Glucose is an important metabolic substrate for all cells, including brain cells. However, homeostatic degradation of glucose due to increased glucose levels affect cerebral functions directly or indirectly. Formation of the advanced glycation end-products and of free radicals as a result of an increase in brain glucose affect the brain indirectly, whereas, the long-term changes at the level of neuronal genes affect the brain directly. All these changes cause many disorders such as neuronopathy, encephalopathy and dementia. Both the indirect pathways that affect the cerebral functions, and the direct neuronal pathways must be identified so that therapeutic strategies can be implemented accordingly inorder to prevent brain injury.
1. Herculano-Houzel S. Scaling of brain metabolism with a fixed energy budget per neuron: implications for neuronal activity, plasticity and evolution. PLoS One 2011;6:e17514. doi: 10.1371/journal. pone.0017514.
2. Clarke DD, Sokoloff L. Circulation and energy metabolism of the brain. In: Siegel, GJ, Agranoff BW, Albers RW, Molinoff SK, Fisher PB, Uhler MD, editors. Basic Neurochemistry. Philadelphia: LippincottRaven, 1999:637–69.
3. Bischof MG, Krssak M, Krebs M, et al. Effects of short-term improvement of insulin treatment and glycemia on hepatic glycogen metabolism in type 1 diabetes. Diabetes 2001;502:392–8. doi: 10.2337/ diabetes.50.2.392
4. Reagan LP, Rosell DR, Alves SE, et al. GLUT8 glucose transporter is localized to excitatory and inhibitory neurons in the rat hippocampus. Brain Res 2002; 932:129–34. doi:10.1016/S0006-8993(02)02308-9
5. Shah K, Desilva S, Abbruscato T. The role of glucose transporters in brain disease: Diabetes and Alzheimer’s disease. Int J Mol Sci 2012;13:12629-55. doi: 10.3390/ijms131012629.
6. Horani MH, Mooradian, AD. Effect of diabetes on the blood brain barrier. Curr Pharmaceut Design 2003;9:833-40. doi:10.2174/1381612033455314
7. Klein JP Waxman SG. The brain in diabetes: molecular changes in neurons and their implications for end-organ damage. Lancet Neurology 2003; 2: 548–54. doi:10.1016/S1474-4422(03)00503-9
8. Pitkanen OM, Martin JM, Hallman M, et al. Free radical activity during development of insulin dependent diabetes mellitus in the rat. Life Sci 1992; 50: 335-9. doi:10.1016/0024-3205(92)90434-Q
9. Van Dam PS, Van Asbeck BS, Erkelens DW, et al. The role of oxidative stress in neuropathy and other diabetic complications. Diabetes Metab Rev 1995; 11:181-92. doi:10.1002/dmr.5610110303
10. Bukan N, Sancak B, Yavuz Ö, et al. Lipid peroxidation and scavenging enzyme levels in the liver of streptozotocin-induced diabetes rats. Indian J Biochem and Biophys 2003;40:447-50.
11. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: A new perspective on an old paradigm. Diabetes 1999: 48:1-9. doi: 10.2337/diabetes.48.1.1
12. Rösen P, Du X, Tschöpe D. Role of oxygen derived radicals for vascular dysfunction in the diabetic heart: prevention by α-tocopherol?. Mol Cell Biochem 1998; 188: 103-11. doi: 10.1007/978-1-4615-5763-0_12
13. Du X, Stockklauser-Farber K, Rösen P. Generation of reactive oxygen intermediates, activation of NFKappaB, and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase? Free Radic Biol Med 1999; 27:752-63.
