Endocrinol Metab.  2014 Jun;29(2):112-121. 10.3803/EnM.2014.29.2.112.

Neurocognitive Changes and Their Neural Correlates in Patients with Type 2 Diabetes Mellitus

• Lee JH
• Choi Y
• Jun C
• Hong YS
• Cho HB
• Kim JE
• Lyoo IK

• KMID: 2169414
• DOI: http://doi.org/10.3803/EnM.2014.29.2.112

Abstract

As the prevalence and life expectancy of type 2 diabetes mellitus (T2DM) continue to increase, the importance of effective detection and intervention for the complications of T2DM, especially neurocognitive complications including cognitive dysfunction and dementia, is receiving greater attention. T2DM is thought to influence cognitive function through an as yet unclear mechanism that involves multiple factors such as hyperglycemia, hypoglycemia, and vascular disease. Recent developments in neuroimaging methods have led to the identification of potential neural correlates of T2DM-related neurocognitive changes, which extend from structural to functional and metabolite alterations in the brain. The evidence indicates various changes in the T2DM brain, including global and regional atrophy, white matter hyperintensity, altered functional connectivity, and changes in neurometabolite levels. Continued neuroimaging research is expected to further elucidate the underpinnings of cognitive decline in T2DM and allow better diagnosis and treatment of the condition.

Keyword

Diabetes mellitus, type 2; Cognition disorders; Dementia; Hyperglycemia; Hypoglycemia; Magnetic resonance imaging; Magnetic resonance spectroscopy

MeSH Terms

Atrophy
Brain
Cognition Disorders
Dementia
Diabetes Mellitus, Type 2*
Diagnosis
Humans
Hyperglycemia
Hypoglycemia
Life Expectancy
Magnetic Resonance Imaging
Magnetic Resonance Spectroscopy
Neuroimaging
Prevalence
Vascular Diseases

Reference

1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004; 27:1047–1053. PMID: 15111519.

2. Strachan MW, Reynolds RM, Marioni RE, Price JF. Cognitive function, dementia and type 2 diabetes mellitus in the elderly. Nat Rev Endocrinol. 2011; 7:108–114. PMID: 21263438.

3. Lutgers HL, Gerrits EG, Sluiter WJ, Ubink-Veltmaat LJ, Landman GW, Links TP, Gans RO, Smit AJ, Bilo HJ. Life expectancy in a large cohort of type 2 diabetes patients treated in primary care (ZODIAC-10). PLoS One. 2009; 4:e6817. PMID: 19714245.

4. Gregg EW, Yaffe K, Cauley JA, Rolka DB, Blackwell TL, Narayan KM, Cummings SR. Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Arch Intern Med. 2000; 160:174–180. PMID: 10647755.

5. Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in diabetes: systematic overview of prospective observational studies. Diabetologia. 2005; 48:2460–2469. PMID: 16283246.

6. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006; 5:64–74. PMID: 16361024.

7. 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; 490:169–175. PMID: 15094083.

8. Messier C, Tsiakas M, Gagnon M, Desrochers A. Effect of age and glucoregulation on cognitive performance. J Clin Exp Neuropsychol. 2010; 32:809–821. PMID: 20209424.

9. Reijmer YD, van den Berg E, Ruis C, Kappelle LJ, Biessels GJ. Cognitive dysfunction in patients with type 2 diabetes. Diabetes Metab Res Rev. 2010; 26:507–519. PMID: 20799243.

10. Whitmer RA. Type 2 diabetes and risk of cognitive impairment and dementia. Curr Neurol Neurosci Rep. 2007; 7:373–380. PMID: 17764626.

11. Sommerfield AJ, Deary IJ, Frier BM. Acute hyperglycemia alters mood state and impairs cognitive performance in people with type 2 diabetes. Diabetes Care. 2004; 27:2335–2340. PMID: 15451897.

12. Yaffe K, Blackwell T, Whitmer RA, Krueger K, Barrett Connor E. Glycosylated hemoglobin level and development of mild cognitive impairment or dementia in older women. J Nutr Health Aging. 2006; 10:293–295. PMID: 16886099.

13. Raffaitin C, Feart C, Le Goff M, Amieva H, Helmer C, Akbaraly TN, Tzourio C, Gin H, Barberger-Gateau P. Metabolic syndrome and cognitive decline in French elders: the three-city study. Neurology. 2011; 76:518–525. PMID: 21288982.

