Background:We investigated whether individuals who likely developed type 2 diabetes (T2D) through predominantly genetic, adverse intrauterine, or lifestyle aetiologies have different clinical presentations and complications. Methods:In this Danish nationwide combined cross-sectional and registry-based follow-up study, we included 7867 individuals with newly diagnosed T2D from the DD2 cohort, enrolled during 2010-2023 through general practices and hospital outpatient clinics across Denmark. Participants were required to have available genotyping and birthweight data; those with GAD antibody levels >30 were excluded. Individuals were grouped by presumed predominant aetiologies: genetic (highest-quartile T2D genetic risk score (GRS), birthweight above lowest quartile; n = 1435); intrauterine (lowest-quartile birthweight, GRS below highest quartile; n = 1195); and lifestyle (birthweight above lowest quartile, GRS below highest quartile; n = 4380). Baseline characteristics at diagnosis were examined using linear and log-binomial or robust Poisson regression. The main follow-up outcomes were standardised 10-year risks of major adverse cardiovascular events and microvascular complications after DD2 enrolment, estimated using the Aalen-Johansen method. Findings:Compared with the genetic group (18%), intrauterine (15%) and lifestyle (56%) aetiologies both showed -6.9% lower Homeostatic Model Assessment-2 (HOMA2) insulin sensitivity, higher triglycerides (+6.6% and +5.3%), higher HOMA2 beta-cell function (+8.9% and +9.6%), and higher high-sensitivity C-reactive protein (+14.8% and +24.1%). Age at T2D diagnosis was 1.2 years lower (intrauterine) and 2.3 year higher (lifestyle). The 10-year risk of major adverse cardiovascular events was 14.8% (intrauterine), 13.2% (lifestyle), and 11.5% (genetic), corresponding to absolute risk differences (RDs) of +3.3% (95% confidence interval [CI] 0.6, 6.0) for intrauterine, and +1.7% (95% CI -0.3, 3.6) for lifestyle, vs. genetic aetiology. The 10-year risk of microvascular complications was 25.9% (intrauterine), 25.4% (lifestyle), and 21.8% (genetic), yielding RDs of +4.1% (95% CI 0.7, 7.5) for intrauterine and +3.5% (95% CI 1.0, 6.1) for lifestyle aetiology. Interpretation:Individuals who developed T2D with predominant intrauterine or lifestyle rather than genetic aetiology exhibited distinct characteristics including higher long-term complication risks. Future studies should validate this framework in more diverse populations and assess whether these proxy-based aetiological domains can improve risk stratification and guide treatment. Funding:This work was funded by Danish Agency for Science, the Danish Health and Medicines Authority, the Danish Diabetes Association, the Region of Southern Denmark, the Swedish Research Council, the Novo Nordisk Foundation, the Swedish ALF for Region Skåne, the Crafoord Foundation, and the Swedish Diabetes Association.

BACKGROUND AND AIM:Vitamin K has been proposed to have a preventive effect against arterial calcification through activation of the vitamin K dependent proteins and potentially protect against progression of atherosclerosis. Our aim was to assess the association between vitamin K status and vascular health in a general elderly population. METHODS AND RESULTS:In a cross-sectional study, the vitamin status was measured using the inverse biomarker, dephospho-uncarboxylated Matrix Gla Protein (dp-ucMGP). Vascular health was reflected by total coronary artery calcification (CAC) score and coronary artery stenosis estimated using a cardiac Computed Tomography scan and by arterial stiffness estimated using carotid-femoral Pulse Wave Velocity (cfPWV). A total of 2167 participants with a mean age of 68 years (48% women) were included. In the fully adjusted analyses adjusted for age, sex, lifestyle factors, waist circumference, mean arterial pressure (for cfPWV) and kidney function, a doubling in dp-ucMGP levels (indicating lower vitamin K status) were independently and significantly associated with higher cfPWV (0.30 m/s (95% CI: 0.08 to 0.52 m/s)) but not with total CAC (21% increased total CAC (95% CI -5 to 54%)) or severity of stenosis (OR 1.26 (95% CI 0.86 to 1.86) for obstructive-extensive stenoses compared to no stenosis). CONCLUSION:Lower vitamin K status was independently associated with higher arterial stiffness but not CAC nor coronary stenosis when adjusting for cardiovascular risk factors. The results point to a complex interplay between vitamin K and vascular health and the need for more research into the possible role of vitamin K in vascular health.