14. Bonnefont-Rousselot D. Glucose and reactive oxygen species. Curr Opin Clin Nutr Metab Care 2002; 5: 561-8. doi: 10.1097/00075197- 200209000-00016
15. Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404:787-90. doi:10.1038/35008121
16. Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes 1998; 47: 859-66. doi:10.2337/ diabetes.47.6.859
17. Parmaksiz I. Advanced glycation end-products in complications of diabetes mellitus. Marmara Med J 2011;24:141-8. doi: 10.5472/ MMJ.2011.0.2037.1
18. Riehl A, Németh J, Angel P, Hess J. The receptor RAGE:bridging inflammation and cancer. Cell Commun Signal 2009;7:12 doi: 10.1186/1478-811X-7-12
19. Chappey O, Dosquet C, Wautier MP, Wautier JL. Advanced glycation end products, oxidant stress and vascular lesions. Eur J Clin Invest 1997;27:97-108. doi: 10.1046/j.1365-2362.1997.710624.x
20. Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). Study Research Group: Long-term effect of diabetes and its treatment on cognitive function. The Diabetes Control and Complications. N Engl J Med 2007;356:1842-5.
21. Maritim AC, Sanders RA, Watkins III JB. Diabetes, oxidative stress and antioxidants: Review. J Biochem Mol Toxicol 2003;17:4-38. doi:10.1002/jbt.10058
22. Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Yorek MA. Effect of treating streptozotocin-induced diabetic rats with sorbinil, myoinositol or aminoguanidine on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve. Int J Exp Diabetes Res 2002;3:21-36. doi: 10.1080/15604280212525
23. Castellani RJ, Harris PLR, Sayre LM, et al. . Active glycation in neurofibrillary pathology of Alzheimer disease: Ne-(carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med 2001;31:175–80. doi: 10.1016/S0891-5849(01)00570-6
24. Valente T, Gella A, Fernàndez-Busquets X, Unzeta M, Durany N. Immunohistochemical analysis of human brain suggests a pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol Dis 2010;37:67–76. doi: 10.1016/j.nbd.2009.09.008
25. McCormick M, Hadley D, McLean JR, et al. Randomized, controlled trial of insulin for acute poststroke hyperglycemia. Ann Neurol 2010; 67:570–8. doi: 10.1002/ana.21983
26. Dheen ST, Tay SS, Wong WC. Arginine vasopressinand oxytocinlike immunoreactive neurons in the hypothalamic paraventricular and supraoptic nuclei of streptozotocin- induced diabetic rats. Arch Histol Cytol 1994; 57: 461–72.
27. Luo Y, Kaur C, Ling EA. Neuronal and glial response in the rat hypothalamus neurohypophysis complex with streptozotocininduced diabetes. Brain Res 2002; 925: 42–54. doi:10.1016/S0006- 8993(01)03258-9
28. Grober E, Hall CB, Hahn SR, Lipton RB. Memory impairment and executive dysfunction are associated with inadequately controlled diabetes in older adults. J Prim Care Community Health. 2011;2:229- 33. doi: 10.1177/2150131911409945
29. Biessels GJ, Kamal A, Ramakers GM, et al. Place learning and hippocampal synaptic plasticity in streptozotocin- induced diabetic rats. Diabetes 1996; 45: 1259-66. doi: 10.2337/diabetes.45.9.1259
30. Levy J, Gavin JR 3rd, Sowers JR. Diabetes mellitus: a disease of abnormal cellular calcium metabolism? Am J Med 1994; 96: 260–73. doi: 10.1016/0002-9343(94)90152-X
31. Russell JW, Feldman EL. Insulin-like growth factor-I prevents apoptosis in sympathetic neurons exposed to high glucose. Horm Metab Res 1999; 31: 90–6. doi: 10.1055/s-2007-978704
32. Holscher C. Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity. Trends Neurosci 1997; 20: 298–303. doi: 10.1016/ S0166-2236(97)01065-5
33. Reck-Peterson SL, Provance DW Jr, Mooseker MS, Mercer JA. Class V myosins. Biochim Biophys Acta 2000;1496:36–51. doi: 10.1016/ S0167-4889(00)00007-0
34. da Costa AV, Calabria LK, Nascimento R, et al. The streptozotocininduced rat model of diabetes mellitus evidences significant reduction of miyosin Va expression in the brain. Metab Brain Dis 2011;26:247- 51. doi: 10.1007/s11011-011-9259-5
Hiperglisemi ve beyin
Year 2013,
Volume: 26 Issue: 3, 118 - 121, 30.09.2015
Glukoz tüm hücrelerde özellikle enerji metabolizmasında kullanılan
önemli bir metabolik substrattır. Ancak glukoz homeostasisinin
bozulmasıyla oluşan glukoz artışı dolaylı olarak ya da direkt olarak
serebral fonksiyonları etkileyebilir. Beyin, glukoz artışı sonucu
oluşan ileri glikasyon ürünleri ve serbest radikallerden ötürü dolaylı
yoldan etkilenirken, nöronal gen düzeyinde meydana gelen uzun
süreli değişikliklerden direkt olarak etkilenir. Bütün bu değişiklikler
nöronopati, ensefalopati, demans gibi önemli klinik bozukluklara
neden olur. Serebral fonksiyonları etkileyen indirekt yolların
yanında, direkt nöronal yolların belirlenmesi ve buna yönelik tedavi
stratejilerinin geliştirilmesi beyin hasarının önlenmesinde önemli
olacaktır
1. Herculano-Houzel S. Scaling of brain metabolism with a fixed energy budget per neuron: implications for neuronal activity, plasticity and evolution. PLoS One 2011;6:e17514. doi: 10.1371/journal. pone.0017514.
