Type 2 diabetes in midlife and risk of cerebrovascular disease in late life: a prospective nested case−control study in a nationwide Swedish twin cohort

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Abstract

Aims/hypothesis

We aimed to examine the association between midlife type 2 diabetes mellitus and cerebrovascular disease (CBD) in late life, and further to explore whether genetic and early-life familial environmental factors (such as shared childhood socioeconomic status and adolescent environment) play a role in this association.

Methods

In this prospective nested case−control study based on the Swedish Twin Registry, 33,086 twin individuals who were born in 1958 or earlier and were CBD-free before the age of 60 were included. Midlife (40–59 years) type 2 diabetes was ascertained from self-report, the National Patient Registry (NPR) and glucose-lowering medication use. CBD diagnosis (cerebral infarction, occlusion of cerebral arteries, subarachnoid haemorrhage, intracerebral haemorrhage and unspecified CBD) and onset age were identified from the NPR. Late-life CBD was defined as CBD onset age ≥60 years. Generalised estimating equation (GEE) models were used to analyse unmatched case−control data (adjusted for the clustering of twins within a pair). Conditional logistic regression was used in co-twin matched case−control analyses in CBD-discordant twin pairs.

Results

Of all the participants, 1248 (3.8%) had midlife type 2 diabetes and 3121 (9.4%) had CBD in late life. In GEE models adjusted for age, sex, education, BMI, smoking, alcohol consumption, marital status, hypertension and heart disease, the ORs (95% CIs) of type 2 diabetes were 1.29 (1.03, 1.61) for cerebral infarction, 2.03 (1.20, 3.44) for occlusion of cerebral arteries, 0.52 (0.12, 2.21) for subarachnoid haemorrhage and 0.78 (0.45, 1.36) for intracerebral haemorrhage. In multi-adjusted conditional logistic regression, the OR of the type 2 diabetes–cerebral infarction association was 0.96 (0.51, 1.80). The differences in ORs from the GEE and co-twin control analyses were not statistically significant ( p = 0.780).

Conclusions/interpretation

Midlife type 2 diabetes is significantly associated with increased risk of cerebral infarction and occlusion of cerebral arteries, but not intracerebral haemorrhage or subarachnoid haemorrhage in late life. Genetic and early-life familial environmental factors do not appear to account for the type 2 diabetes–cerebral infarction association, but further clarification is needed.

Electronic supplementary material

The online version of this article (10.1007/s00125-019-4892-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Most cited references 36

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Midlife overweight and obesity increase late-life dementia risk: a population-based twin study.

W L Xu, A. R. Atti, M Gatz … (2011)

The relation of overweight to dementia is controversial. We aimed to examine the association of midlife overweight and obesity with dementia, Alzheimer disease (AD), and vascular dementia (VaD) in late life, and to verify the hypothesis that genetic and early-life environmental factors contribute to the observed association. From the Swedish Twin Registry, 8,534 twin individuals aged ≥65 (mean age 74.4) were assessed to detect dementia cases (DSM-IV criteria). Height and weight at midlife (mean age 43.4) were available in the Registry. Data were analyzed as follows: 1) unmatched case-control analysis for all twins using generalized estimating equation (GEE) models and 2) cotwin matched case-control approach for dementia-discordant twin pairs by conditional logistic regression taking into account lifespan vascular disorders and diabetes. Among all participants, dementia was diagnosed in 350 subjects, and 114 persons had questionable dementia. Overweight (body mass index [BMI] >25-30) and obesity (BMI >30) at midlife were present in 2,541 (29.8%) individuals. In fully adjusted GEE models, compared with normal BMI (20-25), overweight and obesity at midlife were related to dementia with odds ratios (ORs) (95% CIs) of 1.71 (1.30-2.25) and 3.88 (2.12-7.11), respectively. Conditional logistic regression analysis in 137 dementia-discordant twin pairs led to an attenuated midlife BMI-dementia association. The difference in ORs from the GEE and the matched case-control analysis was statistically significant (p = 0.019). Both overweight and obesity at midlife independently increase the risk of dementia, AD, and VaD. Genetic and early-life environmental factors may contribute to the midlife high adiposity-dementia association.

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Mid- and Late-Life Diabetes in Relation to the Risk of Dementia

Weili Xu, Chengxuan Qiu, Margaret Gatz … (2009)

