Prevalent Type 2 Diabetes Research Articles

The mediating role of the food environment, greenspace, and walkability in the association between socioeconomic position and type 2—diabetes The Maastricht Study

AimsThis study investigates the interplay between socioeconomic position (SEP), the residential food environment, walkability, greenspace, and type 2 diabetes (T2D), particularly whether the environmental factors mediate the association between SEP and T2D MethodsSEP, T2D status, Residential Food Environment Healthiness Index (FEHI), number of fast-food outlets (FF), walkability index (WI), and proportion of greenspace (GS) were ascertained in 9188 participants. The associations between SEP, the environment and T2D were modeled with logistic regression and survival analysis. The proportion of mediation of the association between SEP and T2D was estimated with causal mediation analysis. ResultsLower SEP was associated with higher risk of T2D. Hazard ratios (HR) were 2.03 (95%CI 1.602.58), 1.79 (1.402.30) and 1.77 (1.212.58) for an interquartile range decrease (IQR) of education, income, and occupation, respectively. HRs for IQR changes of the environmental factors were: FEHI 1.20 (1.001.43), FF 0.87 (0.760.99), WI 1.23 (0.951.58) and GS 1.16 (0.961.43). Regression on prevalent T2D yielded similar results. Lower socioeconomic position was associated with a less healthy environment (e.g., FEHI -0.10 (-0.12-0.07) for education). Environmental exposures mediated between 0.1% (-0.70.9) and 2.6% (0.45.2) of the cross-sectional associations and 0.3% (-8.68.6) and 8.5% (2.327.4) of the longitudinal associations. ConclusionsPeople with lower SEP had higher risk and prevalence of T2D and lived in a slightly less healthy residential environment. The association between SEP and T2D is not strongly mediated by the FEHI, FF, WI, or GS.

Prospective Association of the Mediterranean Diet with the Onset of Cardiometabolic Multimorbidity in a UK-Based Cohort: The EPIC-Norfolk Study

BackgroundCardiometabolic multimorbidity (CMM), defined as the co-occurrence of 2 or more cardiometabolic diseases, including myocardial infarction (MI), stroke, and type 2 diabetes (T2D), is an increasing public health challenge. Although poor diet is a known risk factor for a first cardiometabolic disease (FCMD), the relationship with subsequent occurrence of CMM is less studied. ObjectivesThis study aims to investigate the prospective association between baseline adherence to the Mediterranean diet and the onset of CMM across various follow-up durations. MethodsWe used data from the European Prospective Investigation into Cancer-Norfolk cohort study of 21,900 adults, aged 40–79 free of prevalent MI, stroke, and T2D at baseline (1993–1997). A median-based Mediterranean diet score and a pyramid-based MDS (pyr-MDS) were used to measure baseline adherence to the Mediterranean diet. Multistate modeling was employed to investigate associations with the FCMD and the subsequent CMM event. ResultsOver the entire follow-up period of 21.4 y (median), we observed 5028 FCMD and 734 CMM events. Multistate analysis indicated that the association between baseline Mediterranean diet and the risk of CMM may be stronger in shorter follow-up durations. Particularly, baseline pyr-MDS was significantly associated with the risk of subsequent CMM transitioning from FCMD when follow-up durations were limited to 10 and 15 y, with hazard ratio (95% confidence interval) being 0.67 (0.53, 0.84) and 0.80 (0.70, 0.92) per SD increase in pyr-MDS, respectively. Additionally, we observed that the risk of CMM transitioning from FCMD was modified by social class across shorter to longer follow-ups, where the impact of baseline Mediterranean diet was only significant in nonmanual workers. ConclusionsBaseline adherence to the Mediterranean diet was potentially associated with a lower risk of CMM transitioning from FCMD, particularly during shorter follow-up periods.