Low birthweight is a risk factor for type 2 diabetes. We hypothesised that differential associations between birthweight and clinical characteristics in persons with and without type 2 diabetes may provide novel insights into the role of birthweight in type 2 diabetes and its progression. We analysed UK Biobank data from 9,442 persons with and 254,446 without type 2 diabetes. Associations between birthweight, clinical traits, and genetic predisposition were assessed using adjusted linear and logistic regression, comparing the lowest and highest 25% of birthweight to the middle 50%. Each kg increase in birthweight was associated with higher BMI, waist, and hip circumference, with stronger effects in persons with versus without type 2 diabetes (BMI: 0.74 [0.58, 0.90] vs. 0.21 [0.18, 0.24] kg/m2; waist: 2.15 [1.78, 2.52] vs. 1.04 [0.98, 1.09] cm; hip: 1.65 [1.33, 1.97] vs. 1.04 [1.04, 1.09] cm). Family history of diabetes was associated with higher birthweight regardless of diabetes status, albeit with a twofold higher effect estimate in type 2 diabetes. Low birthweight was further associated with prior myocardial infarction regardless of type 2 diabetes status (OR 1.33 [95% CI 1.11, 1.60] for type 2 diabetes; 1.23 [95% CI 1.13, 1.33] without), and hypertension (OR 1.25 [1.23, 1.28] and stroke 1.24 [1.14, 1.34]) only among persons without type 2 diabetes. Differential associations between birthweight and cardiometabolic traits in persons with and without type 2 diabetes illuminate potential causal inferences reflecting the roles of pre- and postnatal environmental versus genetic aetiologies and disease mechanisms.

Individuals born with low birth weight are at increased risk of type 2 diabetes, which potentially may be attributed to immature adipose tissue development and reduced levels of the insulin-sensitizing adipokine, adiponectin. This systematic review and meta-analysis synthesize data from 67 studies, comprising over 8000 individuals across various age groups, to examine the relationship between circulating adiponectin levels and birth weight. The results revealed that individuals with low birth weight have significantly lower adiponectin levels compared to those born with normal birth weight (SMD = -0.46 μg/ml [95% CI: -0.57; -0.35], P < 0.0001). Moderate heterogeneity was observed (I2 = 67%, P < 0.01), but sensitivity analysis and meta-regression did not identify specific factors driving this variation. Pooled Pearson correlation analysis indicated a moderate but statistically significant positive correlation between birth weight and adiponectin levels (correlation estimate = 0.31 [95% CI: 0.16; 0.46], P < 0.0001). These findings suggest that reduced adiponectin levels in low birth weight individuals may contribute to their elevated risk of type 2 diabetes, potentially offering new insights into the developmental origin of this disease.

AIMS:TCF7L2 rs7903146 is the most impactful single genetic risk variant for type 2 diabetes. However, its role on disease progression, complications and mortality among people with type 2 diabetes at diagnosis remains unclear. MATERIALS AND METHODS:We assessed the per allele impact of the rs7903146 T-allele on clinical characteristics and complication risk in 9231 individuals with type 2 diabetes at diagnosis and over a 10-year follow-up period. Log-binomial and robust Poisson regression analyses were used to estimate prevalence ratios for clinical characteristics and macro- and microvascular complications at diabetes onset, while Cox regression was applied to estimate the risk of complications post-diagnosis. Analyses were adjusted for sex, calendar year at birth, age at enrollment and diabetes duration. RESULTS:The per T-allele impact was associated with 0.6 kg/m2 (95% CI: 0.4, 0.8) lower BMI, 1.4 cm (95% CI: 1.0, 1.8) smaller waist circumference, 5.6% (95% CI: 4.2, 7.0) lower insulin secretion and 5.0% (95% CI: 3.3, 6.7) higher insulin sensitivity. Over 10 years, the per T-allele impact was associated with lower risks for major adverse cardiovascular events (0.87 [95% CI 0.79, 0.95]), myocardial infarction (0.82 [95% CI: 0.72, 0.93]) and heart failure (0.85 [95% CI 0.73, 1.00]), with no significant impact on microvascular complications. CONCLUSIONS:The TCF7L2 variant is associated with less obesity, lower insulin secretion and higher insulin action at diabetes onset, and decreased risk of cardiovascular events following type 2 diabetes onset.

