, Volume 37, Issue 7, pp 643–650 | Cite as

Cerebral function in diabetes mellitus

  • G. J. Biessels
  • A. C. Kappelle
  • B. Bravenboer
  • D. W. Erkelens
  • W. H. Gispen


Diabetes mellitus is a common metabolic disorder associated with chronic complications such as nephropathy, angiopathy, retinopathy and peripheral neuropathy. Diabetes is not often considered to have deleterious effects on the brain. However, long-term diabetes results in a variety of subtle cerebral disorders, which occur more frequently than is commonly believed. Diabetic cerebral disorders have been demonstrated at a neurochemical, electrophysiological, structural and cognitive level; however, the pathogenesis is still not clear. Probably alterations in cerebral blood supply and metabolic derangements play a role, as they do in the pathogenesis of diabetic neuropathy. Furthermore, the brain is also affected by recurrent episodes of hypoglycaemia and poor metabolic control. We describe herein the cerebral manifestations of diabetes and discuss the putative pathogenetic mechanisms.

Key words

Diabetes mellitus complications brain cerebral dysfunction cognitive dysfunction pathogenesis cerebral blood flow hypoglycaemia hyperglycaemia review 





cerebralblood flow




  1. 1.
    Greene DA, Lattimer SA, Sima AAF (1987) Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med 316: 599–606Google Scholar
  2. 2.
    Strowig S, Raskin P (1992) Glycemic control and diabetic complications. Diabetes Care 15: 1126–1140Google Scholar
  3. 3.
    Brown MJ, Ashbury AK (1984) Diabetic neuropathy. Ann Neurol 15: 2–12Google Scholar
  4. 4.
    Niakan E, Harati Y, Comstock JP (1986) Diabetic autonomic neuropathy. Metabolism 35: 224–234Google Scholar
  5. 5.
    Vinik AI, Holland MT, Le Beau JM, Liuzzi FJ, Stansberry KB, Colen LB (1992) Diabetic neuropathies. Diabetes Care 15: 1926–1975Google Scholar
  6. 6.
    Mooradian AD (1988) Diabetes and the central nervous system. Endocr Rev 9: 346–356Google Scholar
  7. 7.
    McCall AL (1992) The impact of diabetes on the CNS. Diabetes 41: 557–570Google Scholar
  8. 8.
    Chu PC, Lin MT, Shian LR, Leu SY (1986) Alterations in physiologic functions and brain monoamine content in streptozotocin-diabetic rats. Diabetes 35: 481–485Google Scholar
  9. 9.
    Broderick PA, Jacoby JH (1988) Serotinergic function in diabetic rats: psychotherapeutic implications. Biol Psychiatry 24: 234–239Google Scholar
  10. 10.
    Mooradian AD, Perryman K, Fitten J, Kavonian GD, Mor-ley JE (1988) Cortical function in elderly non-insulin dependent diabetic patients. Behavioral and electrophysiologic studies. Arch Intern Med 148: 2369–2372Google Scholar
  11. 11.
    Haumont D, Dorchy H, Pelc S (1979) EEG abnormalities in diabetic children. Clin Pediatr 18: 750–753Google Scholar
  12. 12.
    Dejgaard A, Gade A, Larsson H, Balle V, Parving A, Parving HH (1991) Evidence for diabetic encephalopathy. Diabetic Med 8: 162–167Google Scholar
  13. 13.
    Pozzessere G, Valle E, De Crignis S et al. (1991) Abnormalities of cognitive functions in IDDM revealed by P300 event-related potential analysis. Diabetes 40: 952–958Google Scholar
  14. 14.
    Roehmholdt ME, Palumbo PJ, Wishnant JP, Elveback LR (1983) Transient ischemic attack and stroke in a community-based diabetic cohort. Mayo Clin Proc 58: 56–58Google Scholar
  15. 15.
    Abbott RD, Donahue RP, Macmahon SW, Reed DM, Yano K (1987) Diabetes and the risk of stroke. The Honolulu heart program. JAMA 257: 949–952Google Scholar
  16. 16.
