Abstract
Background: Type 2 diabetes represents an increasing health burden world-wide and its prevalence in particularly higher in elderly population. Consistent epidemiological evidence suggests an increased risk of dementia associated to type 2 diabetes; the mechanisms underlying these associations, however, remain unclear.
Objective: The study aims to review epidemiological, clinical and pre-clinical data that weigh on pathophysiological links, mechanisms of disease and associations between type 2 diabetes and dementia to identify areas of opportunity for future research.
Methods: We searched the following electronic bibliographic databases: PUBMED, EMBASE, SCIELO, MEDLINE and OVID for clinical, translational and epidemiological research literature that summarize diabetes-related risk factors for dementia, metabolic and neurological changes associated to T2D, evidence of therapeutic approaches in type 2 diabetes and its pathophysiological implications for dementia.
Results: Type 2 diabetes mellitus increases risk for all-cause dementia, vascular dementia and Alzheimer’s disease. The most evaluated mechanisms linking both disorders in pre-clinical studies include an increase in neuronal insulin resistance, impaired insulin signaling, pro-inflammatory state, mitochondrial dysfunction and vascular damage which increase deposition of β-amyloid, tau proteins and GSK3β, leading to an earlier onset of dementia in individuals with impairment in the glucose metabolism. Neuroimaging and neuropathology evidence linking cerebrovascular lesions, neurodegeneration and particularly small-vessel disease in the onset of dementia is consistent with the increased risk of incident dementia in type 2 diabetes, but consistent evidence of AD-related pathology is scarce. Epidemiological data shows increased risk of dementia related to hypoglycemic episodes, glycemic control, metabolic syndrome, insulin resistance and genetic predisposition, but the evidence is not consistent and statistical analysis might be affected by inconsistent covariate controlling. Therapeutic approaches for T2D have shown inconsistent result in relation to dementia prevention and delay of cognitive decline; lifestyle intervention, particularly physical activity, is a promising alternative to ameliorate the impact of disability and frailty on T2D-related dementia.
Conclusion: Vascular disease, inflammation and impaired brain insulin signaling might occur in T2D and contribute to dementia risk. Evidence from epidemiological studies has not consistently reported associations that could integrate a unified mechanism of disease in humans. Evaluation of the effect of antidiabetic medications and non-pharmacological interventions in dementia prevention in type 2 diabetes is promising but has thus far offered inconsistent results.
Keywords: Type 2 diabetes, diabetes-related dementia, Alzheimer’s disease, glycemic control, diabetes complications, dementia.
[1]
Public Health and Aging. Trends in Aging-United States and Worldwide. JAMA 2003; 289(11): 1371-3.
[2]
Wu Y-T, Beiser AS. The changing prevalence and incidence of dementia over time-current evidence. Nat Rev Neurol 2017; 13(6): 327-9.
[3]
Whiting DR, Guariguata L, Weil C, Shaw J. IDF Diabetes atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011; 94(3): 311-21.
[4]
NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 2016; 387(10027): 1513-30.
[5]
Gonzalez-Gonzalez C, Tysinger B, Goldman DP, Wong R. Projecting diabetes prevalence among Mexicans aged 50 years and older: the Future Elderly Model-Mexico (FEM-Mexico). BMJ Open 2017; 7(10)e017330
[6]
Prince M, Acosta D, Ferri CP, et al. Dementia incidence and mortality in middle-income countries, and associations with indicators of cognitive reserve: A 10/66 Dementia Research Group population-based cohort study. Lancet 2012; 380(9836): 50-8.
[7]
Cheng G, Huang C, Wang H, Deng H. Diabetes as a risk factor for dementia and mild cognitive impairment: A meta-analysis of longitudinal studies. Intern Med J 2012; 42(5): 484-91.
[9]
Schnaider M, Ravona-springer R, Moshier E, et al. The Israel Diabetes and Cognitive Decline (IDCD) study : Design and baseline characteristics. Alzheimers Dement 2014; 10(6): 769-78.
