’s disease. Nature 1997, 389:689–695.

    Article  PubMed  CAS  Google Scholar 

  25. Gradman TJ, Laws A, Thompson LW, Reaven GM: Verbal learning and/or memory improves with glycemic control in older subjects with non-insulin-dependent diabetes mellitus. J Am Geriatr Soc 1993, 41:1305–1312.

    PubMed  CAS  Google Scholar 

  26. 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, 29:345–351.

    Article  PubMed  Google Scholar 

  27. Maran A, Lomas J, Macdonald IA, Amiel SA: Lack of preservation of higher brain function during hypoglycaemia in patients with intensively-treated IDDM. Diabetologia 1995, 38:1412–1418.

    Article  PubMed  CAS  Google Scholar 

  28. Deary IJ: Symptoms of hypoglycaemia and effects on mental performance and emotions. In Hypoglycaemia in Clinical Diabetes. Edited by Frier BM, Fisher BM. Chichester: John Wiley and Sons; 1999:29–54.

    Google Scholar 

  29. Picton TW: The P300 wave of the human event-related potential. J Clin Neurophysiol 1992, 9:456–479.

    Article  PubMed  CAS  Google Scholar 

  30. Widom B, Simonson DC: Glycemic control and neuropsychologic function during hypoglycemia in patients with insulin-dependent diabetes mellitus. Ann Intern Med 1990, 112:904–912.

    PubMed  CAS  Google Scholar 

  31. Fanelli CG, Epifano L, Rambotti AM, et al.: Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. Diabetes 1993, 42:1683–1689.

    Article  PubMed  CAS  Google Scholar 

  32. Deary IJ, Sommer.eld AJ, McAulay V, Frier BM: Moderate hypoglycaemia obliterates working memory in humans with and without insulin-treated diabetes. J Neurol Neurosurg Psychiatry 2003, 74:278–279.

    Article  PubMed  CAS  Google Scholar 

  33. Cox DJ, Gonder-Frederick LA, Schroeder DB, et al.: Disruptive effects of acute hypoglycemia on speed of cognitive and motor performance. Diabetes Care 1993, 16:1391–1393.

    Article  PubMed  CAS  Google Scholar 

  34. Rosenthal JM, Amiel SA, Yaguez L, et al.: The effect of acute hypoglycemia on brain function and activation: a functional magnetic resonance imaging study. Diabetes 2001, 50:1618–1626.

    Article  PubMed  CAS  Google Scholar 

  35. Effects of intensive diabetes therapy on neuropsychological function in adults in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial (DCCT) Group [no authors listed]. Ann Intern Med 1996, 124:379–388.

  36. Reichard P, Pihl M, Rosenqvist U, Sule J: Complications in IDDM are caused by elevated blood glucose level: the Stockholm Diabetes Intervention Study (SDIS) at 10-year follow up. Diabetologia 1996, 39:1483–1488.

    Article  PubMed  CAS  Google Scholar 

  37. Warren RE, Frier BM: Hypoglycaemia and cognitive function. Diabetes Obes Metab 2005, 7:493–503.

    Article  PubMed  Google Scholar 

  38. Mitrakou A, Ryan C, Veneman T, et al.: Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 1991, 260:E67-E74.

    PubMed  CAS  Google Scholar 

  39. Boyle PJ, Kempers SF, O’Connor AM, Nagy RJ: Brain glucose uptake and unawareness of hypoglycemia in patients with insulin-dependent diabetes mellitus. N Engl J Med 1995, 333:1726–1731.

    Article  PubMed  CAS  Google Scholar 

  40. Criego AB, Tkac I, Kumar A, et al.: Brain glucose concentrations in patients with type 1 diabetes and hypoglycemia unawareness. J Neurosci Res 2005, 79:42–47. Using recent innovations in MRI, these researchers have developed techniques to measure steady-state in vivo brain glucose transport and metabolism, and found changes in brain glucose transport and metabolism as a result of recurrent hypoglycemia.

    Article  PubMed  CAS  Google Scholar 

  41. Boyle PJ, Nagy RJ, O’Connor AM, et al.: Adaptation in brain glucose uptake following recurrent hypoglycemia. Proc Natl Acad Sci U S A 1994, 91:9352–9356.

    Article  PubMed  CAS  Google Scholar 

  42. Sloviter HA, Shimkin P, Suhara K: Glycerol as a substrate for brain metabolism. Nature 1966, 210:1334–1336.

    Article  PubMed  CAS  Google Scholar 

  43. Veneman T, Mitrakou A, Mokan M, et al.: Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans. Diabetes 1994, 43:1311–1317.

    Article  PubMed  CAS  Google Scholar 

  44. Mitrakou A, Fanelli C, Veneman T, et al.: Reversibility of unawareness of hypoglycemia in patients with insulinomas. N Engl J Med 1993, 329:834–839.

    Article  PubMed  CAS  Google Scholar 

  45. Auer RN: Hypoglycemic brain damage. Metab Brain Dis 2004, 19:169–175.

    Article  PubMed  Google Scholar 

  46. Feise G, Kogure K, Busto KR, et al.: Effect of insulin hypoglycemia upon cerebral energy metabolism and EEG activity in the rat. Brain Res 1977, 126:263–280.