The microbiota in individual habitats differ in both relative composition and absolute abundance. While sequencing approaches determine the relative abundances of taxa and genes, they do not provide information on their absolute abundances. Here, we developed a machine-learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applying our prediction model to a large-scale metagenomic dataset (n = 34,539), we demonstrated that microbial load is the major determinant of gut microbiome variation and is associated with numerous host factors, including age, diet, and medication. We further found that for several diseases, changes in microbial load, rather than the disease condition itself, more strongly explained alterations in patients' gut microbiome. Adjusting for this effect substantially reduced the statistical significance of the majority of disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance for understanding microbiome variation in health and disease.

Low birth weight (LBW) is a risk factor for type 2 diabetes (T2D). We hypothesized that 4 weeks of carbohydrate overfeeding (COF) with +25% energy would unmask key T2D perturbations among 22 nonobese LBW men, including five with screen-detected metabolic dysfunction-associated steatotic liver disease (MASLD), compared with 21 healthy control participants with normal birth weight (NBW). Body weight, lean and fat mass, and hepatic fat content increased to the same extent in both groups during COF, whereas fasting glucose and insulin resistance increased significantly more in LBW compared with NBW participants. The differential COF responses were most pronounced in LBW participants without MASLD, including increased resting energy expenditure. Plasma adiponectin was lower, whereas fibroblast growth factor 21 levels increased more during COF in LBW participants. Subcutaneous adipose tissue (SAT) density was lower in LBW participants and decreased during COF in both groups. Serum alanine, phosphatidylcholines, and triglycerides increased significantly more in LBW participants during COF. Multiomics analysis of SAT RNA sequencing, serum lipidomics, and metabolomics uncovered impaired peroxisome proliferator-activated receptor signaling as well as aberrant collagen and extracellular matrix regulation in LBW participants. The results document differential and MASLD-independent metabolic perturbations in LBW participants during COF. ARTICLE HIGHLIGHTS:Individuals with low birth weight (LBW) are at increased risk of type 2 diabetes. Four weeks of carbohydrate overfeeding (COF) was associated with differential elevations in fasting glucose, lipids, alanine, insulin resistance, and resting energy expenditure in LBW participants versus control participants. Multiomics analyses indicated reduced peroxisome proliferator-activated receptor signaling, as well as differential expression of genes involved in collagen and extracellular matrix metabolism in LBW participants during COF. Interestingly, the COF perturbations in LBW participants became more pronounced when excluding five LBW men with screen-detected metabolic dysfunction-associated steatotic liver disease. The findings support the notion of unhealthy subcutaneous adipose tissue expandability potentially underlying a reduced metabolic buffering capacity in nonobese LBW men.

