Yuxia Wei

Our aim was to provide new data on the incidence, prevalence, and secular trend of type 2 diabetes (T2D) in Sweden, specifically early-onset T2D. We followed the Swedish population 2006 to 2021 and calculated age-standardized incidence (per 100 000) and prevalence (%) of T2D (overall) and early-onset T2D (age 23–39 years) stratified by sex, region of birth, and educational level. We projected the future prevalence of early-onset T2D by combining observed trends with population projections. From 2006 to 2021, the prevalence of T2D rose from 4.87% to 7.50%, and incidence from 477 [95% confidence interval (CI) 471–482] to 574 (CI 568–579). Early-onset T2D incidence increased from 54 to 107 (4.7% annual rise; CI 3.7%–5.7%) during this period. Incidence of early-onset T2D was higher in individuals born outside Europe (211, CI 195–226 vs 89, CI 84–93 in 2021) or low education (204, CI 185–223 vs 71, CI 65–77 in 2021), but a rise in incidence was seen irrespective of educational level, region of origin, and sex. If the incidence of early-onset T2D continues to increase at the same pace, its prevalence is projected to increase from 0.64% in 2021 to 3.2% in 2050. While T2D incidence rose marginally in Sweden 2006 to 2021, there was a significant rise in early-onset T2D, seen across different socioeconomic characteristics, with prevalence more than doubling and incidence nearly doubling. This development calls for targeted preventive efforts.

Incidence of type 1 diabetes is increasing globally, which is hypothesized to be due to environmental influences. We leverage Swedish nationwide registers linked to all children (n = 2,928,704) born in 1982–2010 to investigate if the heritability of childhood-onset type 1 diabetes has changed over time and how alterations in environmental factors have contributed to the rising type 1 diabetes incidence. The heritability is estimated at 0.83 (95% confidence interval: 0.79, 0.86) and stable over the observation period (0.80 [0.71, 0.86] in 1982, 0.83 [0.79, 0.86] in 2000, and 0·83 [0.79, 0.86] in 2010, respectively). Environmental factors including maternal smoking during pregnancy and childhood adiposity explain <10% of the increasing type 1 diabetes incidence. In this work, the heritability of childhood-onset type 1 diabetes has remained high and stable over the last 30 years. Our findings indicate that the available environmental factors are not the major contributors to the rise in type 1 diabetes in Sweden.

Background and Aims: The prognosis of adult-onset type 1 diabetes (T1D) and prognostic factors are sparsely investigated. This study assessed mortality, major adverse cardiovascular events (MACE), and prognostic factors in adult-onset T1D, particularly focusing on those diagnosed at age ≥40. Methods: Participants were people diagnosed with adult-onset T1D (n = 10 184) or type 2 diabetes (T2D, n = 375 523) in 2001–20 from the Swedish National Diabetes Register and 509 172 population controls from the Total Population Register, followed until 2022. Hazard ratios (HR) and population attributable risk fraction (PAR%) were estimated. Results: People with T1D had higher incidence of MACE (HR 1.30 [95% confidence interval 1.17, 1.45]), all-cause mortality (1.71 [1.60, 1.84]), and mortality from cardiovascular or non-cardiovascular diseases, cancer, or infection than population controls. They had lower MACE incidence (0.67 [0.60, 0.75]) and higher mortality from diabetic coma or ketoacidosis (7.04 [4.54, 10.9]) than people with T2D. Smoking (PAR% 10.7%) and glycated haemoglobin (HbA1c) ≥ 53 mmol/mol (10.4%) accounted for most deaths while overweight/obesity (19.8%), smoking (8.4%), and high HbA1c (8.8%) accounted for most MACE events in T1D. Results were similar for T1D diagnosed at age ≥40, although they had lower insulin pump use and higher HbA1c than people diagnosed earlier. Conclusions: Adult-onset T1D carries excess risk of death and MACE compared with population controls but less MACE risk than T2D. Individuals diagnosed after age 40 had similar excess risk and poorer glycaemic control than those diagnosed earlier, underscoring the need for improved management. Key prognostic factors were smoking, poor glycaemic control, and overweight/obesity.

Aims/hypothesis: The aim of this study was to clarify the impact of autoimmune disease (AD) comorbidity on the risk and prognosis of latent autoimmune diabetes in adults (LADA). Methods: We used data from a Swedish study comprising newly diagnosed cases of LADA (n=586, stratified into LADA^low and LADA^high by autoantibody levels), type 2 diabetes (n=2003) and matched control participants (n=2355). Information on 33 ADs and diabetic retinopathy was obtained by linkage to regional and national registers. We estimated the ORs for LADA and type 2 diabetes in relation to ADs before diabetes diagnosis, and the HRs for diabetic retinopathy after diabetes diagnosis. We performed functional pathway analyses to explore biological mechanisms driving the associations. Results: Individuals with ADs exhibit an increased susceptibility to LADA (OR 1.70; 95% CI 1.36, 2.13), particularly those with thyroid dysfunction (OR 1.88; 95% CI 1.38, 2.56), inflammatory bowel disease (OR 1.78; 95% CI 1.00, 3.16) or vitiligo (OR 3.91; 95% CI 1.93, 7.94), with stronger associations being observed for the LADA^high phenotype. Only psoriasis was linked to type 2 diabetes (OR 1.47; 95% CI 1.08, 1.99). The biological pathways shared by LADA and ADs revolved around immune responses, including innate and adaptive immune pathways. The HRs for diabetic retinopathy in LADA patients with and without AD vs those with type 2 diabetes were 2.11 (95% CI 1.34, 3.32) and 1.68 (95% CI 1.15, 2.45), respectively. Conclusions/interpretation: We confirm that several common ADs confer an excess risk of LADA, especially LADA with higher GADA levels, but having such a comorbidity does not appear to affect the risk of diabetic retinopathy. Graphical