14. Christman AL, Matsushita K, Gottesman RF, Mosley T, Alonso A, Coresh J, Hill-Briggs F, Sharrett AR, Selvin E. Glycated haemoglobin and cognitive decline: the Atherosclerosis Risk in Communities (ARIC) study. Diabetologia. 2011; 54:1645–1652. PMID: 21360189.

15. Rizzo MR, Marfella R, Barbieri M, Boccardi V, Vestini F, Lettieri B, Canonico S, Paolisso G. Relationships between daily acute glucose fluctuations and cognitive performance among aged type 2 diabetic patients. Diabetes Care. 2010; 33:2169–2174. PMID: 20573753.

16. Gonder-Frederick LA, Zrebiec JF, Bauchowitz AU, Ritterband LM, Magee JC, Cox DJ, Clarke WL. Cognitive function is disrupted by both hypo- and hyperglycemia in school-aged children with type 1 diabetes: a field study. Diabetes Care. 2009; 32:1001–1006. PMID: 19324943.

17. Bree AJ, Puente EC, Daphna-Iken D, Fisher SJ. Diabetes increases brain damage caused by severe hypoglycemia. Am J Physiol Endocrinol Metab. 2009; 297:E194–E201. PMID: 19435850.

18. Auer RN, Siesjo BK. Hypoglycaemia: brain neurochemistry and neuropathology. Baillieres Clin Endocrinol Metab. 1993; 7:611–625. PMID: 8379907.

19. Suh SW, Gum ET, Hamby AM, Chan PH, Swanson RA. Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J Clin Invest. 2007; 117:910–918. PMID: 17404617.

20. Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities. Diabetes Care. 2005; 28:2948–2961. PMID: 16306561.

21. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009; 301:1565–1572. PMID: 19366776.

22. Punthakee Z, Miller ME, Launer LJ, Williamson JD, Lazar RM, Cukierman-Yaffee T, Seaquist ER, Ismail-Beigi F, Sullivan MD, Lovato LC, Bergenstal RM, Gerstein HC. ACCORD Group of Investigators. ACCORD-MIND Investigators. Poor cognitive function and risk of severe hypoglycemia in type 2 diabetes: post hoc epidemiologic analysis of the ACCORD trial. Diabetes Care. 2012; 35:787–793. PMID: 22374637.

23. de Galan BE, Zoungas S, Chalmers J, Anderson C, Dufouil C, Pillai A, Cooper M, Grobbee DE, Hackett M, Hamet P, Heller SR, Lisheng L, MacMahon S, Mancia G, Neal B, Pan CY, Patel A, Poulter N, Travert F, Woodward M. ADVANCE Collaborative Group. Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Diabetologia. 2009; 52:2328–2336. PMID: 19688336.

24. Munshi M, Grande L, Hayes M, Ayres D, Suhl E, Capelson R, Lin S, Milberg W, Weinger K. Cognitive dysfunction is associated with poor diabetes control in older adults. Diabetes Care. 2006; 29:1794–1799. PMID: 16873782.

25. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000; 321:405–412. PMID: 10938048.

26. Ryan CM, Geckle MO, Orchard TJ. Cognitive efficiency declines over time in adults with type 1 diabetes: effects of micro- and macrovascular complications. Diabetologia. 2003; 46:940–948. PMID: 12819900.

27. Manschot SM, Biessels GJ, de Valk H, Algra A, Rutten GE, van der Grond J, Kappelle LJ. Utrecht Diabetic Encephalopathy Study Group. Metabolic and vascular determinants of impaired cognitive performance and abnormalities on brain magnetic resonance imaging in patients with type 2 diabetes. Diabetologia. 2007; 50:2388–2397. PMID: 17764005.

28. Yoshitake T, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K, Ohmori S, Nomiyama K, Kawano H, Ueda K, Sueishi K, Tsuneyoshi M, Fujishima M. Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study. Neurology. 1995; 45:1161–1168. PMID: 7783883.

29. Akisaki T, Sakurai T, Takata T, Umegaki H, Araki A, Mizuno S, Tanaka S, Ohashi Y, Iguchi A, Yokono K, Ito H. 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. PMID: 16506272.

30. Biessels GJ, van der Heide LP, Kamal A, Bleys RL, Gispen WH. Ageing and diabetes: implications for brain function. Eur J Pharmacol. 2002; 441:1–14. PMID: 12007915.