    Article  PubMed  CAS  Google Scholar 

  47. Sandberg M, Butcher SP, Hagberg H: Extracellular over flow of neuroactive amino acids during severe insulin-induced hypoglycemia: in vivo dialysis of the rat hippocampus. J Neurochem 1986, 47:178–184.

    Article  PubMed  CAS  Google Scholar 

  48. Harris RJ, Wieloch T, Symon L, Siesjo BK: Cerebral extracellular calcium activity in severe hypoglycemia: relation to extracellular potassium and energy state. J Cereb Blood Flow Metab 1984, 4:187–193.

    PubMed  CAS  Google Scholar 

  49. Auer RN, Wieloch T, Olsson Y, Siesjo BK: The distribution of hypoglycemic brain damage. Acta Neuropathol 1984, 64:177–191.

    Article  PubMed  CAS  Google Scholar 

  50. Finelli PF: Diffusion-weighted MR in hypoglycemic coma. Neurology 2001, 57:933.

    PubMed  CAS  Google Scholar 

  51. Davis PH, Dambrosia JM, Schoenberg BS, et al.: Risk factors for ischemic stroke: a prospective study in Rochester, Minnesota. Ann Neurol 1987, 22:319–327.

    Article  PubMed  CAS  Google Scholar 

  52. Tuomilehto J, Rastenyte D, Jousilahti P, et al.: Diabetes mellitus as a risk factor for death from stroke. Stroke 1996, 27:210–215.

    PubMed  CAS  Google Scholar 

  53. Rothwell PM, Coull AJ, Giles MF, et al.: Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study). Lancet 2004, 363:1925–1933.

    Article  PubMed  CAS  Google Scholar 

  54. You RX, McNeil JJ, O’Malley HM, et al.: Risk factors for stroke due to cerebral infarction in young adults. Stroke 1997, 28:1913–1918.

    PubMed  CAS  Google Scholar 

  55. Sacco RL, Gu Q, Boden-Albala BM, et al.: Race-ethnic differences in the magnitude of stroke risk factors: the Northern Manhattan Stroke Study [abstract]. 21st International Joint Conference on Stroke and Cerebral Circulation. San Antonio, TX: January 25–27, 1996.

  56. Stevens RJ, Coleman RL, Adler A, et al.: Risk factors for myocardial infarction case fatality and stroke case fatality in type 2 diabetes. UKPDS 66. Diabetes Care 2004, 27:201–207.

    Article  PubMed  Google Scholar 

  57. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group [no authors listed]. BMJ 1998, 317:703-712.

  58. Atkins D, Psaty B, Koepsell TD, et al.: Cholesterol reduction and the risk for stroke in men: a meta-analysis of randomized, controlled trials. Ann Intern Med 1993, 119:136–145.

    PubMed  CAS  Google Scholar 

  59. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study group [no authors listed]. N Engl J Med 1998, 339:1349-1357.

  60. Plehn JF, Davis BR, Sacks FM, et al.: Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. Circulation 1999, 99:216–223.

    PubMed  CAS  Google Scholar 

  61. Colhoun HM, Betteridge DJ, Durrington PN, et al.: Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled trial. CARDS Investigators. Lancet 2004, 364:685–696.

    Article  PubMed  CAS  Google Scholar 

  62. Sacco RL, Benson RT, Kargman DE, et al.: High-density lipoprotein cholesterol and ischemic stroke in the elderly: the Northern Manhattan Stroke Study. JAMA 2001, 285:2729–2735.

    Article  PubMed  CAS  Google Scholar 

  63. Folsom AR, Rasmussen ML, Chambless LE, et al.: Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Diabetes Care 1999, 22:1077–1083.

    Article  PubMed  CAS  Google Scholar 

  64. Kurth T, Gaziano JM, Berger K, et al.: Body mass index and the risk of stroke in men. Arch Intern Med 2002, 162:2557–2562.

    Article  PubMed  Google Scholar 

  65. Najarian RM, Sullivan LM, Kannel WB, et al.: Metabolic syndrome compared with type 2 diabetes mellitus as a risk factor for stroke: the Framingham Offspring Study. Arch Intern Med 2006, 166:106–111.

    Article  PubMed  Google Scholar 

  66. Aronson SM: Intracranial vascular lesions in patients with diabetes mellitus. J Neuropathol Exp Neurol 1973, 32:183–196.

    PubMed  CAS  Google Scholar 

  67. Karapanayiotides T, Piechowski-Jozwiak B, van Melle G, et al.: Stroke patterns, etiology, and prognosis in patients with diabetes mellitus. Neurology 2004, 62:1558–1562.

    PubMed  Google Scholar 

  68. Inoue T, Fushimi H, Yamada Y, et al.: The changes of lacunar state during a 5-year period in NIDDM. Diabetes Res Clin Pract 1998, 42:155–160.