HbA1c comparable to fasting glucose in the external validation of the African Diabetes Risk Score and other established risk prediction models in Black South Africans

BackgroundThe use of non-invasive risk scores to detect undiagnosed type 2 diabetes (T2D) ensures the restriction of invasive and costly blood tests to those most likely to be diagnosed with the disease. This study assessed and compared the performance of the African Diabetes Risk Score (ADRS) with three other diabetes risk prediction models for identifying screen-detected diabetes based on fasting plasma glucose (FPG) or glycated haemoglobin (HBA1c).MethodsAge, sex, waist circumference, body mass index, blood pressure, history of diabetes and physical activity levels from the SA-NW-PURE study were used to externally validate the ADRS and other established risk prediction models. Discrimination was assessed and compared using C-statistics and nonparametric methods. Calibration was assessed using calibration plots, before and after recalibration.ResultsNine hundred and thirty-seven participants were included; 14% had prevalent undiagnosed T2D according to FPG and 26% according to HbA1c. Discrimination was acceptable and was mostly similar between models for both diagnostic measures. The C-statistics for diagnosis by FPG ranged from 0.69 for the Simplified FINDRISC model to 0.77 for the ADRS model and 0.77 for the Simplified FINDRISC model to 0.79 for the ADRS model for diagnosis by HbA1c. Calibration ranged from acceptable to good, though over- and underestimation were present. All models improved significantly following recalibration.ConclusionsThe models performed comparably, with the ADRS offering a non-invasive way to identify up to 79% of cases. Based on its ease of use and performance, the ADRS is recommended for screening for T2D in certain Black population groups in South Africa. HbA1c as a means of diagnosis also showed comparable performance with FPG. Therefore, further validation studies can potentially use HbA1c as the standard to compare to.

Prevalence of obesity and cardiovascular disease in adults with type 2 diabetes and use of diabetes medication in Germany: A claims data study.

To identify the prevalence of cardiovascular disease (CVD) and obesity in patients with type 2 diabetes (T2D) in Germany and to evaluate if antidiabetic treatment patterns varied by comorbidity status. Patients with T2D (aged ≥18 years) were identified during the study period (2014-2020) from medical claims of 4.5 million publicly insured German residents and divided into different cohorts based on CVD and/or obesity diagnosis. Annual prevalence and incidence were estimated for each study year, while characteristics and treatments were assessed in 2020. Data were extrapolated to the German population by age and sex. The prevalence of T2D in 2020 was 11.4%. Among patients with T2D, 53.0% had CVD, 39.3% had obesity, and 20.9% had CVD and obesity. Since 2014, CVD increased by 1.4%, obesity by 4.5%, and CVD with obesity by 2.7% in patients with T2D. The incidence of T2D in 2020 was 1.0% (42.9% had CVD, 37.9% had obesity, and 15.8% had CVD and obesity). Among the prevalent T2D population in 2020, 4.9% received glucagon-like peptide-1 receptor agonists (GLP-1RAs), 9.7% received sodium-glucose cotransporter-2 (SGLT2) inhibitors, and 13.0% received GLP-1 RAs and/or SGLT2 inhibitors. Of those with CVD, 12.9% received GLP-1 RAs and/or SGLT2 inhibitors (without CVD, 13.2%). Of those with obesity, 19.4% received GLP-1RAs and/or SGLT2 inhibitors (without obesity, 9.0%). In this retrospective claims database study, more than two thirds of patients with T2D also had CVD, obesity, or both CVD and obesity. GLP-1 RA and SGLT2 inhibitor use remained low.

Branched-Chain and Aromatic Amino Acids, Type 2 Diabetes, and Cardiometabolic Risk Factors among Puerto Rican Adults.