INTRODUCTION:The physical activity health paradox refers to the contrasting associations of leisure-time physical activity and occupational physical activity with cardiovascular disease, but whether this applies to Type 2 diabetes risk is unknown. This study aimed to investigate the physical activity health paradox and age-specific Type 2 diabetes. METHODS:Working adults (N=5,866) in Denmark aged 30-60 years enrolled in the Inter99 cohort at baseline in 1999 were followed in a Diabetes Register. Incidence rates of Type 2 diabetes as a function of age, sex, and separate and combined levels of self-reported occupational physical activity and leisure-time physical activity were modeled using Poisson regression, adjusting for relevant covariates in separate analyses (2024). RESULTS:Moderate/vigorous leisure-time physical activity was associated with lower risk of Type 2 diabetes than light (rate ratio=0.63, 95% CI=0.46, 0.85). Strenuous occupational physical activity was associated with a slightly higher risk of Type 2 diabetes than moderate occupational physical activity, but the association diminished adjusted for covariates (rate ratio=1.12, 95% CI=0.79, 1.58). Sedentary leisure-time physical activity combined with any level of occupational physical activity was associated with higher risk of Type 2 diabetes than light leisure-time physical activity/moderate occupational physical activity combined (e.g., sedentary leisure-time physical activity and demanding occupational physical activity) (rate ratio=1.68, 95% CI=1.14, 2.48). Moderate/vigorous leisure-time physical activity combined with any level of occupational physical activity was associated with lower risk of Type 2 diabetes (e.g., moderate/vigorous leisure-time physical activity and moderate occupational physical activity) (rate ratio=0.6, 95% CI=0.39, 0.92). CONCLUSIONS:Leisure-time physical activity lowered the risk of Type 2 diabetes regardless of the level of occupational physical activity, whereas no similar beneficial effects were found for occupational physical activity level. The differential effects of occupational physical activity and leisure-time physical activity on Type 2 diabetes suggest that the paradox may also exist in Type 2 diabetes.

AIMS/HYPOTHESIS:Low birthweight (LBW) is associated with younger age, less obesity and more hypertension among people recently diagnosed with type 2 diabetes, as well as increased cardiovascular morbidity and mortality risk. It is not known whether LBW is associated with an increased risk of incident chronic kidney disease (CKD) among people with a type 2 diabetes diagnosis. METHODS:Original midwife records were retrieved for 5982 participants with recently diagnosed type 2 diabetes enrolled in the Danish Center for Strategic Research in Type 2 Diabetes (DD2) cohort between 2010 and 2024. They were followed until first incident CKD diagnosis, defined as either two eGFR measurements <60 ml/min per 1.73m2 or two urine albumin/creatinine ratio (UACR) measurements >3 mg/mmol, each 90-365 days apart. Confounder-standardised 10 year risks of CKD were estimated, with death considered as a competing risk. Adjusted hazard ratios (aHRs) for CKD were computed using Cox and spline regression analyses. All analyses were controlled for differences in sex, age at enrolment, calendar year at birth, family history of diabetes and born-at-term status. Mixed-effects models were used to examine the trajectories of eGFR and UACR following enrolment. RESULTS:A total of 1501 incident CKD endpoints occurred, corresponding to an incidence rate of 42.4 per 1000 person-years over a median follow-up time of 8.3 years. Spline models with birthweight as a continuous measure showed progressively increasing aHRs for CKD with decreasing birthweight. The 10-year standardised risk of CKD was 36.0% in people with LBW (<2500 g) and 30.6% in people with a normal birthweight (2500-4000 g), yielding a risk difference (RD) of 5.5% (95% CI -0.5%, 11.8%) and an aHR of 1.23 (95% CI 0.98, 1.55). People with type 2 diabetes and high birthweight (>4000 g) had a similar 10-year standardised CKD risk compared with normal birthweight (33.1% and 30.6%, respectively). This yielded an RD of 2.5% (95% CI -1.6%, 6.7%) and an aHR of 1.10 (95% CI 0.93, 1.29). In mixed-effects models examining eGFR and UACR trajectories, each 1 kg decrease in birthweight was associated with a 6.6% (95% CI 1.9, 11.1) increase in UACR, whereas no association was found for eGFR. CONCLUSIONS/INTERPRETATION:A history of LBW was associated with elevated risk of CKD among people with a recent type 2 diabetes diagnosis, although the precision of risk estimates was limited.