[10]
Yogi-morren D, Galioto R, Strandjord SE, et al. Duration of Type 2 Diabetes and very low density lipoprotein levels are associated with cognitive dysfunction in metabolic syndrome. Cardiovasc Psychiatry Neurol 2014; 2014656341
[11]
Li W, Huang E. An Update on Type 2 Diabetes mellitus as a risk factor for dementia type 2 diabetes mellitus and underlying the impaired. J Alzheimers Dis 2016; 53(2): 393-402.
[12]
Fitzpatrick AL, Kuller LH, Lopez OL, et al. Midlife and late-life obesity and the risk of dementia: Cardiovascular health study. Arch Neurol 2009; 66(3): 336-42.
[13]
Holingue C, Wennberg A, Berger S, Polotsky VY, Spira AP. Disturbed sleep and diabetes: A potential nexus of dementia risk. Metabolism 2018; 84: 85-93.
[14]
Katon W, Lyles CR, Parker MM, Karter AJ, Huang ES, Whitmer RA. Association of depression with increased risk of dementia in patients with type 2 diabetes: The Diabetes and Aging Study. Arch Gen Psychiatry 2012; 69(4): 410-7.
[15]
Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H, Johns H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective. Alzheimers Dement 2015; 11(6): 718-26.
[16]
Rebled GAC, Santabárbara SJ, López ARL, Tomás AC, Marcos AG. Occupation and risk of cognitive impairment and dementia in people in over 55 years: A Systematic Review. Rev Esp Salud Publica 2016; 90: e1-e15.
[17]
Plassman BL, Williams JW Jr, Burke JR, Holsinger T, Benjamin S. Systematic review: Factors associated with risk for and possible prevention of cognitive decline in later life. Ann Intern Med 2010; 153(3): 182-93.
[18]
Fei M, Yan Ping Z, Ru Juan M, Ning Ning L, Lin G. Risk factors for dementia with type 2 diabetes mellitus among elderly people in China. Age Ageing 2013; 42(3): 398-400.
[19]
Kuo S, Lai S, Hung H, Muo C, Hung S. Association between comorbidities and dementia in diabetes mellitus patients: population-based retrospective cohort study. J Diabetes Complications 2015; 29(8): 1071-6.
[20]
Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000; 21(3): 383-42.
[21]
Morgan D, Gordon MN, Tan J, Wilcock D, Rojiani AM. Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: Implications for Alzheimer therapeutics. J Neuropathol Exp Neurol 2005; 64(9): 743-53.
[22]
Heneka MT, Sastre M, Dumitrescu-Ozimek L, et al. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation 2005; 2: 22.
[23]
Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001; 60(8): 759-67.
[24]
Lovell MA, Markesbery WR. Ratio of 8-hydroxyguanine in intact DNA to free 8-hydroxyguanine is increased in Alzheimer disease ventricular cerebrospinal fluid. Arch Neurol 2001; 58(3): 392-6.
[25]
Quaegebeur A, Lange C, Carmeliet P. The neurovascular link in health and disease: Molecular mechanisms and therapeutic implications. Neuron 2011; 71(3): 406-24.
[26]
Kalmijn S, Feskens EJ, Launer L, Stijnen T, Kromhout D. Glucose intolerance, hyperinsulinaemia and cognitive function in a general population of elderly men. Diabetologia 1995; 38(9): 1096-102.
[27]
Jacobson AM, Musen G, Ryan CM, et al. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 2007; 356(18): 1842-52.
[28]
Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med 2013; 369(19): 1863-4.
[29]
Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414(6865): 813-20.
[30]
Haroon NN, Austin PC, Shah BR, Wu J, Gill SS, Booth GL. Risk of dementia in seniors with newly diagnosed diabetes: A population-based study. Diabetes Care 2015; 38(10): 1868-75.
[31]
Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia and risk of Alzheimer disease. Neurology 2004; 63(7): 1187-92.
[32]
Kuusisto J, Koivisto K, Mykkänen L, et al. Association between features of the insulin resistance syndrome and Alzheimer’s disease independently of apolipoprotein e4 phenotype: Cross sectional population based study. BMJ 1997; 315(7115): 1045-9.