    Sutherland GR, Peeling J, Sutherland E et al. (1992) Forebrain ischemia in diabetic and nondiabetic BB rats studied with 31P magnetic resonance spectroscopy. Diabetes 41: 1328–1334Google Scholar
  17. 17.
    Foster DW (1991) Diabetes mellitus. In: Wilson JD, Braunwald E, Isselbacher KJ et al. (eds) Harrison's principles of internal medicine. 12th edn. McGraw-Hill Inc., New York, pp 1749–1753Google Scholar
  18. 18.
    Kreis R, Ross BD (1992) Cerebral metabolic disturbances in patients with subacute and chronic diabetes mellitus: detection with proton MR spectroscopy. Radiology 184: 123–130Google Scholar
  19. 19.
    Heller S, Ward JD (1993) Neurologic consequences of hypoglycemia and pathogenic mechanisms involved in diabetic neuropathy. Curr Opin Neurol Neurosurg 6: 423–428Google Scholar
  20. 20.
    Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J (1993) Induction of hypoglycemia unawareness by asymptomatic noctural hypoglycemia. Diabetes 42: 1233–1237Google Scholar
  21. 21.
    Low PA, Tuck PR, Takeuchi M (1987) Nerve microenvironment in diabetic neuropathy. In: Dyck PJ, Thomas PK, Asbury AK, Winegard AI, Porte D (eds) Diabetic neuropathy. Saunders, Philadelphia, pp 289–298Google Scholar
  22. 22.
    Greene DA, Lattimer SA (1988) Pathogenesis and prevention of diabetic neuropathy. Diabetes Metab Rev 4: 201–221Google Scholar
  23. 23.
    Welsh B, Wecker L (1991) Effects of streptozotocin-induced diabetes on acetylcholine metabolism in rat brain. Neurochem Res 16: 453–460Google Scholar
  24. 24.
    Trulson ME, Himmel CD (1985) Effects of insulin and streptozotocin-induced diabetes on brain norepinephrine metabolism in rats. J Neurochem 44: 1873–1876Google Scholar
  25. 25.
    Di Giulio AM, Tenconi B, La Croix R et al. (1989) Denervation and hyperinnervation in the nervous system of diabetic animals II: monoaminergic and peptidergic alterations in diabetic encephalopathy. J Neurosci Res 24: 362–368Google Scholar
  26. 26.
    Lackovic Z, Salkovic M, Kuci Z, Relja M (1990) Effect of long-lasting diabetes mellitus on rat and human brain monoamines. J Neurochem 54: 143–147Google Scholar
  27. 27.
    Bellush LL, Reid SG (1991) Altered behavior and neurochemistry during short-term insulin withdrawal in streptozotocin-induced diabetic rats. Diabetes 40: 217–222Google Scholar
  28. 28.
    Salkovic M, Lackovic Z (1992) Brain D1 dopamine receptor in alloxan-induced diabetes. Diabetes 41: 1119–1121Google Scholar
  29. 29.
    Lozovsky D, Saller CF, Kopin IJ (1981) Dopamine receptor binding is increased in diabetic rats. Science 214: 1031–1033Google Scholar
  30. 30.
    Abbracchio MP, Di Luca M, Di Giulio AM, Cattabeni F, Tenconi B, Gorio A (1989) Denervation and hyperinnervation in the nervous system of diabetic animals III: functional changes of G proteins in diabetic encephalopathy. J Neurosci Res 24: 517–523Google Scholar
  31. 31.
    Rowland NE, Bellush LL (1989) Diabetes mellitus: stress, neurochemistry and behavior. Neurosci Biobehav Rev 13: 199–206Google Scholar
  32. 32.
    Lustman PJ, Griffith LS, Clouse RE, Cryer PE (1986) Psychiatric illness in diabetes mellitus. J Nerv Ment Disease 174: 736–742Google Scholar
  33. 33.
