PDF
ePub
Citation
Print
Abstract
Dementia, a clinical syndrome affecting memory, thinking, and social abilities primarily caused by neurodegeneration, is becoming one of the greatest health and socioeconomic burdens in the aging society. The age-standardized prevalence of dementia for people aged 60 or older was 5% to 7% in most world regions, affecting 47 million people in 2015. This number is expected to almost double every 20 years. Although aging is the greatest but non-modifiable risk factor, approximately 35% of the risk has been attributed to the combination of potentially modifiable risk factors including education, diet and lifestyle factors, psychiatric factors, and metabolic factors. There is ample evidence that people with glucose intolerance, insulin resistance, and metabolic syndrome are at higher risk for cognitive impairment and dementia compared to age- and sex-matched controls. Meta-analyses and large-scaled pooled analyses demonstrate that diabetes is associated with an approximately 60% to 70% increased risk of all types of dementia. In this article, the associations of hyperglycemia, hypoglycemia, and glucose variability with cognitive dysfunction and dementia are demonstrated. Also, the underlying mechanism of this connection and possible effects of anti-diabetic medications are discussed.
References
1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013; 9:63–75.e2.
2. Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N. Dementia prevention, intervention, and care. Lancet. 2017; 390:2673–2734.
3. Ohara T, Doi Y, Ninomiya T, Hirakawa Y, Hata J, Iwaki T, Kanba S, Kiyohara Y. Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology. 2011; 77:1126–1134.
4. Gudala K, Bansal D, Schifano F, Bhansali A. Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J Diabetes Investig. 2013; 4:640–650.
5. Luchsinger JA, Reitz C, Patel B, Tang MX, Manly JJ, Mayeux R. Relation of diabetes to mild cognitive impairment. Arch Neurol. 2007; 64:570–575.
6. Roberts RO, Knopman DS, Geda YE, Cha RH, Pankratz VS, Baertlein L, Boeve BF, Tangalos EG, Ivnik RJ, Mielke MM, Petersen RC. Association of diabetes with amnestic and nonamnestic mild cognitive impairment. Alzheimers Dement. 2014; 10:18–26.
7. Roberts RO, Geda YE, Knopman DS, Christianson TJ, Pankratz VS, Boeve BF, Vella A, Rocca WA, Petersen RC. Association of duration and severity of diabetes mellitus with mild cognitive impairment. Arch Neurol. 2008; 65:1066–1073.
8. Crane PK, Walker R, Hubbard RA, Li G, Nathan DM, Zheng H, Haneuse S, Craft S, Montine TJ, Kahn SE, McCormick W, McCurry SM, Bowen JD, Larson EB. Glucose levels and risk of dementia. N Engl J Med. 2013; 369:540–548.
9. 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.
10. Willette AA, Xu G, Johnson SC, Birdsill AC, Jonaitis EM, Sager MA, Hermann BP, La Rue A, Asthana S, Bendlin BB. Insulin resistance, brain atrophy, and cognitive performance in late middle-aged adults. Diabetes Care. 2013; 36:443–449.
11. Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, Sekita A, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T. Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology. 2010; 75:764–770.
12. Lee SH, Zabolotny JM, Huang H, Lee H, Kim YB. Insulin in the nervous system and the mind: Functions in metabolism, memory, and mood. Mol Metab. 2016; 5:589–601.
13. Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, Arnold SE. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012; 122:1316–1338.
14. Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. J Pathol. 2011; 225:54–62.
15. Deng Y, Li B, Liu Y, Iqbal K, Grundke-Iqbal I, Gong CX. Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: Implication for Alzheimer's disease. Am J Pathol. 2009; 175:2089–2098.
16. Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004; 101:10804–10809.
17. Freiherr J, Hallschmid M, Frey WH 2nd, Brünner YF, Chapman CD, Hölscher C, Craft S, De Felice FG, Benedict C. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs. 2013; 27:505–514.
18. 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.