[33]
Abbatecola AM, Bo M, Barbagallo M, et al. Severe hypoglycemia is associated with antidiabetic oral treatment compared with insulin analogs in nursing home patients with type 2 diabetes and dementia: Results from the DIMORA study. J Am Med Dir Assoc 2015; 16(4): 349.e7-349.e12.
[34]
Shah BR, Wu J. Risk of dementia in seniors with newly diagnosed diabetes: A population-based study. Diabetes Care 2015; 38(10): 1868-75.
[35]
Kalmijn S, Foley D, White L, et al. Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men: The Honolulu-asia aging study. Arterioscler Thromb Vasc Biol 2000; 20(10): 2255-60.
[36]
Yaffe K, Kanaya A, Lindquist K, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004; 292(18): 2237-42.
[37]
Mehlig K, Lapidus L, Thelle DS, et al. Low fasting serum insulin and dementia in nondiabetic women followed for 34 years. Neurology 2018; 91(5): e427-35.
[38]
Townsend MI, Okereke O, Xia W, Yang T, Selkoe D, Grodstein F. Relation between insulin, insulin-related factors, and plasma amyloid beta peptide levels at midlife in a population-based study. Alzheimer Dis Assoc Disord 2012; 26(1): 50-4.
[39]
Simó R, Ciudin A, Simó-Servat O, Hernández C. Cognitive impairment and dementia: A new emerging complication of type 2 diabetes-The diabetologist’s perspective. Acta Diabetol 2017; 54(5): 417-24.
[40]
Avgerinos KI, Kalaitzidis G, Malli A, Kalaitzoglou D, Myserlis PG, Lioutas V-A. Intranasal insulin in Alzheimer’s dementia or mild cognitive impairment: A systematic review. J Neurol 2018; 265(7): 1497-510.
[41]
Exalto LG, Biessels GJ, Karter AJ, Huang ES, Quesenberry CP, Whitmer RA. Severe diabetic retinal disease and dementia risk in type 2 diabetes. J Alzheimers Dis 2014; 42(Suppl. 3): S109-17.
[42]
Ben AE, Eldor R, Korczyn AD, et al. Type 2 diabetes mellitus and impaired renal function are associated with brain alterations and poststroke cognitive decline. Stroke 2017; 48(9): 2368-74.
[43]
Exalto LG, Biessels GJ, Karter AJ, et al. Risk score for prediction of 10 year dementia risk in individuals with type 2 diabetes: A cohort study. Lancet Diabetes Endocrinol 2013; 1(3): 183-90.
[44]
Umemura T, Kawamura T, Hotta N. Pathogenesis and neuroimaging of cerebral large and small vessel disease in type 2 diabetes: A possible link between cerebral and retinal microvascular abnormalities. J Diabetes Investig 2017; 8(2): 134-48.
[45]
Fang F, Ya-Feng Z, Yao-Yao Z, Da-Zhi Y, Kang-An L, Yu-Fan W. Brain atrophy in middle-aged subjects with Type 2 diabetes mellitus, with and without microvascular complications. J Diabetes 2018; 10(8): 625-32.
[46]
Gopinath B, McMahon CM, Burlutsky G, Mitchell P. Hearing and vision impairment and the 5-year incidence of falls in older adults. Age Ageing 2016; 45(3): 409-14.
[47]
Bello-Chavolla O, Aguilar-Salinas AC. Management of type 2 diabetes in the elderly patient. J Lat Am Geriatric Med 2017; 3(1): 26-36.
[48]
Murray AM, Hsu F-C, Williamson JD, et al. ACCORDION MIND: results of the observational extension of the ACCORD MIND randomised trial. Diabetologia 2017; 60(1): 69-80.
[49]
Schernthaner G, Schernthaner-Reiter MH. Diabetes in the older patient: heterogeneity requires individualisation of therapeutic strategies. Diabetologia 2018; 61(7): 1503-16.
[50]
Abdelhafiz AH, McNicholas E, Sinclair AJ. Hypoglycemia, frailty and dementia in older people with diabetes: Reciprocal relations and clinical implications. J Diabetes Complications 2016; 30(8): 1548-54.