(1) Background: Branched-chain and aromatic amino acids (BCAAs/AAAs) have been considered as markers of type 2 diabetes (T2D); however, studies on associations between these metabolites and T2D and cardiometabolic traits in Hispanic populations are limited. The aim of this study was to examine the associations between baseline BCAAs (isoleucine, leucine, valine)/AAAs (phenylalanine, tyrosine) and prevalent and incident T2D, as well as baseline and longitudinal (2 year) changes in cardiometabolic traits (measures of glycemia, dyslipidemia, inflammation, and obesity) in two large cohorts of adults of Puerto Rican descent. (2) Methods: We included participants of the Boston Puerto Rican Health Study (BPRHS, n = 670) and San Juan Overweight Adult Longitudinal study (SOALS, n = 999) with available baseline metabolite and covariate data. T2D diagnosis was defined based on American Diabetes Association criteria. Multivariable logistic (for baseline T2D), Poisson (for incident T2D), and linear (for cardiometabolic traits) regression models were used; cohort-specific results were combined in the meta-analysis and adjusted for multiple comparisons. (3) Results: Higher baseline BCAAs were associated with higher odds of prevalent T2D (OR1SD BCAA score = 1.46, 95% CI: 1.34-1.59, p < 0.0001) and higher risk of incident T2D (IRR1SD BCAA score = 1.24, 95% CI: 1.13-1.37, p < 0.0001). In multivariable longitudinal analysis, higher leucine and valine concentrations were associated with 2-year increase in insulin (beta 1SD leucine = 0.37 mcU/mL, 95% CI: 0.11-0.63, p < 0.05; beta 1SD valine = 0.43 mcU/mL, 95% CI: 0.17-0.68, p < 0.01). Tyrosine was a significant predictor of incident T2D (IRR = 1.31, 95% CI: 1.09-1.58, p < 0.05), as well as 2 year increases in HOMA-IR (beta 1SD tyrosine = 0.13, 95% CI: 0.04-0.22, p < 0.05) and insulin concentrations (beta 1SD tyrosine = 0.37 mcU/mL, 95% CI: 0.12-0.61, p < 0.05). (4) Conclusions: Our results confirmed the associations between BCAAs and prevalent and incident T2D, as well as concurrent measures of glycemia, dyslipidemia, and obesity, previously reported in predominantly White and Asian populations. Baseline leucine, valine, and tyrosine were predictors of 2 year increases in insulin, whereas tyrosine was a significant predictor of deteriorating insulin resistance over time. Our study suggests that BCAAs and tyrosine could serve as early markers of future glycemic changes in Puerto Ricans.

Identifying subtypes of type 2 diabetes mellitus with machine learning: development, internal validation, prognostic validation and medication burden in linked electronic health records in 420 448 individuals

IntroductionNone of the studies of type 2 diabetes (T2D) subtyping to date have used linked population-level data for incident and prevalent T2D, incorporating a diverse set of variables, explainable methods...

Gut Microbiota and Blood Metabolites Related to Fiber Intake and Type 2 Diabetes.

Consistent evidence suggests diabetes-protective effects of dietary fiber intake. However, the underlying mechanisms, particularly the role of gut microbiota and host circulating metabolites, are not fully understood. We aimed to investigate gut microbiota and circulating metabolites associated with dietary fiber intake and their relationships with type 2 diabetes (T2D). This study included up to 11 394 participants from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos). Diet was assessed with two 24-hour dietary recalls at baseline. We examined associations of dietary fiber intake with gut microbiome measured by shotgun metagenomics (350 species/85 genera and 1958 enzymes; n=2992 at visit 2), serum metabolome measured by untargeted metabolomics (624 metabolites; n=6198 at baseline), and associations between fiber-related gut bacteria and metabolites (n=804 at visit 2). We examined prospective associations of serum microbial-associated metabolites (n=3579 at baseline) with incident T2D over 6 years. We identified multiple bacterial genera, species, and related enzymes associated with fiber intake. Several bacteria (eg, Butyrivibrio, Faecalibacterium) and enzymes involved in fiber degradation (eg, xylanase EC3.2.1.156) were positively associated with fiber intake, inversely associated with prevalent T2D, and favorably associated with T2D-related metabolic traits. We identified 159 metabolites associated with fiber intake, 47 of which were associated with incident T2D. We identified 18 of these 47 metabolites associated with the identified fiber-related bacteria, including several microbial metabolites (eg, indolepropionate and 3-phenylpropionate) inversely associated with the risk of T2D. Both Butyrivibrio and Faecalibacterium were associated with these favorable metabolites. The associations of fiber-related bacteria, especially Faecalibacterium and Butyrivibrio, with T2D were attenuated after further adjustment for these microbial metabolites. Among United States Hispanics/Latinos, dietary fiber intake was associated with favorable profiles of gut microbiota and circulating metabolites for T2D. These findings advance our understanding of the role of gut microbiota and microbial metabolites in the relationship between diet and T2D.