19. Yaffe K, Falvey CM, Hamilton N, Harris TB, Simonsick EM, Strotmeyer ES, Shorr RI, Metti A, Schwartz AV. Health ABC Study. Association between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus. JAMA Intern Med. 2013; 173:1300–1306.
20. Diabetes Control and Complications Trial/Epidemiologyof Diabetes Interventions and Complications StudyResearch Group. Jacobson AM, Musen G, Ryan CM, Silvers N, Cleary P, Waberski B, Burwood A, Weinger K, Bayless M, Dahms W, Harth J. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med. 2007; 356:1842–1852.
21. Bruce DG, Davis WA, Casey GP, Clarnette RM, Brown SG, Jacobs IG, Almeida OP, Davis TM. Severe hypoglycaemia and cognitive impairment in older patients with diabetes: the Fremantle Diabetes Study. Diabetologia. 2009; 52:1808–1815.
22. Gorst C, Kwok CS, Aslam S, Buchan I, Kontopantelis E, Myint PK, Heatlie G, Loke Y, Rutter MK, Mamas MA. Long-term glycemic variability and risk of adverse outcomes: a systematic review and meta-analysis. Diabetes Care. 2015; 38:2354–2369.
23. Hirakawa Y, Arima H, Zoungas S, Ninomiya T, Cooper M, Hamet P, Mancia G, Poulter N, Harrap S, Woodward M, Chalmers J. Impact of visit-to-visit glycemic variability on the risks of macrovascular and microvascular events and all-cause mortality in type 2 diabetes: the ADVANCE trial. Diabetes Care. 2014; 37:2359–2365.
24. Kilpatrick ES, Rigby AS, Atkin SL. A1C variability and the risk of microvascular complications in type 1 diabetes: data from the Diabetes Control and Complications Trial. Diabetes Care. 2008; 31:2198–2202.
25. Li TC, Yang CP, Tseng ST, Li CI, Liu CS, Lin WY, Hwang KL, Yang SY, Chiang JH, Lin CC. Visit-to-visit variations in fasting plasma glucose and HbA1c associated with an increased risk of Alzheimer disease: Taiwan Diabetes Study. Diabetes Care. 2017; 40:1210–1217.
26. Lee SH, Han K, Cho H, Park YM, Kwon HS, Kang G, Yoon KH, Kim MK. Variability in metabolic parameters and risk of dementia: a nationwide population-based study. Alzheimers Res Ther. 2018; 10:110.
27. Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R, Boemi M, Giugliano D. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 2008; 57:1349–1354.
28. Quagliaro L, Piconi L, Assaloni R, Da Ros R, Maier A, Zuodar G, Ceriello A. Intermittent high glucose enhances ICAM-1, VCAM-1 and E-selectin expression in human umbilical vein endothelial cells in culture: the distinct role of protein kinase C and mitochondrial superoxide production. Atherosclerosis. 2005; 183:259–267.
29. Chin-Hsiao T. Metformin and the risk of dementia in type 2 diabetes patients. Aging Dis. 2019; 10:37–48.
30. Hsu CC, Wahlqvist ML, Lee MS, Tsai HN. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis. 2011; 24:485–493.
31. Kuan YC, Huang KW, Lin CL, Hu CJ, Kao CH. Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog Neuropsychopharmacol Biol Psychiatry. 2017; 79(Pt B):77–83.
32. Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study. J Am Geriatr Soc. 2012; 60:916–921.
33. Cheng H, Shang Y, Jiang L, Shi TL, Wang L. The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysis. Int J Neurosci. 2016; 126:299–307.
34. Femminella GD, Bencivenga L, Petraglia L, Visaggi L, Gioia L, Grieco FV, de Lucia C, Komici K, Corbi G, Edison P, Rengo G, Ferrara N. Antidiabetic drugs in Alzheimer's disease: mechanisms of action and future perspectives. J Diabetes Res. 2017; 2017:7420796.
XML Download