[51]
Bello-Chavolla OY, Aguilar-Salinas CA, Avila-Funes JA. Geriatric syndromes and not cardiovascular risk factors are associated with cognitive impairment among mexican community-dwelling elderly with type 2 diabetes. Rev Invest Clin 2017; 69(3): 166-72.
[52]
Tseng CL, Soroka O, Maney M, Aron DC, Pogach LM. Assessing potential glycemic overtreatment in persons at hypoglycemic risk. JAMA Intern Med 2014; 174(2): 259-68.
[53]
Thorpe CT, Gellad WF, Good CB, et al. Tight glycemic control and use of hypoglycemic medications in older veterans with type 2 diabetes and comorbid dementia. Diabetes Care 2015; 38(4): 588-95.
[54]
Hambling CE, Seidu SI, Davies MJ, Khunti K. Older people with Type 2 diabetes, including those with chronic kidney disease or dementia, are commonly overtreated with sulfonylurea or insulin therapies. Diabet Med 2017; 34(9): 1219-27.
[55]
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 301(15): 1565-72.
[56]
Lee AK, Rawlings AM, Lee CJ, et al. Severe hypoglycaemia, mild cognitive impairment, dementia and brain volumes in older adults with type 2 diabetes: The Atherosclerosis Risk in Communities (ARIC) cohort study. Diabetologia 2018; 61(9): 1956-65.
[57]
Zhang Z, Lovato J, Battapady H, et al. Effect of hypoglycemia on brain structure in people with type 2 diabetes: Epidemiological analysis of the ACCORD-MIND MRI trial. Diabetes Care 2014; 37(12): 3279-85.
[58]
West RK, Ravona-Springer R, Schmeidler J, et al. The association of duration of type 2 diabetes with cognitive performance is modulated by long-term glycemic control. Am J Geriatr Psychiatry 2014; 22(10): 1055-9.
[59]
Bădescu SV, Tătaru C, Kobylinska L, et al. The association between Diabetes mellitus and Depression. J Med Life 2016; 9(2): 120-5.
[60]
Bose M, Oliván B, Laferrère B. Stress and obesity: The role of the hypothalamic–pituitary–adrenal axis in metabolic disease. Curr Opin Endocrinol Diabetes Obes 2009; 16(5): 340-6.
[61]
Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the lifespan. Diabetes Care 2008; 31(12): 2383-90.
[62]
Katon WJ, Lin EHB, Williams LH, et al. Comorbid depression is associated with an increased risk of dementia diagnosis in patients with diabetes: A prospective cohort study. J Gen Intern Med 2010; 25(5): 423-9.
[63]
Katon W, Pedersen H, Ribe A, et al. Effect of depression and diabetes mellitus on the risk for dementia: A national population-based cohort study. JAMA Psychiatry 2015; 72(6): 612-9.
[64]
Roy T, Lloyd CE. Epidemiology of depression and diabetes: A systematic review. J Affect Disord 2012; 142(Suppl.): S8-S21.
[65]
Ciudin A, Espinosa A, Simó-Servat O, et al. Type 2 diabetes is an independent risk factor for dementia conversion in patients with mild cognitive impairment. J Diabetes Complications. J Diabetes Complications 2017; 31(8): 1272-4.
[66]
Ma F, Wu T, Miao R, Zhang W, Huang G. Conversion of mild cognitive impairment to dementia among subjects with diabetes: A population-based study of incidence and risk factors with five years of follow-up. J Alzheimers Dis 2015; 43(4): 1441-9.
[67]
Laws SM, Gaskin S, Amy W, et al. Insulin resistance is associated with reductions in specific cognitive domains and increases in CSF tau in cognitively normal adults. Sci Rep 2017; 7(1): 9766.
[68]
Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. Cerebral amyloid angiopathy and cognitive function. Neurology 2002; 58(11): 1629-34.
[69]
Peila R, Rodriguez B, Launer L. Type 2 Diabetes, apoe gene, and the risk for dementia and related pathologies the honolulu-asia aging study. Diabetes 2002; 51(4): 1256-62.