Background Birth weight (BW) is associated with risk of cardiometabolic disease (CMD) in adulthood, which may depend on the state of obesity, in particular if developed at a young age. We hypothesised that BW and a polygenic score (PGS) for BW were associated with cardiometabolic risk and related plasma protein levels in children and adolescents. We aimed to determine the modifying effect of childhood obesity on these associations. Methods We used data from The cross-sectional HOLBAEK Study with 4263 participants (median [IQR] age, 11.7 [9.2, 14.3] years; 57.1% girls and 42.9% boys; 48.6% from an obesity clinic and 51.4% from a population-based group). We gathered information on BW and gestational age, anthropometrics, cardiometabolic risk factors, calculated a PGS for BW, and measured plasma proteins using Olink Inflammation and Cardiovascular II panels. We employed multiple linear regression to examine the associations with BW as a continuous variable and performed interaction analyses to assess the effect of childhood obesity on cardiometabolic risk and plasma protein levels. Findings BW and a PGS for BW associated with cardiometabolic risk and plasma protein levels in childhood and adolescence. Childhood obesity modified the associations between BW and measures of insulin resistance, including HOMA-IR (beta adj [95% CI per SD] for obesity: -0.12 [-0.15, -0.08]; normal weight: -0.04 [-0.08, 0.00]; Pinteraction = 0.004), c-peptide (obesity: -0.11 [-0.14, -0.08]; normal weight: -0.02 [-0.06, 0.02]; Pinteraction = 5.05E-04), and SBP SDS (obesity: -0.12 [-0.16, -0.08]; normal weight: -0.06 [-0.11, -0.01]; Pinteraction = 0.0479). Childhood obesity also modified the associations between BW and plasma levels of 14 proteins (e.g., IL15RA, MCP1, and XCL1; Pinteraction < 0.05). Interpretation We identified associations between lower BW and adverse metabolic phenotypes, particularly insulin resistance, blood pressure, and altered plasma protein levels, which were more pronounced in children with obesity. Developing effective prevention and treatment strategies for this group is needed to reduce the risk of future CMD. Copyright (c) 2024 The Author(s). Published by Elsevier B.V.

BackgroundBreast cancer survivors are a growing population due to improved treatment. It is known that postmenopausal women treated for breast cancer may experience weight gain and increased insulin resistance, but detailed knowledge on how chemotherapy impact metabolic and endocrine mechanisms remain unknown.ObjectiveWe performed a thorough, preliminary study to elucidate the differing mechanisms of post-prandial absorption and metabolism in postmenopausal early breast cancer (EBC) patients treated with adjuvant chemotherapy compared to healthy controls. We hypothesize that chemotherapy has a negative impact on metabolism in EBC patients.MethodsWe examined four postmenopausal women shortly after treatment with chemotherapy for EBC and four age-matched healthy women who served as controls using isotopic tracers during a mixed meal-test. Blood was sampled during the 240 min meal-test to examine post-prandial absorption and endogenous synthesis of lipid and carbohydrate metabolites.ResultsWe found that insulin concentrations were numerically higher before the meal-test in the EBC patients compared to controls (76.3 pmol/L vs 37.0 pmol/L; p=0.06). Glucose kinetics was increased post-prandial (most pronounced at 30 minutes, 9.46 mmol/L vs 7.33 mmol/L; p=0.51), with no difference between the groups regarding liver glucose output. Fatty acid kinetics showed a numeric increase in oleic acid rate of appearance in BC patients, but only during the first hour after the mixed meal. There was no significant difference in VLDL-TAG synthesis between the two groups.ConclusionsThis preliminary study is unique in using advanced tracer methods to investigate in vivo metabolism of EBC patients after chemotherapy although no statistical differences in glucose and fatty acid kinetics was seen compared to controls. However, during the first two post-prandial hours, oral glucose and oleic acid appearance in the systematic circulation was elevated in the EBC patients. This could be due to changes in gastrointestinal uptake and further studies with altered set-up could provide valuable insights.