31. den Heijer T, Vermeer SE, van Dijk EJ, Prins ND, Koudstaal PJ, Hofman A, Breteler MM. Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia. 2003; 46:1604–1610. PMID: 14595538.

32. Schmidt R, Launer LJ, Nilsson LG, Pajak A, Sans S, Berger K, Breteler MM, de Ridder M, Dufouil C, Fuhrer R, Giampaoli S, Hofman A. CASCADE Consortium. Magnetic resonance imaging of the brain in diabetes: the Cardiovascular Determinants of Dementia (CASCADE) Study. Diabetes. 2004; 53:687–692. PMID: 14988253.

33. Manschot SM, Brands AM, van der Grond J, Kessels RP, Algra A, Kappelle LJ, Biessels GJ. Utrecht Diabetic Encephalopathy Study Group. Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes. 2006; 55:1106–1113. PMID: 16567535.

34. van Harten B, de Leeuw FE, Weinstein HC, Scheltens P, Biessels GJ. Brain imaging in patients with diabetes: a systematic review. Diabetes Care. 2006; 29:2539–2548. PMID: 17065699.

35. Jongen C, Biessels GJ. Structural brain imaging in diabetes: a methodological perspective. Eur J Pharmacol. 2008; 585:208–218. PMID: 18407264.

36. Frisoni GB, Fox NC, Jack CR, Scheltens P, Thompson PM. The clinical use of structural MRI in Alzheimer disease. Nat Rev Neurol. 2010; 6:67–77. PMID: 20139996.

37. Knopman DS, Mosley TH, Catellier DJ, Sharrett AR. Atherosclerosis Risk in Communities (ARIC) Study. Cardiovascular risk factors and cerebral atrophy in a middle-aged cohort. Neurology. 2005; 65:876–881. PMID: 16186527.

38. Jongen C, van der Grond J, Kappelle LJ, Biessels GJ, Viergever MA, Pluim JP. Utrecht Diabetic Encephalopathy Study Group. Automated measurement of brain and white matter lesion volume in type 2 diabetes mellitus. Diabetologia. 2007; 50:1509–1516. PMID: 17492428.

39. Lee JH, Yoon S, Renshaw PF, Kim TS, Jung JJ, Choi Y, Kim BN, Jacobson AM, Lyoo IK. Morphometric changes in lateral ventricles of patients with recent-onset type 2 diabetes mellitus. PLoS One. 2013; 8:e60515. PMID: 23593231.

40. Brundel M, van den Heuvel M, de Bresser J, Kappelle LJ, Biessels GJ. Utrecht Diabetic Encephalopathy Study Group. Cerebral cortical thickness in patients with type 2 diabetes. J Neurol Sci. 2010; 299:126–130. PMID: 20869085.

41. Carmichael OT, Kuller LH, Lopez OL, Thompson PM, Dutton RA, Lu A, Lee SE, Lee JY, Aizenstein HJ, Meltzer CC, Liu YX, Toga AW, Becker JT. Cerebral ventricular changes associated with transitions between normal cognitive function, mild cognitive impairment, and dementia. Alzheimer Dis Assoc Disord. 2007; 21:14–24. PMID: 17334268.

42. Enzinger C, Fazekas F, Matthews PM, Ropele S, Schmidt H, Smith S, Schmidt R. Risk factors for progression of brain atrophy in aging: six-year follow-up of normal subjects. Neurology. 2005; 64:1704–1711. PMID: 15911795.

43. Korf ESC, White LR, Scheltens P, Launer LJ. Brain aging in very old men with type 2 diabetes: the Honolulu-Asia Aging Study. Diabetes Care. 2006; 29:2268–2274. PMID: 17003305.

44. Musen G, Lyoo IK, Sparks CR, Weinger K, Hwang J, Ryan CM, Jimerson DC, Hennen J, Renshaw PF, Jacobson AM. Effects of type 1 diabetes on gray matter density as measured by voxel-based morphometry. Diabetes. 2006; 55:326–333. PMID: 16443764.

45. Saczynski JS, Siggurdsson S, Jonsson PV, Eiriksdottir G, Olafsdottir E, Kjartansson O, Harris TB, van Buchem MA, Gudnason V, Launer LJ. Glycemic status and brain injury in older individuals: the age gene/environment susceptibility-Reykjavik study. Diabetes Care. 2009; 32:1608–1613. PMID: 19509008.