[70]
Arboleda GH, Yunis JJ, Pardo R, et al. Apolipoprotein E genotyping in a sample of Colombian patients with Alzheimer’s disease. Neurosci Lett 2001; 305(2): 135-8.
[71]
Ma J, Zhou Y, Xu J, et al. Association study of TREM2 polymorphism rs75932628 with late-onset alzheimer’s disease in Chinese Han population. Neurol Res 2014; 36(10): 894-6.
[72]
Hendrie HC, Murrell J, Baiyewu O, et al. APOE ε4 and the risk for Alzheimer disease and cognitive decline in African Americans and Yoruba. Int Psychogeriatr 2014; 26(6): 977-85.
[73]
Yu J-T, Tan L, Hardy J. Apolipoprotein E in Alzheimer’s disease: An update. Annu Rev Neurosci 2014; 37(1): 79-100.
[74]
Bertram L, Tanzi RE. Thirty years of Alzheimer’s disease genetics: The implications of systematic meta-analyses. Nat Rev Neurosci 2008; 9(10): 768-78.
[75]
Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res 1991; 541(1): 163-6.
[76]
Chang S, Ma T, Miranda RD, Balestra ME, Mahley RW, Huang Y. Lipid and receptor binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc Natl Acad Sci USA 2005; 102(51): 18694-9.
[77]
Brecht WJ, Harris FM, Chang S, et al. Neuron-Specific Apolipoprotein E4 Proteolysis Is Associated with Increased Tau Phosphorylation in Brains of Transgenic Mice. J Neurosci 2004; 24(10): 2527-34.
[78]
Xu WL, Pedersen NL, Keller L, et al. HHEX_23 AA genotype exacerbates effect of diabetes on dementia and alzheimer disease: A population-based longitudinal study. PLoS Med 2015; 12(7)e1001853
[79]
Zilkens RR, Davis WA, Spilsbury K, Semmens JB, Bruce DG. Earlier age of dementia onset and shorter survival times in dementia patients with diabetes. Am J Epidemiol 2013; 177(11): 1246-54.
[80]
Weinstein G, Maillard P, Himali JJ, et al. Glucose indices are associated with cognitive and structural brain measures in young adults. Neurology 2015; 84(23): 2329-37.
[81]
Ng T, Feng L, Nyunt M, et al. Metabolic syndrome and the risk of mild cognitive impairment and progression to dementia: Follow-up of the singapore longitudinal ageing study cohort. JAMA Neurol 2016; 73(4): 456-63.
[82]
Ma F, Wu T, Miao R, Yu Xiao Y, Zhang W, Huang G. Conversion of mild cognitive impairment to dementia among subjects with diabetes: A population-based study of incidence and risk factors with five years of follow-up. J Alzheimers Dis 2015; 43(4): 1441-9.
[83]
Yaffe K, Falvey C, Hamilton N, et al. Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. Arch Neurol 2012; 69(9): 1170-5.
[84]
van den Berg E, Reijmer YD, de Bresser J, Kessels RPC, Kappelle LJ, Biessels GJA. 4 year follow-up study of cognitive functioning in patients with type 2 diabetes mellitus. Diabetologia 2010; 53(1): 58-65.
[85]
Yau PL, Castro MG, Tagani A, Tsui WH, Convit A. Obesity and metabolic syndrome and functional and structural brain impairments in adolescence. Pediatrics 2012; 130(4): e856-64.
[86]
Craft S. Insulin resistance and Alzheimer’s disease: Untangling the web. J Alzheimers Dis 2013; 33(Suppl. 1): S263-75.
[87]
Gasparini L, Xu H. Potential roles of insulin and IGF-1 in Alzheimer’s disease. Trends Neurosci 2003; 26(8): 404-6.
[88]
Frölich L, Blum-Degen D, Bernstein H-G, et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm (Vienna) 1998; 105(4-5): 423-38.
[89]
Rönnemaa E, Zethelius B, Sundelöf J, et al. Glucose metabolism and the risk of Alzheimer’s disease and dementia: A population-based 12 year follow-up study in 71-year-old men. Diabetologia 2009; 52(8): 1504-10.