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AIMS/HYPOTHESIS:A better understanding of the mechanisms underlying an elevated infection risk in individuals with type 2 diabetes is needed to guide risk stratification and prevention. We investigated the risk of infection in subgroups of individuals with type 2 diabetes according to indices of insulin sensitivity and beta cell function. METHODS:We classified 7265 individuals with recently diagnosed type 2 diabetes (median duration 1.4 years, IQR 0.5-2.9 years) into hyperinsulinaemic (high beta cell function [HOMA 2-beta-cell function, HOMA2-B], low insulin sensitivity [HOMA 2-insulin sensitivity, HOMA2-S]), classical (low HOMA2-B, low HOMA2-S) and insulinopenic (low HOMA2-B, high HOMA2-S) type 2 diabetes. Individuals were followed until first hospital-treated infection or first prescription for an anti-infective agent (community-treated infection). We used Cox regression analysis to estimate HRs adjusted for age, sex, index year, diabetes duration and treatment, lifestyle behaviours and comorbidities. RESULTS:Among study participants, 28% had hyperinsulinaemic, 63% had classical and 9% had insulinopenic type 2 diabetes. The 10 year risks of hospital-treated infections were 42.3%, 36.8% and 31.0% in the three subgroups, respectively. Compared with the insulinopenic subgroup, adjusted HRs for hospital-treated infections were elevated for hyperinsulinaemic (1.38 [95% CI 1.16, 1.65]) and classical type 2 diabetes (1.20 [95% CI 1.02, 1.42]). The 10 year risks of community-treated infections were high in all three subgroups at 91.6%, 90.1% and 88.3%, respectively, corresponding to adjusted HRs of 1.20 (95% CI 1.08, 1.33) for the hyperinsulinaemic and 1.10 (95% CI 1.00, 1.21) for the classical subgroup. Infection risk in the hyperinsulinaemic subgroup decreased substantially when further adjusted for abdominal obesity, metabolic derangements and low-grade inflammation. CONCLUSIONS/INTERPRETATION:The risk of severe infections is clearly elevated in individuals with type 2 diabetes characterised by a higher degree of insulin resistance/hyperinsulinaemia.

Introduction The population-based Inter99 cohort has contributed extensively to our understanding of effects of a systematic screening and lifestyle intervention, as well as the multifactorial aetiology of type 2 diabetes (T2D) and cardiovascular disease. To understand causes, trajectories and patterns of early and overt cardiometabolic disease manifestations, we will perform a combined clinical deep phenotyping and registry follow-up study of the now 50–80 years old Inter99 participants.Methods and analysis The Inter99 cohort comprises individuals aged 30–60 years, who lived in a representative geographical area of greater Copenhagen, Denmark, in 1999. Age-stratified and sex-stratified random subgroups were invited to participate in either a lifestyle intervention (N=13 016) or questionnaires (N=5264), while the rest served as a reference population (N=43 021). Of the 13 016 individuals assigned to the lifestyle intervention group, 6784 (52%) accepted participation in a baseline health examination in 1999, including screening for cardiovascular risk factors and prediabetic conditions. In total, 6004 eligible participants, who participated in the baseline examination, will be invited to participate in the deep phenotyping 20-year follow-up clinical examination including measurements of anthropometry, blood pressure, arterial stiffness, cardiometabolic biomarkers, coronary artery calcification, heart rate variability, heart rhythm, liver stiffness, fundus characteristics, muscle strength and mass, as well as health and lifestyle questionnaires. In a subsample, 10-day monitoring of diet, physical activity and continuous glucose measurements will be performed. Fasting blood, urine and faecal samples to be stored in a biobank. The established database will form the basis of multiple analyses. A main purpose is to investigate whether low birth weight independent of genetics, lifestyle and glucose tolerance predicts later common T2D cardiometabolic comorbidities.Ethics and dissemination The study was approved by the Medical Ethics Committee, Capital Region, Denmark (H-20076231) and by the Danish Data Protection Agency through the Capital Region of Denmark’s registration system (P-2020-1074). Informed consent will be obtained before examinations. Findings will be disseminated in peer-reviewed journals, at conferences and via presentations to stakeholders, including patients and public health policymakers.Trial registration number NCT05166447.