46. Toth C, Schmidt AM, Tuor UI, Francis G, Foniok T, Brussee V, Kaur J, Yan SF, Martinez JA, Barber PA, Buchan A, Zochodne DW. Diabetes, leukoencephalopathy and rage. Neurobiol Dis. 2006; 23:445–461. PMID: 16815028.

47. Francis GJ, Martinez JA, Liu WQ, Xu K, Ayer A, Fine J, Tuor UI, Glazner G, Hanson LR, Frey WH 2nd, Toth C. Intranasal insulin prevents cognitive decline, cerebral atrophy and white matter changes in murine type I diabetic encephalopathy. Brain. 2008; 131(Pt 12):3311–3334. PMID: 19015157.

48. Yaffe K, Blackwell T, Kanaya AM, Davidowitz N, Barrett-Connor E, Krueger K. Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology. 2004; 63:658–663. PMID: 15326238.

49. Tan ZS, Beiser AS, Fox CS, Au R, Himali JJ, Debette S, Decarli C, Vasan RS, Wolf PA, Seshadri S. Association of metabolic dysregulation with volumetric brain magnetic resonance imaging and cognitive markers of subclinical brain aging in middle-aged adults: the Framingham Offspring Study. Diabetes Care. 2011; 34:1766–1770. PMID: 21680719.

50. Klein JP, Waxman SG. The brain in diabetes: molecular changes in neurons and their implications for end-organ damage. Lancet Neurol. 2003; 2:548–554. PMID: 12941577.

51. Enhamre E, Carlsson A, Gronbladh A, Watanabe H, Hallberg M, Nyberg F. The expression of growth hormone receptor gene transcript in the prefrontal cortex is affected in male mice with diabetes-induced learning impairments. Neurosci Lett. 2012; 523:82–86. PMID: 22750159.

52. Gold SM, Dziobek I, Sweat V, Tirsi A, Rogers K, Bruehl H, Tsui W, Richardson S, Javier E, Convit A. Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia. 2007; 50:711–719. PMID: 17334649.

53. Ajilore O, Narr K, Rosenthal J, Pham D, Hamilton L, Watari K, Elderkin-Thompson V, Darwin C, Toga A, Kumar A. Regional cortical gray matter thickness differences associated with type 2 diabetes and major depression. Psychiatry Res. 2010; 184:63–70. PMID: 20832254.

54. Lyoo IK, Yoon S, Jacobson AM, Hwang J, Musen G, Kim JE, Simonson DC, Bae S, Bolo N, Kim DJ, Weinger K, Lee JH, Ryan CM, Renshaw PF. Prefrontal cortical deficits in type 1 diabetes mellitus: brain correlates of comorbid depression. Arch Gen Psychiatry. 2012; 69:1267–1276. PMID: 23090665.

55. Kumar A, Haroon E, Darwin C, Pham D, Ajilore O, Rodriguez G, Mintz J. Gray matter prefrontal changes in type 2 diabetes detected using MRI. J Magn Reson Imaging. 2008; 27:14–19. PMID: 18050330.

56. Lyoo IK, Yoon SJ, Musen G, Simonson DC, Weinger K, Bolo N, Ryan CM, Kim JE, Renshaw PF, Jacobson AM. Altered prefrontal glutamate-glutamine-gamma-aminobutyric acid levels and relation to low cognitive performance and depressive symptoms in type 1 diabetes mellitus. Arch Gen Psychiatry. 2009; 66:878–887. PMID: 19652127.

57. Koenigs M, Grafman J. The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex. Behav Brain Res. 2009; 201:239–243. PMID: 19428640.

58. Mollica RF, Lyoo IK, Chernoff MC, Bui HX, Lavelle J, Yoon SJ, Kim JE, Renshaw PF. Brain structural abnormalities and mental health sequelae in South Vietnamese ex-political detainees who survived traumatic head injury and torture. Arch Gen Psychiatry. 2009; 66:1221–1232. PMID: 19884610.

59. Schmidt R, Enzinger C, Ropele S, Schmidt H, Fazekas F. Austrian Stroke Prevention Study. Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study. Lancet. 2003; 361:2046–2048. PMID: 12814718.

60. de Leeuw FE, de Groot JC, Achten E, Oudkerk M, Ramos LM, Heijboer R, Hofman A, Jolles J, van Gijn J, Breteler MM. 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. PMID: 11118240.

61. Taylor WD, MacFall JR, Provenzale JM, Payne ME, McQuoid DR, Steffens DC, Krishnan KR. Serial MR imaging of volumes of hyperintense white matter lesions in elderly patients: correlation with vascular risk factors. AJR Am J Roentgenol. 2003; 181:571–576. PMID: 12876050.