2. Clarke DD, Sokoloff L. Circulation and energy metabolism of the brain. In: Siegel, GJ, Agranoff BW, Albers RW, Molinoff SK, Fisher PB, Uhler MD, editors. Basic Neurochemistry. Philadelphia: LippincottRaven, 1999:637–69.
3. Bischof MG, Krssak M, Krebs M, et al. Effects of short-term improvement of insulin treatment and glycemia on hepatic glycogen metabolism in type 1 diabetes. Diabetes 2001;502:392–8. doi: 10.2337/ diabetes.50.2.392
4. Reagan LP, Rosell DR, Alves SE, et al. GLUT8 glucose transporter is localized to excitatory and inhibitory neurons in the rat hippocampus. Brain Res 2002; 932:129–34. doi:10.1016/S0006-8993(02)02308-9
5. Shah K, Desilva S, Abbruscato T. The role of glucose transporters in brain disease: Diabetes and Alzheimer’s disease. Int J Mol Sci 2012;13:12629-55. doi: 10.3390/ijms131012629.
6. Horani MH, Mooradian, AD. Effect of diabetes on the blood brain barrier. Curr Pharmaceut Design 2003;9:833-40. doi:10.2174/1381612033455314
7. Klein JP Waxman SG. The brain in diabetes: molecular changes in neurons and their implications for end-organ damage. Lancet Neurology 2003; 2: 548–54. doi:10.1016/S1474-4422(03)00503-9
8. Pitkanen OM, Martin JM, Hallman M, et al. Free radical activity during development of insulin dependent diabetes mellitus in the rat. Life Sci 1992; 50: 335-9. doi:10.1016/0024-3205(92)90434-Q
9. Van Dam PS, Van Asbeck BS, Erkelens DW, et al. The role of oxidative stress in neuropathy and other diabetic complications. Diabetes Metab Rev 1995; 11:181-92. doi:10.1002/dmr.5610110303
10. Bukan N, Sancak B, Yavuz Ö, et al. Lipid peroxidation and scavenging enzyme levels in the liver of streptozotocin-induced diabetes rats. Indian J Biochem and Biophys 2003;40:447-50.
11. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: A new perspective on an old paradigm. Diabetes 1999: 48:1-9. doi: 10.2337/diabetes.48.1.1
12. Rösen P, Du X, Tschöpe D. Role of oxygen derived radicals for vascular dysfunction in the diabetic heart: prevention by α-tocopherol?. Mol Cell Biochem 1998; 188: 103-11. doi: 10.1007/978-1-4615-5763-0_12
13. Du X, Stockklauser-Farber K, Rösen P. Generation of reactive oxygen intermediates, activation of NFKappaB, and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase? Free Radic Biol Med 1999; 27:752-63.