    Article  PubMed  CAS  Google Scholar 

  69. Factor SM, Okun EM, Minase T: Capillary microaneurysms in the human diabetic heart. N Engl J Med 1980, 302:384–388.

    Article  PubMed  CAS  Google Scholar 

  70. Andresen JL, Rasmussen LM, Ledet T: Diabetic macroangiopathy and atherosclerosis. Diabetes 1996, 45:S91-S94.

    Article  PubMed  CAS  Google Scholar 

  71. Molina C, Sabin JA, Montaner J, et al.: Impaired cerebrovascular reactivity as a risk marker for first-ever lacunar infarction: a case-control study. Stroke 1999, 30:2296–2301.

    PubMed  CAS  Google Scholar 

  72. Fulesdi B, Limburg M, Bereczki D, et al.: Cerebrovascular reactivity and reserve capacity in type II diabetes mellitus. J Diabetes Complications 1999, 13:191–199.

    Article  PubMed  CAS  Google Scholar 

  73. Capes SE, Hunt D, Malmberg K, et al.: Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001, 32:2426–2432.

    PubMed  CAS  Google Scholar 

  74. Megherbi SA, Milan C, Minier D, et al.: Association between diabetes and stroke subtype on survival and functional outcome 3 months after stroke. Data from the European BIOMED Stroke Project. Stroke 2003, 344:688–694.

    Article  Google Scholar 

  75. Idris I, Thomson GA, Sharma JC: Diabetes mellitus and stroke. Int J Clin Pract 2006, 60:48–56.

    Article  PubMed  CAS  Google Scholar 

  76. Gray CS, Scott JF, French JM, et al.: Prevalence and prediction of unrecognised diabetes mellitus and impaired glucose tolerance following acute stroke. Age Ageing 2004, 33:71–77.

    Article  PubMed  Google Scholar 

  77. Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS: Stroke in patients with diabetes: the Copenhagen Stroke Study. Stroke 1994, 25:1977–1984.

    PubMed  CAS  Google Scholar 

  78. Burchfiel CM, Curb JD, Rodriguez BL, et al.: Glucose and 22-year stroke incidence: the Honolulu Heart Program. Stroke 1994, 25:951–957.

    PubMed  CAS  Google Scholar 

  79. Alex M, Baron EK, Goldenberg S, Blumenthal HT: An autopsy study of cerebrovascular accident in diabetes mellitus. Circulation 1962, 25:663–673.

    PubMed  CAS  Google Scholar 

  80. Reske-Nielsen E, Lundbaek K: Pathological changes in the central and peripheral nervous system of young long-term diabetics. II. The spinal cord and peripheral nerves. Diabetologia 1968, 4:34–43.

    Article  PubMed  CAS  Google Scholar 

  81. Reske-Nielsen E, Lundbaek K, Gregersen G, Harmsen A: Pathological changes in the central and peripheral nervous system of young long-term diabetics. The terminal neuromuscular apparatus. Diabetologia 1970, 6:98–103.

    Article  PubMed  CAS  Google Scholar 

  82. Eaton SE, Harris ND, Rajbhandari SM, et al.: Spinal-cord involvement in diabetic peripheral neuropathy. Lancet 2001, 358:35–36.

    Article  PubMed  CAS  Google Scholar 

  83. Selvarajah D, Wilkinson ID, Griffiths PD, et al.: Involvement of the spinal cord is early in diabetic neuropathy. Diabetes Care 2006, in press.

  84. Cameron FJ, Kean MJ, Wellard RM, et al.: Insights into the acute cerebral metabolic changes associated with childhood diabetes. Diabet Med 2005, 22:648–653.

    Article  PubMed  CAS  Google Scholar 

  85. Wootton-Gorges SL, Buonocore MH, Kuppermann N, et al.: Detection of cerebral beta-hydroxy butyrate, acetoacetate, and lactate on proton MR spectroscopy in children with diabetic ketoacidosis. AJNR Am J Neuroradiol 2005, 26:1286–1291.

    PubMed  Google Scholar 

  86. Kreis R, Ross BD: Cerebral metabolic disturbances in patients with subacute and chronic diabetes mellitus: detection with proton MR spectroscopy. Radiology 1992, 184:123–130.

    PubMed  CAS  Google Scholar 

  87. Geissler A, Frund R, Scholmerich J, et al.: Alterations of cerebral metabolism in patients with diabetes mellitus studied by proton magnetic resonance spectroscopy. Exp Clin Endocrinol Diabetes 2003, 111:421–427.

    Article  PubMed  CAS  Google Scholar 

  88. Selvarajah D, Wilkinson ID, Griffiths PD, et al.: Abnormal thalamic MR spectroscopy: evidence for functional impairment of the thalamus in diabetic neuropathy. Diabet Med 2004, 21(suppl 2):2.

    Google Scholar 

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  1. Diabetes Research Unit, Royal Hallamshire Hospital, Glossop Road, S10 2JF, Sheffield, UK

    Solomon Tesfaye FRCP, MD

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  1. Dinesh Selvarajah MbChB, MRCP
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Correspondence to Solomon Tesfaye FRCP, MD.

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Selvarajah, D., Tesfaye, S. Central nervous system involvement in diabetes mellitus. Curr Diab Rep 6, 431–438 (2006). https://doi.org/10.1007/s11892-006-0075-y

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