    Lustman PJ, Griffith LS, Gavard JA, Clouse RE (1992) Depression in adults with diabetes. Diabetes Care 15: 1631–1639Google Scholar
  34. 34.
    Leedom L, Meehan WP, Procci W, Zeidler A (1991) Symptoms of depression in patients with type II diabetes mellitus. Psychosomatics 32: 280–286Google Scholar
  35. 35.
    Sima AAF, Zhang WX, Cherian PV, Chakrabarti S (1992) Impaired visual evoked potential and primary axonopathy in the optic nerve in the diabetic BB/W-rat. Diabetologia 35: 602–607Google Scholar
  36. 36.
    Kamijo M, Cherian PV, Sima AAF (1993) The preventive effect of aldose reductase inhibition on diabetic optic neuropathy in the BB/W-rat. Diabetologia 36: 893–898Google Scholar
  37. 37.
    Pozzessere G, Rizzo PA, Valle E et al. (1988) Early detection of neurological involvement in IDDM and NIDDM. Multimodal evoked potentials versus metabolic control. Diabetes Care 11: 473–480Google Scholar
  38. 38.
    Martini A, Comacchio F, Magnavita V (1991) Auditory brainstem and middle latency evoked responses in the clinical evaluation of diabetes. Diabet Med 8 [Suppl]: S74-S77Google Scholar
  39. 39.
    Nakamura R, Noritake M, Hosoda Y, Kamakura K, Nagata N, Shibasaki H (1992) Somatosensory conduction delay in central and peripheral nervous system of diabetic patients. Diabetes Care 15: 532–535Google Scholar
  40. 40.
    Donald MW, Williams Erdahl DL, Surridge DHC et al. (1984) Functional correlates of reduced central conduction velocity in diabetic subjects. Diabetes 33: 627–633Google Scholar
  41. 41.
    Khardori R, Soler NG, Good DC, Devlesc Howard AB, Broughton D, Walbert J (1986) Brainstem auditory and visual evoked potentials in type 1 (insulin-dependent) diabetic patients. Diabetologia 29: 362–365Google Scholar
  42. 42.
    Polich J, Howard L, Star A (1983) P300 and digit span. Curr Opin Neurol Neurosurg 6: 423–428Google Scholar
  43. 43.
    Surwillo WW (1984) P300 latency and digit span. Psychophysiology 21: 708–709Google Scholar
  44. 44.
    Hillyard SA, Kutas M (1983) Electrophysiology of cognitive processing. Annu Rev Psychol 34: 33–61Google Scholar
  45. 45.
    Luse SA, Gerritsen GC, Dulin WE (1970) Cerebral abnormalities in diabetes mellitus: an ultrastructural study of the brain in early-onset diabetes mellitus in the Chinese hamster. Diabetologia 6: 192–198Google Scholar
  46. 46.
    Mukai N, Hori S, Pomeroy M (1980) Cerebral lesions in rats with streptozotocin-induced diabetes. Acta Neuropathol (Berl) 51: 79–84Google Scholar
  47. 47.
    Jakobsen J, Sidenius P, Gundersen HJG, Osterby R (1987) Quantitative changes of cerebral neocortical structure in insulin-treated long-term streptozotocin-induced diabetes in rats. Diabetes 36: 597–601Google Scholar
  48. 48.
    Junker U, Jaggi C, Bestetti G, Rossi GL (1985) Basement membrane of hypothalamus and cortex capillaries from normotensive and spontaneously hypertensive rats with streptozotocin-induced diabetes. Acta Neuropathol (Berl) 65: 202–208Google Scholar
  49. 49.
    Reske-Nielsen E, Lundbaek K, Rafaelsen OJ (1965) Pathological changes in the central and peripheral nervous system of young long-term diabetics. Diabetologia 1: 233–241Google Scholar
  50. 50.
    Bale RN (1973) Brain damage in diabetes mellitus. Br J Psychiatry 122: 337–341Google Scholar
  51. 51.
    Cox DJ, Gonder-Frederick L (1992) Major developments in behavioral diabetes research. J Consult Clin Psychol 60: 628–638Google Scholar
  52. 52.
