Cerebral complications of diabetes: clinical findings and pathogenetic mechanisms.

This review describes the cerebral complications of diabetes mellitus from a neuropsychological, neurophysiological and neuroradiological perspective. In addition, possible pathogenetic mechanisms are discussed. Neuropsychological studies of diabetic patients generally report modest deficits in learning and memory and information processing. Notably, in elderly diabetic patients cognitive deficits may be more prominent. Recent epidemiological studies show that in the elderly diabetes is associated with an increased risk for dementia. Neurophysiological studies show increased latencies of evoked potentials and event-related potentials. Neuroradiological findings are enhanced peripheral and central cerebral atrophy, as well as focal lesions. The pathophysiology of the effects of diabetes on the brain has not been fully elucidated. The putative involvement of cerebral metabolic and microvascular disturbances, similar to those implicated in the pathogenesis of peripheral diabetic neuropathy, is discussed. In addition, the role of repeated hypoglycaemic episodes, cerebrovascular disease and hypertension is addressed. Finally, the potential differential effects of insulin dependent and non-insulin dependent diabetes on the brain are discussed, as well as possible links with brain ageing.

[1]  P. Broderick,et al.  Serotonergic function in diabetic rats: Psychotherapeutic implications , 1988, Biological Psychiatry.

[2]  Klaus P. Ebmeier,et al.  Regional cerebral blood flow in IDDM patients: Effects of diabetes and of recurrent severe hypoglycaemia , 1994, Diabetologia.

[3]  J. Carlson,et al.  Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat , 1987, Mechanisms of Ageing and Development.

[4]  G. Pozzessere,et al.  Peripheral, but not Central, Nervous System Abnormalities are Reversed by Pancreatic Islet Transplantation in Diabetic Lewis Rats , 1996, The European journal of neuroscience.

[5]  J. Biller,et al.  Diabetes und Schlaganfall1 , 2005, Deutsche medizinische Wochenschrift.

[6]  A. Mooradian,et al.  Diabetic complications of the central nervous system. , 1988, Endocrine reviews.

[7]  D. Bell,et al.  Stroke in the diabetic patient. , 1994, Diabetes care.

[8]  W. Jeffcoate,et al.  Effect of Long-Term Glycemic Control on Cognitive Function , 1996, Diabetes Care.

[9]  A. Kurita,et al.  Neurophysiological Evidence for Altered Higher Brain Functions in NIDDM , 1996, Diabetes Care.

[10]  G. Reaven,et al.  Relationship Between Hyperglycemia and Cognitive Function in Older NIDDM Patients , 1990, Diabetes Care.

[11]  J. Sredy,et al.  Polyol pathway activity in nervous tissues of diabetic and galactose-fed rats: effect of dietary galactose withdrawal or tolrestat intervention therapy. , 1991, The Journal of diabetic complications.

[12]  S. Stone-Elander,et al.  Cerebral blood flow and substrate utilization in insulin-treated diabetic subjects. , 1990, The American journal of physiology.

[13]  P. Metcalf,et al.  Clustering of dyslipidemia, hyperuricemia, diabetes, and hypertension and its association with fasting insulin and central and overall obesity in a general population. Atherosclerosis Risk in Communities Study Investigators. , 1996, Metabolism: clinical and experimental.

[14]  L. Hansson,et al.  Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. , 1998, Hypertension.

[15]  P. Tun,et al.  Cognitive and affective disorders in elderly diabetics. , 1990, Clinics in geriatric medicine.

[16]  A. Hofman,et al.  Insulin and Cognitive Function in an Elderly Population: The Rotterdam Study , 1997, Diabetes Care.

[17]  P. Low,et al.  Endoneurial blood flow and oxygen tension in the sciatic nerves of rats with experimental diabetic neuropathy. , 1984, Brain : a journal of neurology.

[18]  M. Donaghy,et al.  Nonenzymatic glycation of peripheral and central nervous system proteins in experimental diabetes mellitus , 1997, Muscle & nerve.

[19]  A. Drash,et al.  Cognitive deficits in adolescents who developed diabetes early in life. , 1985, Pediatrics.

[20]  L. Niskanen,et al.  Short-Term and Long-Term Memory in Elderly Patients with NIDDM , 1995, Diabetes Care.

[21]  R. Duckrow,et al.  Regional cerebral blood flow decreases during chronic and acute hyperglycemia. , 1987, Stroke.

[22]  H. Lithell,et al.  Cognitive function, vascular risk factors and education. A cross‐sectional study based on a cohort of 70‐year‐old men , 1997, Journal of internal medicine.