62. Gouw AA, van der Flier WM, Fazekas F, van Straaten EC, Pantoni L, Poggesi A, Inzitari D, Erkinjuntti T, Wahlund LO, Waldemar G, Schmidt R, Scheltens P, Barkhof F. LADIS Study Group. 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. PMID: 18323505.

63. van Harten B, Oosterman JM, Potter van Loon BJ, Scheltens P, Weinstein HC. Brain lesions on MRI in elderly patients with type 2 diabetes mellitus. Eur Neurol. 2007; 57:70–74. PMID: 17179707.

64. Murray AD, Staff RT, Shenkin SD, Deary IJ, Starr JM, Whalley LJ. Brain white matter hyperintensities: relative importance of vascular risk factors in nondemented elderly people. Radiology. 2005; 237:251–257. PMID: 16126931.

65. van Swieten JC, van den Hout JH, van Ketel BA, Hijdra A, Wokke JH, van Gijn J. Periventricular lesions in the white matter on magnetic resonance imaging in the elderly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces. Brain. 1991; 114(Pt 2):761–774. PMID: 2043948.

66. Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, Radner H, Lechner H. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993; 43:1683–1689. PMID: 8414012.

67. Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke. 1997; 28:652–659. PMID: 9056627.

68. Devous MD. Functional brain imaging in the dementias: role in early detection, differential diagnosis, and longitudinal studies. Eur J Nucl Med Mol Imaging. 2002; 29:1685–1696. PMID: 12458405.

69. Wolf H, Jelic V, Gertz HJ, Nordberg A, Julin P, Wahlund LO. A critical discussion of the role of neuroimaging in mild cognitive impairment. Acta Neurol Scand Suppl. 2003; 179:52–76. PMID: 12603252.

70. Allen G, Barnard H, McColl R, Hester AL, Fields JA, Weiner MF, Ringe WK, Lipton AM, Brooker M, McDonald E, Rubin CD, Cullum CM. Reduced hippocampal functional connectivity in Alzheimer disease. Arch Neurol. 2007; 64:1482–1487. PMID: 17923631.

71. Sorg C, Riedl V, Muhlau M, Calhoun VD, Eichele T, Laer L, Drzezga A, Forstl H, Kurz A, Zimmer C, Wohlschlager AM. Selective changes of resting-state networks in individuals at risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2007; 104:18760–18765. PMID: 18003904.

72. Zhou H, Lu W, Shi Y, Bai F, Chang J, Yuan Y, Teng G, Zhang Z. Impairments in cognition and resting-state connectivity of the hippocampus in elderly subjects with type 2 diabetes. Neurosci Lett. 2010; 473:5–10. PMID: 20123114.

73. Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol. 2011; 68:51–57. PMID: 20837822.

74. Musen G, Jacobson AM, Bolo NR, Simonson DC, Shenton ME, McCartney RL, Flores VL, Hoogenboom WS. Resting-state brain functional connectivity is altered in type 2 diabetes. Diabetes. 2012; 61:2375–2379. PMID: 22664957.

75. van Duinkerken E, Schoonheim MM, Sanz-Arigita EJ, RG IJ, Moll AC, Snoek FJ, Ryan CM, Klein M, Diamant M, Barkhof F. Resting-state brain networks in type 1 diabetic patients with and without microangiopathy and their relation to cognitive functions and disease variables. Diabetes. 2012; 61:1814–1821. PMID: 22438575.

76. Garnett MR, Blamire AM, Corkill RG, Cadoux-Hudson TA, Rajagopalan B, Styles P. Early proton magnetic resonance spectroscopy in normal-appearing brain correlates with outcome in patients following traumatic brain injury. Brain. 2000; 123(Pt 10):2046–2054. PMID: 11004122.

77. Lin Y, Zhou J, Sha L, Li Y, Qu X, Liu L, Chen H, An Z, Wang Y, Sun C. Metabolite differences in the lenticular nucleus in type 2 diabetes mellitus shown by proton MR spectroscopy. AJNR Am J Neuroradiol. 2013; 34:1692–1696. PMID: 23598834.

78. Biessels GJ, Braun KP, de Graaf RA, van Eijsden P, Gispen WH, Nicolay K. Cerebral metabolism in streptozotocin-diabetic rats: an in vivo magnetic resonance spectroscopy study. Diabetologia. 2001; 44:346–353. PMID: 11317667.