[90]
Tschritter O, Preissl H, Hennige AM, et al. The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: A magnetoencephalographic study. Proc Natl Acad Sci 2006; 103(32): 12103-8.
[91]
Anthony K, Reed LJ, Dunn JT, et al. Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance. Diabetes 2006; 55(11): 2986-92.
[92]
Yoo DY, Yim HS, Jung HY, et al. Chronic type 2 diabetes reduces the integrity of the blood-brain barrier by reducing tight junction proteins in the hippocampus. J Vet Med Sci 2016; 78(6): 957-62.
[93]
Prasad S, Sajja RK, Naik P, Cucullo L. Diabetes mellitus and blood-brain barrier dysfunction: an overview. J Pharmacovigil 2014; 2(2): 125.
[94]
Schubert M, Brazil DP, Burks DJ, et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci 2003; 23(18): 7084-92.
[95]
Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 2003; 423(6938): 435-59.
[96]
Niedowicz DM, Reeves VL, Platt TL, et al. Obesity and diabetes cause cognitive dysfunction in the absence of accelerated β-amyloid deposition in a novel murine model of mixed or vascular dementia. Acta Neuropathol Commun 2014; 2(1): 64.
[97]
Benedict C, Hallschmid M, Hatke A, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 2004; 29(10): 1326-34.
[98]
Novak V, Milberg W, Hao Y, et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care 2014; 37(3): 751-9.
[99]
Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial. Arch Neurol 2012; 69(1): 29-38.
[100]
Biessels GJ, Despa F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol 2018; 14(10): 591-604.
[101]
Bell GA, Fadool DA. Awake, long-term intranasal insulin treatment does not affect object memory, odor discrimination, or reversal learning in mice. Physiol Behav 2017; 174: 104-13.
[102]
Marks DR, Tucker K, Cavallin MA, Mast TG, Fadool DA. Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. J Neurosci 2009; 29(20): 6734-51.
[103]
van Harten B, de Leeuw FE, Weinstein HC, Scheltens P, Biessels GJ. Brain imaging in patients with diabetes. Diabetes Care 2006; 29(11): 2539-48.
[104]
de Bresser J, Tiehuis AM, van den Berg E, et al. Progression of cerebral atrophy and white matter hyperintensities in patients with type 2 diabetes. Diabetes Care 2010; 33(6): 1309-14.
[105]
Xiulian S, Kelley B, Weihong S. Regulation of β‐site APP‐cleaving enzyme 1 gene expression and its role in Alzheimer’s Disease. J Neurochem 2012; 120(Suppl. 1): 62-70.
[106]
Wang F, Hull RL, Vidal J, Cnop M, Kahn SE. Islet amyloid develops diffusely throughout the pancreas before becoming severe and replacing endocrine cells. Diabetes 2001; 50(11): 2514-20.
[107]
Westermark P, Wernstedt C, O’Brien TD, Hayden DW, Johnson KH. Islet amyloid in type 2 human diabetes mellitus and adult diabetic cats contains a novel putative polypeptide hormone. Am J Pathol 1987; 127(3): 414-7.
[108]
Meier JJ, Kayed R, Lin C-Y, et al. Inhibition of human IAPP fibril formation does not prevent β-cell death: Evidence for distinct actions of oligomers and fibrils of human IAPP. Am J Physiol Endocrinol Metab 2006; 291(6): E1317-24.
[109]
Han L, Nirmal V, Fengen W, et al. Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia. Ann Neurol 2017; 82(2): 208-22.
[110]
Pruzin JJ, Schneider JA, Capuano AW, et al. Diabetes, hemoglobin a1c, and regional alzheimer’s disease and infarct pathology. Alzheimer Dis Assoc Disord 2017; 31(1): 41-7.
[111]
Matioli MNP dos S, et al. Diabetes is not associated with alzheimer’s disease neuropathology. J Alzheimers Dis 2017; 60(3): 1035-43.
[112]
Gottesman RF, Schneider ALC, Zhou Y, et al. Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA 2017; 317(14): 1443-50.
[113]
Moran C, Beare R, Phan TG, Bruce DG, Callisaya ML, Srikanth V. Type 2 diabetes mellitus and biomarkers of neurodegeneration. Neurology 2015; 85(13): 1123-30.