Introduction & Objective: Low birth weight (BW) is associated with increased type 2 diabetes (T2D) severity and high plasma leptin levels in people without diabetes. In a cross-sectional study of 6402 people recently diagnosed with T2D, we examined if BW is associated with plasma leptin and if leptin is associated with clinical characteristics reflecting disease severity. Methods: Plasma leptin levels were measured using a Meso Scale Discovery U-plex assay. The association between BW (exposure) and plasma leptin levels and then between leptin (exposure) and clinical T2D severity, at T2D diagnosis were assessed. We used linear regression to estimate continuous outcomes and log-binomial/robust Poisson regression to determine prevalence ratios (PRs) in categorical analyses. Analyses were first adjusted for sex, age, and T2D family history, then + BMI, and + BW. Results: A 1kg lower BW was only associated with a 12.0% (95% CI: 8.0, 15.9) higher plasma leptin level when adjusted for BMI. A 20% increase in leptin was associated with 0.52kg/m2 (95% CI: 0.5, 0.54) higher BMI, 1.7% (95% CI: 1.5, 1.9) higher triglyceride, 3.8% (95% CI: 3.6, 4.0) higher plasma C-peptide, 6.0% (95% CI: 5.5, 6.5) higher hsCRP, 2.4% (95% CI: 2.2, 2.7) higher HOMA2-insulin secretion, and 3.7% (95% CI: 3.5, 3.9) lower HOMA2-insulin sensitivity. Having a plasma leptin level within the top 25% (>34ng/ml) was associated with increased use of glucose-lowering medications (PR for insulin-and-oral/insulin only: 1.27 [95% CI: 1.01, 1.59]), Charlson Comorbidity Index score (PR ≥ 3, 1.57 [95% CI: 1.22, 2.00]), macro- (PR 1.25 [95% CI: 1.10, 1.42]) -and-microvascular (PR 1.22 [95% CI: 1.02, 1.45]) complications, compared to having the middle 50% leptin (6-34ng/ml). The associations remained robust when further adjusted for BMI and then BW. Conclusion: Low BW is associated with elevated plasma leptin levels, potentially contributing to disease severity in people recently diagnosed with T2D. Disclosure P.A. Obeng: None. A. Lühr Hansen: None. L.M. Engelhard: None. C. Brøns: Stock/Shareholder; Novo Nordisk A/S. V. Hirschberg Jensen: None. T. Hansen: None. N. Jessen: None. P. Vestergaard: None. J.S. Nielsen: None. K. Hojlund: None. M. Olsen: Other Relationship; AstraZeneca, Novo Nordisk A/S. Advisory Panel; Novo Nordisk A/S. Other Relationship; Teva Pharmaceutical Industries Ltd. R.W. Thomsen: None. A.A. Vaag: None. Funding Danish Agency for Science (09-067009 and 09-075724), the Danish Health and Medicines Authority, the Danish Diabetes Association, the Region of Southern Denmark, and the Novo Nordisk Foundation (NNF17SA0030962-2, NNF20O0063292, and NNF17SA0030364).This study was conducted during Prince's scholarship period at Lund University, funded by the Swedish Institute.