OBJECTIVE—We aimed to verify the association between diabetes and the risk of dementia, Alzheimer's disease, and vascular dementia in twins and to explore whether genetic and early-life environmental factors could contribute to this association. RESEARCH DESIGN AND METHODS—This study included 13,693 twin individuals aged ≥65 years. Dementia was diagnosed according to DSM-IV (Diagnostic Manual of Mental Disorders, 4th ed.) criteria. Information on diabetes was collected from the inpatient registry and self- or informant-reported history of diabetes. Data were analyzed following two strategies: 1) unmatched case-control analysis for all participants using generalized estimating equation (GEE) models and 2) cotwin matched case-control analysis for dementia-discordant twin pairs using conditional logistic regression. RESULTS—Of all participants, 467 were diagnosed with dementia, including 292 with Alzheimer's disease and 105 with vascular dementia, and an additional 170 were diagnosed with questionable dementia. Diabetes was present in 1,396 subjects. In GEE models, diabetes was associated with adjusted odds ratios (ORs) (95% CI) of 1.89 (1.51–2.38) for dementia, 1.69 (1.16–2.36) for Alzheimer's disease, and 2.17 (1.36–3.47) for vascular dementia. Compared with late-life diabetes (onset age ≥65 years), the risk effect of mid-life diabetes (onset age <65 years) on dementia was stronger. Conditional logistic analysis of 210 dementia-discordant twin pairs led to ORs of 2.41 (1.05–5.51) and 0.68 (0.30–1.53) for dementia related to mid- and late-life diabetes, respectively. CONCLUSIONS—Diabetes increases the risk of Alzheimer disease and vascular dementia. The risk is stronger when diabetes occurs at mid-life than in late life. Genetic and early-life environmental factors might contribute to the late-life diabetes–dementia association but could not account for the mid-life diabetes–dementia association.

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Duration of diabetes and risk of ischemic stroke: the Northern Manhattan Study.

Chirantan Banerjee, Yeseon P Moon, Myunghee C Paik … (2012)

Diabetes increases stroke risk, but whether diabetes status immediately before stroke improves prediction and whether duration is important are less clear. We hypothesized that diabetes duration independently predicts ischemic stroke. Among 3298 stroke-free participants in the Northern Manhattan Study, baseline diabetes and age at diagnosis were determined. Incident diabetes was assessed annually (median, 9 years). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% CI for incident ischemic stroke using baseline diabetes, diabetes as a time-dependent covariate, and duration of diabetes as a time-varying covariate; models were adjusted for demographic and cardiovascular risk factors. Mean age was 69 ± 10 years (52% Hispanic, 21% white, and 24% black); 22% had diabetes at baseline and 10% had development of diabetes. There were 244 ischemic strokes, and both baseline diabetes (HR, 2.5; 95% CI, 1.9-3.3) and diabetes considered as a time-dependent covariate (HR, 2.4; 95% CI, 1.8-3.2) were similarly associated with stroke risk. Duration of diabetes was associated with ischemic stroke (adjusted HR, 1.03 per year with diabetes; 95% CI, 1.02-1.04). Compared to nondiabetic participants, those with diabetes for 0 to 5 years (adjusted HR, 1.7; 95% CI, 1.1-2.7), 5 to 10 years (adjusted HR, 1.8; 95% CI, 1.1-3.0), and ≥ 10 years (adjusted HR, 3.2; 95% CI, 2.4-4.5) were at increased risk. Duration of diabetes is independently associated with ischemic stroke risk adjusting for risk factors. The risk increases 3% each year, and triples with diabetes ≥ 10 years.

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Author and article information

Contributors

Xiuying Qi: qixiuying@tmu.edu.cn

Weili Xu: weili.xu@ki.se , xuweili@tmu.edu.cn

Journal

Journal ID (nlm-ta): Diabetologia

Journal ID (iso-abbrev): Diabetologia

Title: Diabetologia

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0012-186X

ISSN (Electronic): 1432-0428

Publication date (Electronic): 5 June 2019

Publication date PMC-release: 5 June 2019

Publication date (Print): 2019

Volume: 62

Issue: 8

Pages: 1403-1411

Affiliations

[1 ]ISNI 0000 0000 9792 1228, GRID grid.265021.2, Department of Epidemiology and Biostatistics, School of Public Health, , Tianjin Medical University, ; Qixiangtai Road 22, Heping District, 300070 Tianjin, People’s Republic of China

[2 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Medical Epidemiology and Biostatistics, , Karolinska Institutet, ; Stockholm, Sweden

[3 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Department of Psychology, , University of Southern California, ; Los Angeles, CA USA

[4 ]Department of Radiology, Tianjin Union Medical Centre, Tianjin, People’s Republic of China

[5 ]Department of Radiology, Tianjin Gongan Hospital, Tianjin, People’s Republic of China

[6 ]GRID grid.465198.7, Aging Research Center, Department of Neurobiology, Care Sciences and Society, , Karolinska Institutet, ; Tomtebodavägen 18A Floor 10, SE-171 65 Solna, Stockholm Sweden

Article

Publisher ID: 4892

DOI: 10.1007/s00125-019-4892-3

PMC ID: 6647245

PubMed ID: 31172222

SO-VID: 78d733a3-c392-4081-901a-214a093e384c

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 13 December 2018

Date accepted : 10 April 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: No. 81771519

Funded by: Konung Gustaf V:s och Drottning Victorias Frimurare Foundation

Award ID: No. 2016-2017

Funded by: European Union’s Horizon

Award ID: No 667375

Funded by: Swedish Research Council

Award ID: No. 2017-00981

Funded by: Demensfonden, Strokefonden, Cornells Stiftelse and Alzheimerfonden

Award ID: 2017-2018

Custom metadata

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: cerebrovascular disease,prospective nested case−control study,the swedish twin cohort,type 2 diabetes

Data availability: