Association of BMI and waist circumference with diabetic microvascular complications: A prospective cohort study from the UK Biobank and Mendelian randomization analysis

Aims: To investigate the precise association between BMI and waist circumference (WC) and diabetic complications, including retinopathy (DR), nephropathy (DN) and peripheral neuropathy (DPN). Methods: A multivariable-adjusted Cox proportional hazard model was used to evaluate the observed association from 30,541 UK Biobank participants with diabetes. A two-sample Mendelian randomization (MR) framework was applied to summary-level GWASs of BMI and WC comprising a total of 461,460 and 462,166 participants from UK Biobank to explore the potential causal association. Results: Higher BMI and WC were associated with increased risks of DR, DN, and DPN (HR (95% CI), per-SD increase: BMI: DR 1.09 (1.04-1.13), DN 1.37 (1.33-1.41), DPN 1.27 (1.20-1.34); WC: DR 1.11 (1.07-1.16), DN 1.41 (1.36-1.46), DPN 1.38 (1.30-1.45)) in the UK Biobank cohort. Univariate MR indicated that increased BMI and WC were causal risk factors for these complications (OR (95% CI), per-SD increase: BMI: DR 1.33 (1.22-1.45), DN 1.74 (1.47-2.07), DPN 2.20 (1.67-2.90); WC: DR 1.43 (1.27-1.61), DN 2.03 (1.62-2.55), DPN 2.80 (1.99-3.92)), and the effect sizes remained significant after adjustment for glycated hemoglobin. Conclusions: Prospective observational and MR analyses provided evidence that high BMI and WC may represent potential causal risk factors for diabetic microvascular complications. Weight control might modify the risks of these complications independently of glycemic control and should be considered as a therapeutic recommendation.