Introduction & Objective: Low birthweight (BW), a proxy for an adverse intrauterine environment, has been associated with risk of type 2 diabetes (T2D) and chronic kidney disease (CKD) later in life. The extent to which lower birthweight among people with T2D increases risk of CKD is unknown. Methods: Original midwife records were reviewed for 5979 people recently diagnosed with T2D in the Danish Center for Strategic Research in T2D (DD2) cohort. Individuals were followed for the incidence of CKD, defined by 1) two eGFR values <60ml/min per 1.73m2, 90 to 365 days apart, or 2) two urine albumin/creatinine ratios >30mg/g, 90 to 365 days apart. Ten-year standardized risks of CKD were estimated by the parametric G-formula using the Aalen-Johansen estimator, considering death as a competing risk. Adjusted hazard ratios (aHRs) were computed using Cox regression analysis. Continuous relations between BW and incident CKD were assessed with linear and restricted cubic spline regression. All models were standardized or adjusted for sex, age, calendar year at birth, family history of diabetes, and born-at-term status. Results: A total of 1443 incident CKD outcomes occurred in people with T2D during median follow-up of 8.5 years. Spline models showed progressively increasing aHRs of CKD with successively lower BW. The 10-year standardized risk of CKD was 39.9% in people with low BW <2500 g, compared with 33.5% in people with a BW of 2500-4500 g, yielding a CKD risk difference of 6.4% (95% CI: -0.3, 13.3) and an aHR of 1.25 (95% CI: 0.99, 1.58). People with T2D and a high BW >4500 g, compared with a BW of 2500-4500 g, had similar 10-year standardized CKD risks of 31.7% vs. 33.5%, respectively, corresponding to an aHR of 0.93 (95% CI: 0.59, 1.47). Conclusion: Lower birthweight is associated with elevated risk of CKD among people with type 2 diabetes. Disclosure A. Lühr Hansen: None. C. Christiansen: None. C. Brøns: Stock/Shareholder; Novo Nordisk A/S. L.M. Engelhard: None. T. Hansen: None. J.S. Nielsen: None. P. Vestergaard: None. K. Hojlund: None. N. Jessen: None. M. Olsen: Other Relationship; AstraZeneca, Novo Nordisk A/S. Advisory Panel; Novo Nordisk A/S. Other Relationship; Teva Pharmaceutical Industries Ltd. H.T. Sørensen: Other Relationship; See text. P. Rossing: Other Relationship; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Gilead Sciences, Inc., Novo Nordisk, Eli Lilly and Company, Novartis AG, Abbott Diagnostics. R.W. Thomsen: None. A.A. Vaag: None. Funding Danish Agency for Science (09-067009 and 09-075724); Novo Nordisk Foundation ( NNF17SA0030962-2, NNF20O0063292, NNF17SA0030364)

AIMS/HYPOTHESIS:Low birthweight is a risk factor for type 2 diabetes and CVD. This prospective cohort study investigated whether lower birthweight increases CVD risk after diagnosis of type 2 diabetes. METHODS:Original midwife records were evaluated for 8417 participants recently diagnosed with type 2 diabetes in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort. Patients were followed for the first occurrence of a composite CVD endpoint (myocardial infarction, coronary revascularisation, peripheral arterial disease, stroke, unstable angina, heart failure or CVD death), a three-component endpoint comprising major adverse cardiovascular events (MACE), and all-cause mortality. Ten-year risks were estimated using the Aalen-Johansen estimator considering non-CVD death as a competing risk. HRs were determined by Cox regression. Models were controlled for sex, age, calendar year at birth, family history of diabetes and born-at-term status. RESULTS:A total of 1187 composite CVD endpoints, 931 MACE, and 1094 deaths occurred during a median follow-up period of 8.5 years. The 10-year standardised composite CVD risk was 19.8% in participants with a birthweight <3000 g compared with 16.9% in participants with a birthweight of 3000-3700 g, yielding a risk difference (RD) of 2.9% (95% CI 0.4, 5.4) and an adjusted HR of 1.20 (95% CI 1.03, 1.40). The 10-year MACE risk for birthweight <3000 g was similarly elevated (RD 2.4%; 95% CI 0.1, 4.7; HR 1.22; 95% CI 1.01, 1.46). The elevated CVD risk was primarily driven by stroke, peripheral arterial disease and CVD death. All-cause mortality showed no substantial difference. CONCLUSIONS/INTERPRETATION:Having a birthweight <3000 g is associated with higher CVD risk among patients with type 2 diabetes, driven primarily by risk of stroke and CVD death.