79. Kario K, Ishikawa J, Hoshide S, Matsui Y, Morinari M, Eguchi K, Ishikawa S, Shimada K. Diabetic brain damage in hypertension: role of renin-angiotensin system. Hypertension. 2005; 45:887–893. PMID: 15824198.

80. 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. PMID: 1319074.

81. Sahin I, Alkan A, Keskin L, Cikim A, Karakas HM, Firat AK, Sigirci A. Evaluation of in vivo cerebral metabolism on proton magnetic resonance spectroscopy in patients with impaired glucose tolerance and type 2 diabetes mellitus. J Diabetes Complications. 2008; 22:254–260. PMID: 18413166.

82. Modi S, Bhattacharya M, Sekhri T, Rana P, Tripathi RP, Khushu S. Assessment of the metabolic profile in type 2 diabetes mellitus and hypothyroidism through proton MR spectroscopy. Magn Reson Imaging. 2008; 26:420–425. PMID: 18164573.

83. Bitsch A, Bruhn H, Vougioukas V, Stringaris A, Lassmann H, Frahm J, Bruck W. Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. AJNR Am J Neuroradiol. 1999; 20:1619–1627. PMID: 10543631.

84. Trudeau F, Gagnon S, Massicotte G. Hippocampal synaptic plasticity and glutamate receptor regulation: influences of diabetes mellitus. Eur J Pharmacol. 2004; 490:177–186. PMID: 15094084.

85. Lisman JE, Fellous JM, Wang XJ. A role for NMDA-receptor channels in working memory. Nat Neurosci. 1998; 1:273–275. PMID: 10195158.

86. Schubert F, Gallinat J, Seifert F, Rinneberg H. Glutamate concentrations in human brain using single voxel proton magnetic resonance spectroscopy at 3 Tesla. Neuroimage. 2004; 21:1762–1771. PMID: 15050596.

87. Pfund Z, Chugani DC, Juhasz C, Muzik O, Chugani HT, Wilds IB, Seraji-Bozorgzad N, Moore GJ. Evidence for coupling between glucose metabolism and glutamate cycling using FDG PET and 1H magnetic resonance spectroscopy in patients with epilepsy. J Cereb Blood Flow Metab. 2000; 20:871–878. PMID: 10826538.

88. Mangia S, Kumar AF, Moheet AA, Roberts RJ, Eberly LE, Seaquist ER, Tkac I. Neurochemical profile of patients with type 1 diabetes measured by (1)H-MRS at 4 T. J Cereb Blood Flow Metab. 2013; 33:754–759. PMID: 23403373.

89. Ajilore O, Haroon E, Kumaran S, Darwin C, Binesh N, Mintz J, Miller J, Thomas MA, Kumar A. Measurement of brain metabolites in patients with type 2 diabetes and major depression using proton magnetic resonance spectroscopy. Neuropsychopharmacology. 2007; 32:1224–1231. PMID: 17180124.

90. Sickmann HM, Waagepetersen HS, Schousboe A, Benie AJ, Bouman SD. Obesity and type 2 diabetes in rats are associated with altered brain glycogen and amino-acid homeostasis. J Cereb Blood Flow Metab. 2010; 30:1527–1537. PMID: 20424632.

91. Li Q, Puro DG. Diabetes-induced dysfunction of the glutamate transporter in retinal Muller cells. Invest Ophthalmol Vis Sci. 2002; 43:3109–3116. PMID: 12202536.

92. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996; 16:675–686. PMID: 8785064.

93. Bergles DE, Jahr CE. Glial contribution to glutamate uptake at Schaffer collateral-commissural synapses in the hippocampus. J Neurosci. 1998; 18:7709–7716. PMID: 9742141.

94. Coleman ES, Dennis JC, Braden TD, Judd RL, Posner P. Insulin treatment prevents diabetes-induced alterations in astrocyte glutamate uptake and GFAP content in rats at 4 and 8 weeks of diabetes duration. Brain Res. 2010; 1306:131–141. PMID: 19822133.

95. Brands AM, Biessels GJ, de Haan EH, Kappelle LJ, Kessels RP. The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes Care. 2005; 28:726–735. PMID: 15735218.

96. Howarth C, Gleeson P, Attwell D. Updated energy budgets for neural computation in the neocortex and cerebellum. J Cereb Blood Flow Metab. 2012; 32:1222–1232. PMID: 22434069.