Social isolation, loneliness, and incident type 2 diabetes mellitus: results from two large prospective cohorts in Europe and East Asia and Mendelian randomization

Abstract

Background: Social isolation and loneliness pose significant public health challenges globally. The objective of this study is to investigate the association between social isolation, loneliness, and the risk of type 2 diabetes mellitus (T2DM).

Methods: 423,503 UK adults from the UK Biobank (UKB) and 13,800 Chinese adults from the China Health and Retirement Longitudinal Study (CHARLS) were analyzed. The exposures of interest were social isolation and loneliness. Social isolation was evaluated based on the number of household members, frequency of social activities, contact with others, and marriage status (CHARLS only). Loneliness was evaluated by the subjective feeling of loneliness and the willingness to confide in others (UKB only). The primary endpoint was incident T2DM. The two-sample Mendelian randomization (MR) analysis was based on the genome-wide association studies of UKB (n = 463,010) and the European Bioinformatics Institute (n = 655,666).

Findings: The UKB cohort study documented 15,072 T2DM cases during a mean follow-up of 13.5 years, and the CHARLS cohort study recorded 1,249 T2DM cases during a mean follow-up of 5.8 years. Social isolation and loneliness showed significant associations with an elevated risk of T2DM in both UKB (social isolation [most vs least]: HR 1.17, 95% CI 1.11-1.23; loneliness [yes vs no]: HR 1.21, 95% CI 1.13-1.30) and CHARLS cohorts (social isolation [yes vs no]: HR 1.22, 95% CI 1.06-1.40; loneliness [yes vs no]: HR 1.21, 95% CI 1.07-1.36). These associations remained significant after accounting for baseline glucose status and genetic susceptibility to T2DM. Two-sample MR analyses determined that feeling lonely (OR 1.04, 95% CI 1.02-1.06) and engaging in fewer leisure/social activities (OR 1.03, 95% CI 1.02-1.05) were associated with increased T2DM risk, whereas more contact with friends or family (OR 0.99, 95% CI 0.98-0.99) was associated with reduced T2DM risk.

Interpretation: Social isolation and loneliness are each associated with an elevated risk of T2DM, with MR analyses suggesting potential causal links. These associations remain significant after considering genetic susceptibility to T2DM. The findings highlight the importance of promoting initiatives to address social isolation and loneliness as part of T2DM prevention strategies.

Funding: CAMS Innovation Fund for Medical Sciences (No. 2021-I2M-1-008) and National Natural Science Foundation of China (No. 72103187).

Keywords: Cohort study; Loneliness; Mendelian randomization; Public health; Social isolation; Type 2 diabetes mellitus.

Fig. 1

Separate (A) and joint (B) association of social isolation and loneliness with the long-term risk of T2DM among subjects with different levels of PRS for T2DM in the UKB. P interaction of genic risk subgroups for social isolation: 0.420. P interaction of genic risk subgroups for loneliness: 0.070. The analysis was performed in Model 3 (adjusted with age, sex, ethnicity, BMI, grip strength, assessment center, household income, college/university degree, employed, healthy sleep score, current smoking, current drinking, physical activity, sun exposure, healthy diet score, family history of T2DM, prediabetes, history of CVD, history of hypertension, history of dyslipidemia, history of CLD, and history of cancer). Abbreviations: BMI, body mass index; CVD, cardiovascular disease; CLD, chronic lung disease; PRS, polygenic risk score; T2DM, type 2 diabetes mellitus; UKB, UK biobank.

Fig. 2

MR analyses for the causal effects of loneliness and social isolation on the risk of T2DM by using IVW method based on GWAS of UKB (A) and EBI (B). Abbreviations: GWAS, genome-wide association studies; EBI, European Bioinformatics Institute; MR, Mendelian randomization; IVW, inverse-variance weighted; T2DM, type 2 diabetes mellitus; UKB, UK biobank.