[23]  A. McCall The Impact of Diabetes on the CNS , 1992, Diabetes.

[24]  R. Kreis,et al.  Cerebral metabolic disturbances in patients with subacute and chronic diabetes mellitus: detection with proton MR spectroscopy. , 1992, Radiology.

[25]  J. Rovet,et al.  Attentional Functioning in Children and Adolescents With IDDM , 1997, Diabetes Care.

[26]  J. D. L. Torre,et al.  Can disturbed brain microcirculation cause Alzheimer’s disease? , 1993 .

[27]  D. Reed,et al.  Diabetes and the risk of stroke. The Honolulu Heart Program. , 1987, JAMA.

[28]  C. Ryan,et al.  Effects of insulin-dependent diabetes on learning and memory efficiency in adults. , 1993, Journal of clinical and experimental neuropsychology.

[29]  B. Siesjö,et al.  Calcium Fluxes, Calcium Antagonists, and Calcium-Related Pathology in Brain Ischemia, Hypoglycemia, and Spreading Depression: A Unifying Hypothesis , 1989, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[30]  G. Pozzessere,et al.  Abnormalities of Cognitive Functions in IDDM Revealed by P300 Event-Related Potential Analysis: Comparison With Short-Latency Evoked Potentials and Psychometric Tests , 1991, Diabetes.

[31]  A Parving,et al.  Evidence for Diabetic Encephalopathy , 1991, Diabetic medicine : a journal of the British Diabetic Association.

[32]  K. Stringer,et al.  Glycation of rat sciatic nerve tubulin in experimental diabetes mellitus , 1991, Diabetologia.

[33]  R. Floyd,et al.  Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[34]  V. Menon,et al.  Effect of diabetes on levels of lipid peroxides and glycolipids in rat brain. , 1993, Metabolism: clinical and experimental.

[35]  F. Bellavere,et al.  Impaired Auditory Brainstem-evoked Responses in Insulin-dependent Diabetic Subjects , 1984, Diabetes.

[36]  A. Bossuyt,et al.  Regional cerebral hypoperfusion in long-term type 1 (insulin-dependent) diabetic patients: relation to hypoglycaemic events. , 1995, Nuclear medicine communications.

[37]  H. Tuokko,et al.  The effect of improved glycemic control on cognitive functions in the elderly patient with diabetes. , 1993, Journal of gerontology.

[38]  G. Biessels,et al.  Place Learning and Hippocampal Synaptic Plasticity in Streptozotocin-Induced Diabetic Rats , 1996, Diabetes.

[39]  R. Glynn,et al.  Correlates of Cognitive Function Scores in Elderly Outpatients , 1993, Journal of the American Geriatrics Society.

[40]  R. Rubin,et al.  Levels and Risks of Depression and Anxiety Symptomatology Among Diabetic Adults , 1997, Diabetes Care.

[41]  J. Garthwaite,et al.  Excitatory amino acid neurotoxicity and neurodegenerative disease. , 1990, Trends in pharmacological sciences.

[42]  R. Hawkins,et al.  Brain energy metabolism in streptozotocin-diabetes. , 1988, The Biochemical journal.

[43]  R. Ehrlich,et al.  Intellectual Deficits Associated With Early Onset of Insulin-Dependent Diabetes Mellitus in Children , 1987, Diabetes Care.

[44]  J. Mordes,et al.  Autoimmune diabetes mellitus in the BB rat. , 1992, Diabetes/metabolism reviews.

[45]  M. Laakso,et al.  Essential hypertension and cognitive function. The role of hyperinsulinemia. , 1993, Hypertension.

[46]  Allan H. Ropper,et al.  Evoked potentials in clinical medicine (second of two parts). , 1982 .

[47]  G. Knudsen,et al.  Myo-inositol normalizes decreased sodium permeability of the blood-brain barrier in streptozotocin diabetes , 1989, Neuroscience.

[48]  P. Wong,et al.  Visual evoked responses in diabetes. , 1983, Journal of neurology, neurosurgery, and psychiatry.

[49]  M. Donald,et al.  Functional Correlates of Reduced Central Conduction Velocity in Diabetic Subjects , 1984, Diabetes.

[50]  A. Cerami,et al.  Excessive Nonenzymatic Glycosylation of Peripheral and Central Nervous System Myelin Components in Diabetic Rats , 1983, Diabetes.

[51]  W. Markesbery,et al.  Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[52]  W. Lanier,et al.  Effects of insulin on blood, plasma, and brain glucose in hyperglycemic diabetic rats. , 1991, Stroke.

[53]  D. Greene,et al.  Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. , 1987, The New England journal of medicine.

[54]  D. Singer,et al.  Decreased cognitive function in aging non-insulin-dependent diabetic patients. , 1984, The American journal of medicine.

[55]  W. J. Litchy,et al.  The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population‐based cohort , 1993, Neurology.

[56]  J. Biller,et al.  Cerebrovascular disorders in patients with diabetes mellitus. , 1996, Journal of diabetes and its complications.

[57]  G. Biessels,et al.  The calcium hypothesis of brain aging and neurodegenerative disorders: significance in diabetic neuropathy. , 1996, Life sciences.

[58]  P Drouin,et al.  Improved Visual Evoked Potential Latencies In Poorly Controlled Diabetic Patients After Short-Term Strict Metabolic Control , 1994, Diabetes Care.

[59]  P. Mehler,et al.  Associations of hypertension and complications in non-insulin-dependent diabetes mellitus. , 1997, American journal of hypertension.

[60]  P. O'Brien,et al.  Risk of dementia among persons with diabetes mellitus: a population-based cohort study. , 1997, American journal of epidemiology.

[61]  S. Hori,et al.  Cerebral lesions in rats with streptozotocin-induced diabetes , 2004, Acta Neuropathologica.

[62]  K. Perryman,et al.  Cortical function in elderly non-insulin dependent diabetic patients. Behavioral and electrophysiologic studies. , 1988, Archives of internal medicine.

[63]  N. Lassen,et al.  Impaired autoregulation of cerebral blood flow in long-term type I (insulin-dependent) diabetic patients with nephropathy and retinopathy. , 2008, Clinical physiology.

[64]  G. Ingersoll,et al.  Longitudinal Relationship of Asymptomatic Hypoglycemia to Cognitive Function in IDDM , 1989, Diabetes Care.

[65]  P. Genton,et al.  Visual Evoked Potentials in Diabetic Patients , 1989, Diabetes Care.

[66]  H Lechner,et al.  White matter signal abnormalities in normal individuals: correlation with carotid ultrasonography, cerebral blood flow measurements, and cerebrovascular risk factors. , 1988, Stroke.

[67]  Z. Lacković,et al.  Effect of Long‐Lasting Diabetes Mellitus on Rat and Human Brain Monoamines , 1990, Journal of neurochemistry.

[68]  A. Hofman,et al.  Non-insulin-dependent Diabetes Mellitus (niddm) Association of Diabetes Mellitus and Dementia: the Rotterdam Study , 2022 .

[69]  L. Dorfman,et al.  Spinal somatosensory conduction in diabetes , 1981, Neurology.

[70]  D. Cox,et al.  Major developments in behavioral diabetes research. , 1992, Journal of consulting and clinical psychology.

[71]  M. Mattson Calcium and Neuronal Injury in Alzheimer's Disease , 1994, Annals of the New York Academy of Sciences.

[72]  J. Arezzo The use of electrophysiology for the assessment of diabetic neuropathy , 1997 .

[73]  Z. Khachaturian Calcium Hypothesis of Alzheimer's Disease and Brain Aging a , 1994, Annals of the New York Academy of Sciences.

[74]  G. Pozzessere,et al.  Early Detection of Neurological Involvement in IDDM and NIDDM: Multimodal Evoked Potentials Versus Metabolic Control , 1988, Diabetes Care.

[75]  C. Jagger,et al.  Diabetes and cognitive impairment: a community-based study of elderly subjects. , 1995, Age and ageing.

[76]  S. Marenco,et al.  Regional Cerebral Blood Flow and Cerebrovascular Reactivity in IDDM , 1993, Diabetes Care.

[77]  P. Reichard,et al.  Hypoglycaemic episodes during intensified insulin treatment: increased frequency but no effect on cognitive function , 1991, Journal of internal medicine.

[78]  J. Mahon,et al.  Glycation of Brain Actin in Experimental Diabetes , 1993, Journal of neurochemistry.

[79]  A. Mooradian The antioxidative potential of cerebral microvessels in experimental diabetes mellitus , 1995, Brain Research.

[80]  P. Johnson,et al.  Thickened cerebral cortical capillary basement membranes in diabetics. , 1982, Archives of pathology & laboratory medicine.

[81]  F. Udaka,et al.  Asymptomatic Cerebral Small Infarcts (Lacunae), Their Risk Factors and Intellectual Disturbances , 1996, Diabetes.

[82]  R. Bale Brain Damage in Diabetes Mellitus , 1973, British Journal of Psychiatry.

