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Diabetologia

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Open Access 01-10-2019 | Insulins | Article

The effect of mid-life insulin resistance and type 2 diabetes on older-age cognitive state: the explanatory role of early-life advantage

Authors: Sarah-Naomi James, Andrew Wong, Therese Tillin, Rebecca Hardy, Nishi Chaturvedi, Marcus Richards

Published in: Diabetologia | Issue 10/2019

Abstract

Aims/hypothesis

Type 2 diabetes, hyperglycaemia and insulin resistance are associated with cognitive impairment and dementia, but causal inference studies using Mendelian randomisation do not confirm this. We hypothesised that early-life cognition and social/educational advantage may confound the relationship.

Methods

From the population-based British 1946 birth cohort, a maximum number of 1780 participants had metabolic variables (type 2 diabetes, insulin resistance [HOMA2-IR] and HbA_1c) assessed at age 60–64 years, and cognitive state (Addenbrooke’s Cognitive Examination III [ACE-III]) and verbal memory assessed at age 69 years. Earlier-life measures included socioeconomic position (SEP), cognition at age 8 years and educational attainment. Polygenic risk scores (PRSs) for type 2 diabetes were calculated. We first used a PRS approach with multivariable linear regression to estimate associations between PRSs and metabolic traits and later-life cognitive state. Second, using a path model approach, we estimated the interrelationships between earlier-life measures, features of mid-life type 2 diabetes and cognitive state at age 69 years. All models were adjusted for sex.

Results

The externally weighted PRS for type 2 diabetes was associated with mid-life metabolic traits (e.g. HOMA2-IR β = 0.08 [95% CI 0.02, 0.16]), but not with ACE-III (β = 0.04 [−0.02, 0.90]) or other cognitive outcomes. While there was an association between HOMA2-IR and subsequent ACE-III (β = −0.09 [−0.15, −0.03]), path modelling showed no direct effect (β = −0.01 [−0.06, 0.03]) after accounting for the association between childhood SEP and education with HOMA2-IR. The same pattern was observed for later-life verbal memory.

Conclusions/interpretation

Associations between type 2 diabetes and mid-life metabolic traits with subsequent cognitive state do not appear causal, and instead they may be explained by SEP in early life, childhood cognition and educational attainment. Therefore, glucose-lowering medication may be unlikely to combat cognitive impairment in older age.

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Cheng G, Huang C, Deng H, Wang H (2012) Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J 42(5):484–491. https://doi.org/10.1111/j.1445-5994.2012.02758.x CrossRefPubMed

Chatterjee S, Peters SAE, Woodward M et al (2015) Type 2 diabetes as a risk factor for dementia in women compared with men: a pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia. Diabetes Care 39(2):300–307. https://doi.org/10.2337/dc15-1588 CrossRefPubMedPubMedCentral

Nooyens ACJ, Baan CA, Spijkerman AMW, Verschuren WMM (2010) Type 2 diabetes and cognitive decline in middle-aged men and women: the Doetinchem Cohort Study. Diabetes Care 33(9):1964–1969. https://doi.org/10.2337/dc09-2038 CrossRefPubMedPubMedCentral

Cukierman-Yaffe T, Gerstein HC, Williamson JD et al (2009) Relationship between baseline glycemic control and cognitive function in individuals with type 2 diabetes and other cardiovascular risk factors: the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial. Diabetes Care 32(2):221–226. https://doi.org/10.2337/dc08-1153 CrossRefPubMedPubMedCentral

Altschul DM, Starr JM, Deary IJ (2018) Cognitive function in early and later life is associated with blood glucose in older individuals: analysis of the Lothian Birth Cohort of 1936. Diabetologia 61(9):1946–1955. https://doi.org/10.1007/s00125-018-4645-8 CrossRefPubMedPubMedCentral

Livingston G, Sommerlad A, Orgeta V et al (2017) Dementia prevention, intervention, and care. Lancet 390(10113):2673–2734. https://doi.org/10.1016/S0140-6736(17)31363-6 CrossRefPubMed

Tuligenga RH, Dugravot A, Tabák AG et al (2014) Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the Whitehall II cohort study. Lancet Diabetes Endocrinol 2(3):228–235. https://doi.org/10.1016/S2213-8587(13)70192-X CrossRefPubMedPubMedCentral

Rawlings AM, Sharrett AR, Schneider ALC et al (2014) Diabetes in midlife and cognitive change over 20 years. Ann Intern Med 161(11):785–793. https://doi.org/10.7326/M14-0737 CrossRefPubMedPubMedCentral

Saczynski JS, Jonsdottir MK, Garcia ME et al (2008) Cognitive impairment: an increasingly important complication of type 2 diabetes: the Age, Gene/Environment Susceptibility-Reykjavik Study. Am J Epidemiol 168(10):1132–1139. https://doi.org/10.1093/aje/kwn228 CrossRefPubMedPubMedCentral

10.

