Overweight, obesity and the risk of LADA: results from a Swedish case-control study and the Norwegian HUNT Study

Abstract

Aims/hypothesis: Excessive weight is a risk factor for type 2 diabetes, but its role in the promotion of autoimmune diabetes is not clear. We investigated the risk of latent autoimmune diabetes in adults (LADA) in relation to overweight/obesity in two large population-based studies.

Methods: Analyses were based on incident cases of LADA (n = 425) and type 2 diabetes (n = 1420), and 1704 randomly selected control participants from a Swedish case-control study and prospective data from the Norwegian HUNT Study including 147 people with LADA and 1,012,957 person-years of follow-up (1984-2008). We present adjusted ORs and HRs with 95% CI.

Results: In the Swedish data, obesity was associated with an increased risk of LADA (OR 2.93, 95% CI 2.17, 3.97), which was even stronger for type 2 diabetes (OR 18.88, 95% CI 14.29, 24.94). The association was stronger in LADA with low GAD antibody (GADA; <median) (OR 4.25; 95% CI 2.76, 6.52) but present also in LADA with high GADA (OR 2.14; 95% CI 1.42, 3.24). In the Swedish data, obese vs normal weight LADA patients had lower GADA levels, better beta cell function, and were more likely to have low-risk HLA-genotypes. The combination of overweight and family history of diabetes (FHD) conferred an OR of 4.57 (95% CI 3.27, 6.39) for LADA and 24.51 (95% CI 17.82, 33.71) for type 2 diabetes. Prospective data from HUNT indicated even stronger associations; HR for LADA was 6.07 (95% CI 3.76, 9.78) for obesity and 7.45 (95% CI 4.02, 13.82) for overweight and FHD.

Conclusions/interpretation: Overweight/obesity is associated with increased risk of LADA, particularly when in combination with FHD. These findings support the hypothesis that, even in the presence of autoimmunity, factors linked to insulin resistance, such as excessive weight, could promote onset of diabetes.

Keywords: ANDIS; ANDiU; Body mass index; Case–control study; ESTRID; HUNT Study; LADA; Latent autoimmune diabetes in adults; Prospective study; Type 2 diabetes.

Fig. 1

ORs with 95% CIs for (a) LADA, (b) type 2 diabetes, (c) LADA^high, and (d) LADA^low by BMI (kg/m²) fitted with restricted cubic splines using data from ESTRID 2010–2016. The reference value is BMI 23 kg/m² and models were adjusted for age, sex, FHD, physical activity level and smoking. Black solid lines represent the spline line, long dashed lines represent the 95% CIs of the spline line and the red dotted lines represent the linear line. The histogram at the bottom of each figure part represents the distribution of BMI in the study population. The left y-axes are on a log_e scale

Fig. 2

ORs for (a) LADA and (b) type 2 diabetes in ESTRID. HRs for (c) LADA and (d) type 2 diabetes in HUNT by combinations of overweight/obesity (BMI ≥ 25 kg/m²) and FHD. The reference is normal weight (BMI < 25 kg/m²) and no FHD. The y-axis is on the log₁₀ scale and error bars are 95% CI