    Ryan CM (1988) Neurobehavioral complications of type I diabetes. Diabetes Care 11: 86–93Google Scholar
  53. 53.
    Ryan CM, Williams TM, Orchard TJ, Finegold DN (1992) Psychomotor slowing is associated with distal symmetrical polyneuropathy in adults with diabetes mellitus. Diabetes 41: 107–113Google Scholar
  54. 54.
    Ryan CM, Williams TM, Finegold DN, Orchard TJ (1993) Cognitive dysfunction in adults with type 1 (insulin-dependent) diabetes mellitus of long duration: effects of recurrent hypoglycaemia and other chronic complications. Diabetologia 36: 329–334Google Scholar
  55. 55.
    Richardson JT (1990) Cognitive function in diabetes mellitus. Neurosci Biobehav Rev 14: 385–388Google Scholar
  56. 56.
    Deary IJ, Crawford JR, Hepburn DA, Langan SJ, Blackmore LM, Frier BM (1993) Severe hypoglycaemia and intelligence in adult patients with insulin-treated diabetes. Diabetes 42: 341–344Google Scholar
  57. 57.
    Reaven GM, Thompson LW, Nahum D, Haskins E (1990) Relationship between hyperglycaemia and cognitive function in older NIDDM patients. Diabetes Care 13: 16–21Google Scholar
  58. 58.
    Ack M, Miller I, Weil WB (1961) Intelligence of children with diabetes mellitus. Pediatrics 28: 764–770Google Scholar
  59. 59.
    Ryan CM, Vega A, Drash A (1985) Cognitive deficits in adolescents who developed diabetes early in life. Pediatrics 75: 921–927Google Scholar
  60. 60.
    Rovet JF, Ehrlich RM, Hoppe M (1987) Intellectual deficits associated with early onset of insulin dependent diabetes mellitus in children. Diabetes Care 10: 510–515Google Scholar
  61. 61.
    Fowler MG, Johnson MP, Atkinson SS (1985) School achievement and absence in children with chronic health conditions. J Pediatr 106: 683–687Google Scholar
  62. 62.
    Golden MP, Ingersoll GM, Brack CJ, Russel BA, Wright JC, Huberty TJ (1989) Longitudinal relationship of asymptomatic hypoglycemia to cognitive function in IDDM. Diabetes Care 12: 89–93Google Scholar
  63. 63.
    Reichard P, Berglund A, Britz A, Levander S, Rosenqvist U (1991) Hypoglycaemic episodes during intensified insulin treatment: increased frequency but no effect on cognitive function. J Intern Med 229: 9–16Google Scholar
  64. 64.
    DCCT Research Group (1991) Epidemiology of severe hypoglycemia in the diabetes control and complications trial. Am J Med 90: 450–459Google Scholar
  65. 65.
    Wredling R, Levander S, Adamson U, Lins PE (1990) Permanent neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man. Diabetologia 33: 152–157Google Scholar
  66. 66.
    Langan SJ, Deary IJ, Hepburn DA, Frier BM (1991) Cumulative cognitive impairment following recurrent severe hypoglycaemia in adult patients with insulin-treated diabetes mellitus. Diabetologia 34: 337–344Google Scholar
  67. 67.
    Rennick PM, Wider RM, Sargent J, Ashley BJ (1968) Retinopathy as an indicator of cognitive-perceptual-motor impairment in diabetic adults (Summary). Proc 76th Annu Conv AM Psychol Assoc: 473–474Google Scholar
  68. 68.
    Popkin MK, Callies AL, Lentz RD, Colon EA, Sutherland DE (1988) Prevalence of major depression, simple phobia, and other psychiatric disorders in patients with long-standing type I diabetes mellitus. Arch Gen Psychiatry 45: 64–68Google Scholar
  69. 69.
    Surridge DHC, Williams Erdahl DL, Lawson JS et al. (1984) Psychiatric aspects of diabetes mellitus. Br J Psychiat 145: 269–276Google Scholar
  70. 70.