Marden JR, Mayeda ER, Tchetgen Tchetgen EJ, Kawachi I, Glymour MM (2017) High hemoglobin A1c and diabetes predict memory decline in the health and retirement study. Alzheimer Dis Assoc Disord 31(1):48–54. https://doi.org/10.1097/WAD.0000000000000182 CrossRefPubMedPubMedCentral

11.

Crane PK, Walker R, Hubbard RA et al (2013) Glucose levels and risk of dementia. N Engl J Med 369(6):540–548. https://doi.org/10.1056/NEJMoa1215740 CrossRefPubMedPubMedCentral

12.

Lutski M, Weinstein G, Goldbourt U, Tanne D (2017) Insulin resistance and future cognitive performance and cognitive decline in elderly patients with cardiovascular disease. J Alzheimers Dis 57(2):633–643. https://doi.org/10.3233/JAD-161016 CrossRefPubMed

13.

Spauwen PJJ, Kohler S, Verhey FRJ, Stehouwer CDA, van Boxtel MPJ (2013) Effects of type 2 diabetes on 12-year cognitive change: results from the Maastricht Aging Study. Diabetes Care 36(6):1554–1561. https://doi.org/10.2337/dc12-0746 CrossRefPubMedPubMedCentral

14.

Sutherland GT, Lim J, Srikanth V, Bruce DG (2017) Epidemiological approaches to understanding the link between type 2 diabetes and dementia. J Alzheimers Dis 59(2):393–403. https://doi.org/10.3233/JAD-161194 CrossRefPubMed

15.

Hagenaars SP, Gale CR, Deary IJ, Harris SE (2017) Cognitive ability and physical health: a Mendelian randomization study. Sci Rep 7(1):2651. https://doi.org/10.1038/s41598-017-02837-3 CrossRefPubMedPubMedCentral

16.

Hagenaars SP, Harris SE, Davies G et al (2016) Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia. Mol Psychiatry 21(11):1624–1632. https://doi.org/10.1038/mp.2015.225 CrossRefPubMedPubMedCentral

17.

Larsson SC, Traylor M, Malik R et al (2017) Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis. BMJ 359:j5375. https://doi.org/10.1136/BMJ.J5375 CrossRefPubMedPubMedCentral

18.

Østergaard SD, Mukherjee S, Sharp SJ et al (2015) Associations between potentially modifiable risk factors and Alzheimer disease: a Mendelian randomization study. PLoS Med 12(6):e1001841. https://doi.org/10.1371/journal.pmed.1001841 CrossRefPubMedPubMedCentral

19.

Tamayo T, Herder C, Rathmann W (2010) Impact of early psychosocial factors (childhood socioeconomic factors and adversities) on future risk of type 2 diabetes, metabolic disturbances and obesity: a systematic review. BMC Public Health 10(1):525. https://doi.org/10.1186/1471-2458-10-525 CrossRefPubMedPubMedCentral

20.

Richards SA (2003) Lifetime antecedents of cognitive reserve. J Clin Exp Neuropsychol 25(5):614–624. https://doi.org/10.1076/jcen.25.5.614.14581 CrossRefPubMed

21.

Wadsworth M, Kuh D, Richards M, Hardy R (2006) Cohort profile: the 1946 National Birth Cohort (MRC National Survey of Health and Development). Int J Epidemiol 35(1):49–54. https://doi.org/10.1093/ije/dyi201 CrossRefPubMed

22.

Kuh D, Wong A, Shah I et al (2016) The MRC National Survey of Health and Development reaches age 70: maintaining participation at older ages in a birth cohort study. Eur J Epidemiol 31(11):1135–1147. https://doi.org/10.1007/s10654-016-0217-8 CrossRefPubMedPubMedCentral

23.

Hsieh S, Schubert S, Hoon C, Mioshi E, Hodges JR (2013) Validation of the Addenbrooke’s Cognitive Examination III in frontotemporal dementia and Alzheimer’s disease. Dement Geriatr Cogn Disord 36(3–4):242–250. https://doi.org/10.1159/000351671 CrossRefPubMed

24.

Pastorino S, Richards M, Hardy R et al (2015) Validation of self-reported diagnosis of diabetes in the 1946 British birth cohort. Prim Care Diabetes 9(5):397–400. https://doi.org/10.1016/j.pcd.2014.05.003 CrossRefPubMedPubMedCentral

25.