[83]  J. Jakobsen,et al.  Quantitative Changes of Cerebral Neocortical Structure in Insulin-Treated Long-Term Streptozocin-lnduced Diabetes in Rats , 1987, Diabetes.

[84]  M. Laakso,et al.  Risk for non‐insulindependent diabetes in the normoglycaemic elderly is associated with impaired cognitive function , 1997, Neuroreport.

[85]  P. Hedera,et al.  Differential degeneration of the cerebral microvasculature in Alzheimer's disease. , 1995, Neuroreport.

[86]  H. Shibasaki,et al.  Somatosensory Conduction Delay in Central and Peripheral Nervous System of Diabetic Patients , 1992, Diabetes Care.

[87]  T. Welty,et al.  Type II Diabetes and Cognitive Function: A population-based study of Native Americans , 1994, Diabetes Care.

[88]  J. Mordes,et al.  Animal models of diabetes. , 1981, American Journal of Medicine.

[89]  J. Colwell The Feasibility of Intensive Insulin Management in Non-Insulin-dependent Diabetes Mellitus: Implications of the Veterans Affairs Cooperative Study on Glycemic Control and Complications in NIDDM , 1996, Annals of Internal Medicine.

[90]  J. Greenberg,et al.  The Effect of Hyperglycemia on Intracellular Calcium in Stroke , 1992, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[91]  G. Meneilly,et al.  Alterations in Glucose Metabolism in Patients with Alzheimer's Disease , 1993, Journal of the American Geriatrics Society.

[92]  M. Nedergaard,et al.  Regional Brain Glucose Metabolism and Blood Flow in Streptozocin-Induced Diabetic Rats , 1990, Diabetes.

[93]  R. Bressler,et al.  Oral Antidiabetic Drug Use in the Elderly , 1996, Drugs & aging.

[94]  T. Orchard,et al.  Psychomotor Slowing Is Associated With Distal Symmetrical Polyneuropathy in Adults With Diabetes Mellitus , 1992, Diabetes.

[95]  H. Soininen,et al.  Diabetes mellitus and brain atrophy: A computed tomography study in an elderly population , 1992, Neurobiology of Aging.

[96]  G. Pizzamiglio,et al.  Visual evoked potentials in NIDDM: a longitudinal study , 1995, Diabetologia.

[97]  T. Brismar,et al.  Reversible and irreversible nodal dysfunction in diabetic neuropathy , 1987, Annals of neurology.

[98]  Thomas L. Smith,et al.  The effect of experimentally induced diabetes mellitus on the lipid order and composition of rat cerebral microvessels , 1992, Neuroscience Letters.

[99]  M. Cotter,et al.  The relationship of vascular changes to metabolic factors in diabetes mellitus and their role in the development of peripheral nerve complications. , 1994, Diabetes/metabolism reviews.

[100]  Evidence by magnetic resonance imaging of cerebral alterations of atrophy type in young insulin-dependent diabetic patients , 1994, Journal of endocrinological investigation.

[101]  I. Deary,et al.  Severe Deterioration in Cognitive Function and Personality in Five Patients with Long‐standing Diabetes: A Complication of Diabetes or a Consequence of Treatment? , 1994, Diabetic medicine : a journal of the British Diabetic Association.

[102]  J F Disterhoft,et al.  The Calcium Rationale in Aging and Alzheimer's Disease , 1994, Annals of the New York Academy of Sciences.

[103]  P. Fernyhough,et al.  Diabetic neuropathy, nerve growth factor and other neurotrophic factors , 1994, Trends in Neurosciences.

[104]  D. Choi,et al.  Glutamate neurotoxicity and diseases of the nervous system , 1988, Neuron.

[105]  N. Desai,et al.  Cognitive Function in Younger Type II Diabetes , 1997, Diabetes Care.

[106]  G. Reaven,et al.  Verbal Learning and/or Memory Improves with Glycemic Control in Older Subjects with Non‐Insulin‐Dependent Diabetes Mellitus , 1993, Journal of the American Geriatrics Society.

[107]  B. Bravenboer,et al.  Oxidative stress and antioxidant treatment in diabetic neuropathy , 1997 .

[108]  W. Pardridge,et al.  Downregulation of Blood-Brain Barrier Glucose Transporter in Experimental Diabetes , 1990, Diabetes.

[109]  M. Limburg,et al.  Impairment of Cerebrovascular Reactivity in Long-Term Type 1 Diabetes , 1997, Diabetes.

[110]  R. Auer Progress review: hypoglycemic brain damage. , 1986, Stroke.