    Gavard JA, Lustman PJ, Clouse RE (1993) Prevalence of depression in adults with diabetes. Diabetes Care 16: 1167–1178Google Scholar
  71. 71.
    Rodin G, Voshart K (1986) Depression in the medically ill: an overview. Am J Psychiatry 143: 696–705Google Scholar
  72. 72.
    Lustman PJ, Harper GW, Griffith LS, Clouse RE (1986) Use of the diagnostic interview schedule in patients with diabetes mellitus. J Nerv Ment Disease 174: 743–746Google Scholar
  73. 73.
    Johnson PC, Brendel K, Meezan E (1982) Thickened cerebral cortical capillary basement membranes in diabetics. Arch Pathol Lab Med 106: 214–217Google Scholar
  74. 74.
    Duckrow RB, Beard DC, Brennan RW (1987) Regional cerebral blood flow decreases during chronic and acute hyperglycemia. Stroke 18: 52–58Google Scholar
  75. 75.
    Harik SI, LaManna JC (1988) Vascular perfusion and blood-brain glucose transport in acute and chronic hyperglycemia. J Neurochem 51: 1924–1929Google Scholar
  76. 76.
    Kikano GE, La Manna JC, Harik SI (1989) Brain perfusion in acute and chronic hyperglycemia in rats. Stroke 20: 1027–1031Google Scholar
  77. 77.
    Rodriguez G, Nobili F, Celestino MA et al. (1993) Regional cerebral blood flow and cerebrovascular reactivity in IDDM. Diabetes Care 16: 462–468Google Scholar
  78. 78.
    Grill V, Gutniak M, Björkman O et al. (1990) Cerebral blood flow and substrate utilization in insulin-treated diabetic subjects. Am J Physiol 258: E813-E820Google Scholar
  79. 79.
    Kastrup J, Rorsgaard S, Parving HH, Lassen NA (1986) Impaired autoregulation of cerebral blood flow in long-term type I (insulin-dependent) diabetic patients with nephropathy and neuropathy. Clin Physiol 6: 549–559Google Scholar
  80. 80.
    Albert SG, Gomez CR, Russeli S, Chaitman BR, Bernbaum M, Kong BA (1993) Cerebral and ophthalmic artery hemodynamic responses in diabetes mellitus. Diabetes Care 16: 476–482Google Scholar
  81. 81.
    Mayhan WG, Simmons LK, Sharpe GM (1991) Mechanism of impaired response of cerebral arterioles during diabetes mellitus. Am J Physiol 260: H319-H326Google Scholar
  82. 82.
    Pelligrino DA, Albrecht RF (1991) Chronic hyperglycemic diabetes in the rat is associated with a selective impairment of cerebral vasodilatory responses. J Cereb Blood Flow Metab 11: 667–677Google Scholar
  83. 83.
    Wirsén A, Tallroth G, Lindgren M, Agarhd CD (1992) Neuropsychological performance differs betweeen type I diabetic and normal men during insulin-induced hypoglycaemia. Diabetic Med 9: 156–165Google Scholar
  84. 84.
    Hoffman RG, Speelman DJ, Hinnen DA, Conley KL, Guthrie RA, Knapp RK (1989) Changes in cortical functioning with acute hypoglycaemia and hyperglycemia in type I diabetes. Diabetes Care 12: 193–197Google Scholar
  85. 85.
    Blackman JD, Towle VL, Lewis GF, Spire JP, Polonsky KS (1990) Hypoglycemic thresholds for cognitive dysfunction in humans. Diabetes 39: 828–835Google Scholar
  86. 86.
    Auer RN (1986) Progress review: hypoglycemic brain damage. Stroke 17: 699–708Google Scholar
  87. 87.
    Auer RN, Olsson Y, Siesjö BK (1984) Hypoglycemic brain injury in the rat. Correlation of density of brain damage with the EEG isoelectric time: a quantative study. Diabetes 33: 1090–1098Google Scholar
  88. 88.