Background: Smokers are at increased risk of type 2 diabetes (T2D), but the underlying mechanisms are unclear. We investigated if the smoking-T2D association is mediated by alterations in the metabolome and assessed potential interaction with genetic susceptibility to diabetes or insulin resistance. Methods: In UK Biobank (n = 93,722), cross-sectional analyses identified 208 metabolites associated with smoking, of which 131 were confirmed in Mendelian Randomization analyses, including glycoprotein acetyls, fatty acids, and lipids. Elastic net regression was applied to create a smoking-related metabolic signature. We estimated hazard ratios (HR) of incident T2D in relation to baseline smoking/metabolic signature and calculated the proportion of the smoking-T2D association mediated by the signature. Additive interaction between the signature and genetic risk scores for T2D (GRS-T2D) and insulin resistance (GRS-IR) on incidence of T2D was assessed as relative excess risk due to interaction (RERI). Findings: The HR of T2D was 1·73 (95% confidence interval (CI) 1·54 − 1·94) for current versus never smoking, and 38·3% of the excess risk was mediated by the metabolic signature. The metabolic signature and its mediation role were replicated in TwinGene. The metabolic signature was associated with T2D (HR: 1·61, CI 1·46 − 1·77 for values above vs. below median), with evidence of interaction with GRS-T2D (RERI: 0·81, CI: 0·23 − 1·38) and GRS-IR (RERI 0·47, CI: 0·02 − 0·92). Interpretation: The increased risk of T2D in smokers may be mediated through effects on the metabolome, and the influence of such metabolic alterations on diabetes risk may be amplified in individuals with genetic susceptibility to T2D or insulin resistance.

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) is a heterogenous, slowly progressing autoimmune diabetes. We aim to contribute new knowledge on the long-term prognosis of LADA with varying degrees of autoimmunity by comparing it to type 2 diabetes and adult-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: This Swedish population-based study included newly diagnosed LADA (n = 550, stratified into LADAlow and LADAhigh by median autoimmunity level), type 2 diabetes (n = 2,001), adult-onset type 1 diabetes (n = 1,573), and control subjects without diabetes (n = 2,355) in 2007–2019. Register linkages provided information on all-cause mortality, cardiovascular diseases (CVDs), diabetic retinopathy, nephropathy, and clinical characteristics during follow-up. RESULTS: Mortality was higher in LADA (hazard ratio [HR] 1.44; 95% CI 1.03, 2.02), type 1 (2.31 [1.75, 3.05]), and type 2 diabetes (1.31 [1.03, 1.67]) than in control subjects. CVD incidence was elevated in LADAhigh (HR 1.67; 95% CI 1.04, 2.69) and type 2 diabetes (1.53 [1.17, 2.00]), but not in LADAlow or type 1 diabetes. Incidence of retinopathy but not nephropathy was higher in LADA (HR 2.25; 95% CI 1.64, 3.09), including LADAhigh and LADAlow than in type 2 diabetes (unavailable in type 1 diabetes). More favorable blood pressure and lipid profiles, but higher HbA1c levels, were seen in LADA than type 2 diabetes at baseline and throughout follow-up, especially in LADAhigh, which resembled type 1 diabetes in this respect. CONCLUSIONS: Despite having fewer metabolic risk factors than type 2 diabetes, LADA has equal to higher risks of death, CVD, and retinopathy. Poorer glycemic control, particularly in LADAhigh, highlights the need for improved LADA management.

Aims/hypothesis: We investigated whether the impacts of childhood adiposity on adult-onset diabetes differ across proposed diabetes subtypes using a Mendelian randomisation (MR) design. Methods: We performed MR analysis using data from European genome-wide association studies of childhood adiposity, latent autoimmune diabetes in adults (LADA, proxy for severe autoimmune diabetes), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD). Results: Higher levels of childhood adiposity had positive genetically predicted effects on LADA (OR 1.62, 95% CI 1.05, 2.52), SIDD (OR 2.11, 95% CI 1.18, 3.80), SIRD (OR 2.76, 95% CI 1.60, 4.75) and MOD (OR 7.30, 95% CI 4.17, 12.78), but not MARD (OR 1.06, 95% CI 0.70, 1.60). Conclusions/interpretation: Childhood adiposity is a risk factor not only for adult-onset diabetes primarily characterised by obesity or insulin resistance, but also for subtypes primarily characterised by insulin deficiency or autoimmunity. These findings emphasise the importance of preventing childhood obesity. Graphical