14. Bonnefont-Rousselot D. Glucose and reactive oxygen species. Curr Opin Clin Nutr Metab Care 2002; 5: 561-8. doi: 10.1097/00075197- 200209000-00016
15. Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404:787-90. doi:10.1038/35008121
16. Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes 1998; 47: 859-66. doi:10.2337/ diabetes.47.6.859
17. Parmaksiz I. Advanced glycation end-products in complications of diabetes mellitus. Marmara Med J 2011;24:141-8. doi: 10.5472/ MMJ.2011.0.2037.1
18. Riehl A, Németh J, Angel P, Hess J. The receptor RAGE:bridging inflammation and cancer. Cell Commun Signal 2009;7:12 doi: 10.1186/1478-811X-7-12
19. Chappey O, Dosquet C, Wautier MP, Wautier JL. Advanced glycation end products, oxidant stress and vascular lesions. Eur J Clin Invest 1997;27:97-108. doi: 10.1046/j.1365-2362.1997.710624.x
20. Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). Study Research Group: Long-term effect of diabetes and its treatment on cognitive function. The Diabetes Control and Complications. N Engl J Med 2007;356:1842-5.
21. Maritim AC, Sanders RA, Watkins III JB. Diabetes, oxidative stress and antioxidants: Review. J Biochem Mol Toxicol 2003;17:4-38. doi:10.1002/jbt.10058
22. Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Yorek MA. Effect of treating streptozotocin-induced diabetic rats with sorbinil, myoinositol or aminoguanidine on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve. Int J Exp Diabetes Res 2002;3:21-36. doi: 10.1080/15604280212525
23. Castellani RJ, Harris PLR, Sayre LM, et al. . Active glycation in neurofibrillary pathology of Alzheimer disease: Ne-(carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med 2001;31:175–80. doi: 10.1016/S0891-5849(01)00570-6
24. Valente T, Gella A, Fernàndez-Busquets X, Unzeta M, Durany N. Immunohistochemical analysis of human brain suggests a pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol Dis 2010;37:67–76. doi: 10.1016/j.nbd.2009.09.008
25. McCormick M, Hadley D, McLean JR, et al. Randomized, controlled trial of insulin for acute poststroke hyperglycemia. Ann Neurol 2010; 67:570–8. doi: 10.1002/ana.21983
26. Dheen ST, Tay SS, Wong WC. Arginine vasopressinand oxytocinlike immunoreactive neurons in the hypothalamic paraventricular and supraoptic nuclei of streptozotocin- induced diabetic rats. Arch Histol Cytol 1994; 57: 461–72.
27. Luo Y, Kaur C, Ling EA. Neuronal and glial response in the rat hypothalamus neurohypophysis complex with streptozotocininduced diabetes. Brain Res 2002; 925: 42–54. doi:10.1016/S0006- 8993(01)03258-9
28. Grober E, Hall CB, Hahn SR, Lipton RB. Memory impairment and executive dysfunction are associated with inadequately controlled diabetes in older adults. J Prim Care Community Health. 2011;2:229- 33. doi: 10.1177/2150131911409945
29. Biessels GJ, Kamal A, Ramakers GM, et al. Place learning and hippocampal synaptic plasticity in streptozotocin- induced diabetic rats. Diabetes 1996; 45: 1259-66. doi: 10.2337/diabetes.45.9.1259
30. Levy J, Gavin JR 3rd, Sowers JR. Diabetes mellitus: a disease of abnormal cellular calcium metabolism? Am J Med 1994; 96: 260–73. doi: 10.1016/0002-9343(94)90152-X
31. Russell JW, Feldman EL. Insulin-like growth factor-I prevents apoptosis in sympathetic neurons exposed to high glucose. Horm Metab Res 1999; 31: 90–6. doi: 10.1055/s-2007-978704
32. Holscher C. Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity. Trends Neurosci 1997; 20: 298–303. doi: 10.1016/ S0166-2236(97)01065-5
33. Reck-Peterson SL, Provance DW Jr, Mooseker MS, Mercer JA. Class V myosins. Biochim Biophys Acta 2000;1496:36–51. doi: 10.1016/ S0167-4889(00)00007-0
34. da Costa AV, Calabria LK, Nascimento R, et al. The streptozotocininduced rat model of diabetes mellitus evidences significant reduction of miyosin Va expression in the brain. Metab Brain Dis 2011;26:247- 51. doi: 10.1007/s11011-011-9259-5