[111]  I. Deary,et al.  Is Type II Diabetes Associated With an Increased Risk of Cognitive Dysfunction?: A critical review of published studies , 1997, Diabetes Care.

[112]  I J Deary,et al.  Severe Hypoglycemia and Intelligence in Adult Patients With Insulin-Treated Diabetes , 1993, Diabetes.

[113]  B. Chaitman,et al.  Cerebral and Ophthalmic Artery Hemodynamic Responses in Diabetes Mellitus , 1993, Diabetes Care.

[114]  D. Good,et al.  Brainstem auditory and visual evoked potentials in Type 1 (insulin-dependent) diabetic patients , 1986, Diabetologia.

[115]  U. Junker,et al.  Basement membrane of hypothalamus and cortex capillaries from normotensive and spontaneously hypertensive rats with streptozotocin-induced diabetes , 2004, Acta Neuropathologica.

[116]  Arthur J. L. Cooper,et al.  Antioxidant Defense Systems in the Brains of Type II Diabetic Mice , 1995, Journal of neurochemistry.

[117]  R. Clouse,et al.  Depression in Adults with Diabetes , 1992, Diabetes Care.

[118]  W. H. Gispen,et al.  Cerebral function in diabetes mellitus , 1994, Diabetologia.

[119]  M. Laakso,et al.  Predictors of stroke in middle-aged patients with non-insulin-dependent diabetes. , 1996, Stroke.

[120]  C. Ryan Neurobehavioral Complications of Type I Diabetes: Examination of Possible Risk Factors , 1988, Diabetes Care.

[121]  B. Dubois,et al.  Cognitive function, insulin‐dependent diabetes and hypoglycaemia , 1992, Journal of internal medicine.

[122]  S. Wolff,et al.  Protein glycation and oxidative stress in diabetes mellitus and ageing. , 1991, Free radical biology & medicine.

[123]  W. Surwillo P300 latency and digit span. , 1984, Psychophysiology.

[124]  L. Elveback,et al.  Transient ischemic attack and stroke in a community-based diabetic cohort. , 1983, Mayo Clinic proceedings.

[125]  R. Tattersall,et al.  A Community Survey of Diabetes in the Elderly , 1992, Diabetic medicine : a journal of the British Diabetic Association.

[126]  P. Low,et al.  Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits. , 1991, The American journal of physiology.

[127]  I. Deary,et al.  Severe hypoglycaemia and cognitive impairment in diabetes , 1996, BMJ.

[128]  R. D'Agostino,et al.  NIDDM and Blood Pressure as Risk Factors for Poor Cognitive Performance: The Framingham Study , 1997, Diabetes Care.

[129]  G. Pozzessere,et al.  Electrophysiological alterations of the central nervous system in diabetes mellitus. , 1995, Diabetes/metabolism reviews.

[130]  N. Bornstein,et al.  Vascular Risks of Asymptomatic Carotid Stenosis , 1991, Stroke.

[131]  R. Seidl,et al.  Brainstem Auditory Evoked Potentials and Visually Evoked Potentials in Young Patients With IDDM , 1996, Diabetes Care.

[132]  G. Biessels,et al.  Effects of nimodipine on sciatic nerve blood flow and vasa nervorum responsiveness in the diabetic rat. , 1993, European journal of pharmacology.

[133]  M. Gagnon,et al.  Glucose regulation and cognitive functions: relation to Alzheimer's disease and diabetes , 1996, Behavioural Brain Research.

[134]  A. Sinclair,et al.  Observations of Diabetes Care in Long-Term Institutional Settings With Measures of Cognitive Function and Dependency , 1997, Diabetes Care.

[135]  G. Worrall,et al.  Effect of type II diabetes mellitus on cognitive function. , 1993, The Journal of family practice.

[136]  Early Involvement of Central Nervous System in type I Diabetic Patients , 1995, Diabetes Care.

[137]  J. Richardson Cognitive function in diabetes mellitus , 1990, Neuroscience & Biobehavioral Reviews.

[138]  S. Levander,et al.  Permanent neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man , 1990, Diabetologia.

[139]  S. Haffner,et al.  The relation between serum insulin levels and 8-year changes in lipid, lipoprotein, and blood pressure levels. , 1992, American journal of epidemiology.

[140]  K. Lundbaek,et al.  Pathological changes in the central and peripheral nervous system of young long-term diabetics , 1970, Diabetologia.

[141]  T. Nakada,et al.  Aldose reductase and sorbitol dehydrogenase activities in diabetic brain: in vivo kinetic studies using 19F 3‐FDG NMR in rats , 1996, Neuroreport.