[114]
Launer LJ, Miller ME, Williamson JD, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): A randomised open-label substudy. Lancet Neurol 2011; 10(11): 969-77.
[115]
Areosa SA, Vernooij RW, González-Colaço HM, Martínez G. Effect of the treatment of Type 2 diabetes mellitus on the development of cognitive impairment and dementia. Cochrane Database Syst Rev 2017; 6CD003804
[116]
Mayeda ER, Haan MN, Kanaya AM, Yaffe K, Neuhaus J. Type 2 diabetes and 10-year risk of dementia and cognitive impairment among older Mexican Americans. Diabetes Care 2013; 36(9): 2600-6.
[117]
Salinas RM, Hiriart M, Acosta I, Sosa AL, Prince MJ. Type 2 diabetes mellitus as a risk factor for dementia in a Mexican population. J Diabetes Complications 2016; 30(7): 1234-9.
[118]
Ye F, Luo Y-J, Xiao J, Yu N-W, Yi G. Impact of Insulin Sensitizers on the Incidence of Dementia: A Meta-Analysis. Dement Geriatr Cogn Disord 2016; 41(5-6): 251-60.
[119]
Orkaby AR, Cho K, Cormack J, Gagnon DR, Driver JA. Metformin vs sulfonylurea use and risk of dementia in US veterans aged ≥65 years with diabetes. Neurology 2017; 89(18): 1877-85.
[120]
Patrick I, Michael BS. Metformin, other antidiabetic drugs, and risk of alzheimer’s disease: a population-based case–control study. J Am Geriatr Soc 2012; 60(5): 916-21.
[121]
Cheng C, Lin C-H, Tsai YW, Tsai CJ, Chou PH, Lan T-H. Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J Gerontol Ser A 2014; 69(10): 1299-305.
[122]
Hsu CC, Wahlqvist M, Lee MS, Tsai H-N. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis 2011; 24(3): 485-93.
[123]
Koenig AM, Mechanic-Hamilton D, Xie SX, et al. Effects of the insulin sensitizer metformin in alzheimer’s disease: Pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis Assoc Disord 2017; 31(2): 107-13.
[124]
Kenawy S, Hegazy R, Hassan A, et al. Involvement of insulin resistance in D-galactose-induced age-related dementia in rats: Protective role of metformin and saxagliptin. PLoS One 2017; 12(8)e0183565
[125]
Chiang MC, Cheng YC, Chen SJ, Yen CH, Huang RN. Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against Amyloid-beta-induced mitochondrial dysfunction. Exp Cell Res 2016; 347(2): 322-31.
[126]
Chen B, Teng Y, Zhang X, Lv X, Yin Y. Metformin Alleviated A β -Induced Apoptosis via the Suppression of JNK MAPK Signaling Pathway in Cultured Hippocampal Neurons. BioMed Res Int 2016; 20161421430
[127]
Asadbegi M, Yaghmaei P, Salehi I, Ebrahim-Habibi A, Komaki A. Neuroprotective effects of metformin against Aβ-mediated inhibition of long-term potentiation in rats fed a high-fat diet. Brain Res Bull 2016; 121: 178-85.
[128]
Heneka MT, Fink A, Doblhammer G. Effect of pioglitazone medication on the incidence of dementia. Ann Neurol 2015; 78(2): 284-94.
[129]
Chou PS, Ho BL, Yang YH. Effects of pioglitazone on the incidence of dementia in patients with diabetes. J Diabet Comp 2017; 31(6): 1053-7.
[130]
Wang L, Liu W, Fan Y, Liu T, Yu C. Effect of rosiglitazone on amyloid precursor protein processing and Aβ clearance in streptozotocin-induced rat model of Alzheimer’s disease. Iran J Basic Med Sci 2017; 20(5): 474-80.
[131]
Quansah E, Peelaerts W, Langston JW, Simon DK, Colca J, Brundin P. Targeting energy metabolism via the mitochondrial pyruvate carrier as a novel approach to attenuate neurodegeneration. Mol Neurodegener 2018; 13(1): 28.