    Wieloch T (1985) Hypoglycaemia-induced neuronal damage prevented by an N-methyl-D-aspartate antagonist. Science 230: 681–683Google Scholar
  89. 89.
    Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1: 623–634Google Scholar
  90. 90.
    Siesjö BK, Bengtsson F (1989) Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia hypoglycaemia and spreading depression: a unifying hypothesis. J Cerb Blood Flow Metab 9: 127–140Google Scholar
  91. 91.
    Araki N, Greenberg JH, Sladky JT, Uematsu D, Karp A, Reivich M (1992) The effect of hyperglycemia on intracellular calcium in stroke. J Cereb Blood Flow Metab 12: 469–476Google Scholar
  92. 92.
    Meldrum B, Garthwaite J (1990) Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Parmacol Sci 11: 379–387Google Scholar
  93. 93.
    Young AB, Fagg GE (1990) Excitatory amino acid receptors in the brain: membrane binding and receptor autoradiographic approaches. Trends Pharmacol Sci 11: 126–133Google Scholar
  94. 94.
    Papagapiou MP, Auer RN (1990) Regional neuroprotective effects of the NMDA receptor antagonist MK-801 (Dizocilpine) in hypoglycemic brain damage. J Cereb Blood Flow Metab 10: 270–276Google Scholar
  95. 95.
    Pizzi M, Ribola M, Valerio A, Memo M, Spano PF (1991) Various Ca2+ entry blockers prevent glutamate-induced neurotoxicity. Eur J Pharmacol 209: 169–173Google Scholar
  96. 96.
    Mooradian AD, Morin AM (1991) Brain uptake of glucose in diabetes mellitus: the role of glucose transporters. Am J Med Sci 301: 173–177Google Scholar
  97. 97.
    Knudsen GM, Jakobsen J, Barry DI, Compton AM, Tomlinson DR (1989) Myo-inositol normalizes decreased sodium permeability of the blood-brain barrier in streptozotocin diabetes. Neuroscience 29: 773–777Google Scholar
  98. 98.
    Crandall EA, Fernstrom JD (1983) Effect of experimental diabetes on the levels of aromatic and branched-chain amino acids in rat blood and brain. Diabetes 32: 222–230Google Scholar
  99. 99.
    Trachtman H, Futterweit S, Sturman JA (1992) Cerebral taurine transport is increased during streptozotocin-induced diabetes in rats. Diabetes 41: 1130–1140Google Scholar
  100. 100.
    Pardridge WM, Triguero D, Farrell CR (1990) Downregulation of blood-brain barrier glucose transporter in experimental diabetes. Diabetes 39: 1040–1044Google Scholar
  101. 101.
    Gutniak M, Blomqvist G, Widén L, Stone-Elander S, Hamberger B, Grill V (1990) D-[U-11C] glucose uptake and metabolism in the brain of insulin-treated diabetic subjects. Am J Physiol 258: E805-E812Google Scholar
  102. 102.
    Bruhn H, Michaelis T, Merboldt KD, Hänicke W, Gyngell ML, Frahm J (1991) Monitoring cerebral glucose in diabetics by proton MRS. Lancet 337: 745–746Google Scholar
  103. 103.
    Hofer RE, Lanier WL (1991) Effects of insulin on blood, plasma, and brain glucose in hyperglycemic diabetic rats. Stroke 22: 505–509Google Scholar
  104. 104.
    Leong SF, Leung TKC (1991) Diabetes induced by streptozotocin causes reduced Na-K ATPase in the brain. Neurochem Res 16: 1161–1165Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • G. J. Biessels
    • 1
  • A. C. Kappelle
    • 1
  • B. Bravenboer
    • 2
  • D. W. Erkelens
    • 3
  • W. H. Gispen
    • 1
  1. 1.Department of Medical Pharmacology, Rudolf Magnus InstituteUniversity of UtrechtGD UtrechtThe Netherlands
  2. 2.Division of Internal MedicineCatharina HospitalEindhovenThe Netherlands
  3. 3.Department of Internal MedicineAcademic HospitalUtrechtThe Netherlands

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