British Medical Association and Royal Pharmaceutical Society of Great Britain (2011) British National Formulary (March edn). BMJ Books and Pharmaceutical Press, London

26.

Levy JC, Matthews DR, Hermans MP (1998) Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 21(12):2191–2192. https://doi.org/10.2337/DIACARE.21.12.2191 CrossRefPubMed

27.

Voight BF, Kang HM, Ding J et al (2012) The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet 8(8):e1002793. https://doi.org/10.1371/journal.pgen.1002793 CrossRefPubMedPubMedCentral

28.

Shah T, Engmann J, Dale C et al (2013) Population genomics of cardiometabolic traits: design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium. PLoS One 8(8):e71345. https://doi.org/10.1371/journal.pone.0071345 CrossRefPubMedPubMedCentral

29.

Talmud PJ, Cooper JA, Morris RW et al (2015) Sixty-five common genetic variants and prediction of type 2 diabetes. Diabetes 64(5):1830–1840. https://doi.org/10.2337/db14-1504 CrossRefPubMed

30.

Morris AP, Voight BF, Teslovich TM et al (2012) Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 44(9):981–990. https://doi.org/10.1038/ng.2383 CrossRefPubMedPubMedCentral

31.

Sanghera DK, Blackett PR (2012) Type 2 diabetes genetics: beyond GWAS. J Diabetes Metab 3(198):pii:6948. https://doi.org/10.4172/2155-6156.1000198

32.

Scott RA, Lagou V, Welch RP et al (2012) Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet 44(9):991–1005. https://doi.org/10.1038/ng.2385 CrossRefPubMedPubMedCentral

33.

Euesden J, Lewis CM, O’Reilly PF, O’Reilly PF (2015) PRSice: polygenic risk score software. Bioinformatics 31(9):1466–1468. https://doi.org/10.1093/bioinformatics/btu848 CrossRefPubMed

34.

Pigeon D (1964) Tests used in the 1954 and 1957 surveys. In: Douglas JWB (ed) The home and the school. Macgibbon and Kee, London (Appendix 1)

35.

Hatch SL, Mishra G, Hotopf M, Jones PB, Kuh D (2009) Appraisals of stressors and common mental disorder from early to mid-adulthood in the 1946 British birth cohort. J Affect Disord 119(1):66–75. https://doi.org/10.1016/j.jad.2009.03.021 CrossRefPubMedPubMedCentral

36.

Ben-Shlomo Y, Kuh D (2002) A life course approach to chronic disease epidemiology: conceptual models, empirical challenges and interdisciplinary perspectives. Int J Epidemiol 31(2):285–293. https://doi.org/10.1093/intjepid/31.2.285 CrossRefPubMed

37.

Streiner DL (2005) Finding our way: an introduction to path analysis. Can J Psychiatr 50(2):115–122. https://doi.org/10.1177/070674370505000207 CrossRef

38.

Richards M, James S-N, Sizer A et al (2019) Identifying the lifetime cognitive and socioeconomic antecedents of cognitive state: seven decades of follow-up in a British birth cohort study. BMJ Open 9(4):24404. https://doi.org/10.1136/bmjopen-2018-024404 CrossRef

39.

Lawlor DA, Tilling K, Davey Smith G (2017) Triangulation in aetiological epidemiology. Int J Epidemiol 45(6):1866–1886. https://doi.org/10.1093/ije/dyw314 CrossRefPubMedCentral

40.

Steptoe A, Marmot M (2002) The role of psychobiological pathways in socio-economic inequalities in cardiovascular disease risk. Eur Heart J 23(1):13–25. https://doi.org/10.1053/euhj.2001.2611 CrossRefPubMed

41.

Biessels GJ, Despa F (2018) Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol 14(10):591–604. https://doi.org/10.1038/s41574-018-0048-7 CrossRefPubMedPubMedCentral

42.

Lu C-H, Yang C-Y, Li C-Y, Hsieh C-Y, Ou H-T (2018) Lower risk of dementia with pioglitazone, compared with other second-line treatments, in metformin-based dual therapy: a population-based longitudinal study. Diabetologia 61(3):562–573. https://doi.org/10.1007/s00125-017-4499-5 CrossRefPubMed

Title: The effect of mid-life insulin resistance and type 2 diabetes on older-age cognitive state: the explanatory role of early-life advantage
Authors: Sarah-Naomi James
Andrew Wong
Therese Tillin
Rebecca Hardy
Nishi Chaturvedi
Marcus Richards
Publication date: 01-10-2019
Publisher: Springer Berlin Heidelberg
Keywords: Insulins
Hyperglycemia
Insulins
Type 2 Diabetes
Published in: Diabetologia / Issue 10/2019
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-019-4949-3

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Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

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