[132]
Isik AT, Soysal P, Yay A, Usarel C. The effects of sitagliptin, a DPP-4 inhibitor, on cognitive functions in elderly diabetic patients with or without Alzheimer’s disease. Diabetes Res Clin Pract 2017; 123: 192-8.
[133]
Kornelius E, Lin C, Chang H, et al. DPP‐4 Inhibitor linagliptin attenuates Aβ‐induced cytotoxicity through activation of AMPK in neuronal cells. CNS Neurosci Ther 2015; 21(7): 549-57.
[134]
Kosaraju J, Holsinger RMD, Guo L, Tam KY. Linagliptin, a Dipeptidyl peptidase-4 inhibitor, mitigates cognitive deficits and pathology in the 3xTg-AD mouse model of Alzheimer’s Disease. Mol Neurobiol 2017; 54(8): 6074-84.
[135]
Danish S, Shaikh S, Naaz D, et al. Kinetics and molecular docking study of an anti-diabetic drug glimepiride as acetylcholinesterase inhibitor: Implication for Alzheimer’s disease-diabetes dual therapy. Neurochem Res 2016; 41(6): 1475-82.
[136]
Osborne C, West E, Nolan W, McHale-Owen H, Williams A, Bate C. Glimepiride protects neurons against amyloid-β-induced synapse damage. Neuropharmacology 2016; 101: 225-36.
[137]
Kuan YC, Huang KW, Yen DJ, Hu CJ, Lin CL, Kao CH. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers reduced dementia risk in patients with diabetes mellitus and hypertension. Int J Cardiol 2016; 220: 462-6.
[138]
Liao D, Cooper L, Cai J, et al. Presence and severity of cerebral white matter lesions and hypertension, its treatment, and its control. Stroke 1996; 27(12): 2262-70.
[139]
Kurinami H, Shimamura M, Sato N, Nakagami H, Morishita R. Do Angiotensin receptor blockers protect against alzheimer’s disease? drugs aging. Drugs Aging 2013; 30(6): 367-72.
[140]
Richardson K, Schoen M, French B, et al. Statins and cognitive function: A systematic review. Ann Intern Med 2013; 159(10): 688-97.
[141]
McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev 2016; (1): CD003160
[142]
Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: A systematic review and meta-analysis of short and long-term cognitive effects. Mayo Clin Proc 2013; 88(11): 1213-21.
[143]
Sánchez-Ferro Á, Benito-León J, Mitchell AJ, Bermejo-Pareja F. A review of the potential therapeutic role of statins in the treatment of Alzheimer’s disease: Current research and opinion. Neuropsychiatr Dis Treat 2013; 9: 55-63.
[144]
Chang C-W, Horng J-T, Hsu C-C, Chen J-M. Mean daily dosage of aspirin and the risk of incident alzheimer’s dementia in patients with type 2 diabetes mellitus: A nationwide retrospective cohort study in Taiwan. J Diab Res 2016; 2016: 1-8.
[145]
Zhang C, Wang Y, Wang D, Zhang J, Zhang F. NSAID exposure and risk of Alzheimer’s disease: An updated meta-analysis from cohort studies. Front Aging Neurosci 2018; 10: 83.
[146]
Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004; 256(3): 183-94.
Call for Papers in Thematic Issues
26 August, 2024
Advancing Diabetic Wound Healing: Mechanisms and Interventions
In recent years, diabetic wounds have become a global health concern with the increase in the incidence of diabetes. Diabetic wounds are a kind of chronic and refractory ulcer. It is generally due to the microcirculatory disturbances and the reduced levels of endogenous growth factors. Delayed cutaneous wound healing is ...read more
16 June, 2024
Oxidative and inflammatory responses in the development of secondary diabetic complications
Diabetes, along with its associated secondary complications, represents a significant global health challenge, contributing significantly to morbidity and mortality. Unhealthy lifestyle habits, reduced physical activity, environmental pollutants, and stress are pivotal factors in the onset of diabetes, particularly type-2 diabetes. Poorly managed hyperglycemia can lead to various complications, including neuropathy, ...read more
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