Cardiovascular Significance and Genetics of Epicardial and Pericardial Adiposity

Epicardial and pericardial adipose tissue (EPAT) has been associated with cardiovascular diseases such as atrial fibrillation or flutter (AF) and coronary artery disease (CAD), but studies have been limited in sample size or drawn from selected populations. It has been suggested that the association between EPAT and cardiovascular disease could be mediated by local or paracrine effects. To evaluate the association of EPAT with prevalent and incident cardiovascular disease and to elucidate the genetic basis of EPAT in a large population cohort. A deep learning model was trained to quantify EPAT area from 4-chamber magnetic resonance images using semantic segmentation. Cross-sectional and prospective cardiovascular disease associations were evaluated, controlling for sex and age. Prospective associations were additionally controlled for abdominal visceral adipose tissue (VAT) volumes. A genome-wide association study was performed, and a polygenic score (PGS) for EPAT was examined in independent FinnGen cohort study participants. Data analyses were conducted from March 2022 to December 2023. The primary exposures were magnetic resonance imaging-derived continuous measurements of epicardial and pericardial adipose tissue area and visceral adipose tissue volume. Prevalent and incident CAD, AF, heart failure (HF), stroke, and type 2 diabetes (T2D). After exclusions, this study included 44 475 participants (mean [SD] age, 64.1 [7.7] years; 22 972 female [51.7%]) from the UK Biobank. Cross-sectional and prospective cardiovascular disease associations were evaluated for a mean (SD) of 3.2 (1.5) years of follow-up. Prospective associations were additionally controlled for abdominal VAT volumes for 38 527 participants. A PGS for EPAT was examined in 453 733 independent FinnGen cohort study participants. EPAT was positively associated with male sex (β = +0.78 SD in EPAT; P < 3 × 10-324), age (Pearson r = 0.15; P = 9.3 × 10-229), body mass index (Pearson r = 0.47; P < 3 × 10-324), and VAT (Pearson r = 0.72; P < 3 × 10-324). EPAT was more elevated in prevalent HF (β = +0.46 SD units) and T2D (β = +0.56) than in CAD (β = +0.23) or AF (β = +0.18). EPAT was associated with incident HF (hazard ratio [HR], 1.29 per +1 SD in EPAT; 95% CI, 1.17-1.43), T2D (HR, 1.63; 95% CI, 1.51-1.76), and CAD (HR, 1.19; 95% CI, 1.11-1.28). However, the associations were no longer significant when controlling for VAT. Seven genetic loci were identified for EPAT, implicating transcriptional regulators of adipocyte morphology and brown adipogenesis (EBF1, EBF2, and CEBPA) and regulators of visceral adiposity (WARS2 and TRIB2). The EPAT PGS was associated with T2D (odds ratio [OR], 1.06; 95% CI, 1.05-1.07; P =3.6 × 10-44), HF (OR, 1.05; 95% CI, 1.04-1.06; P =4.8 × 10-15), CAD (OR, 1.04; 95% CI, 1.03-1.05; P =1.4 × 10-17), AF (OR, 1.04; 95% CI, 1.03-1.06; P =7.6 × 10-12), and stroke in FinnGen (OR, 1.02; 95% CI, 1.01-1.03; P =3.5 × 10-3) per 1 SD in PGS. Results of this cohort study suggest that epicardial and pericardial adiposity was associated with incident cardiovascular diseases, but this may largely reflect a metabolically unhealthy adiposity phenotype similar to abdominal visceral adiposity.

Impact of type 2 diabetes on complications after primary breast cancer surgery: Danish population-based cohort study.

Knowledge is sparse on the impact of type 2 diabetes (T2D) on surgical outcomes after breast cancer surgery. This study investigated the association between T2D and risk of complications after primary breast cancer surgery, and evaluated the biological interaction between T2D and co-morbidities. Using the Danish Breast Cancer Group clinical database, a cohort of all Danish women diagnosed with early-stage breast cancer during 1996-2022 was created. All patients underwent mastectomy or breast-conserving surgery. Information on prevalent T2D was collected from Danish medical and prescription registries. Surgical complications were defined as hospital diagnoses for medical or surgical complications developing within 30 days after primary breast cancer surgery. The 30-day cumulative incidence proportion of complications was calculated, and Cox regression was used to estimate HRs. Interaction contrasts were computed to determine the additive interaction between T2D and co-morbidities on the incidence rate of complications. Among 98 589 women with breast cancer, 6332 (6.4%) had T2D at breast cancer surgery. Overall, 1038 (16.4%) and 9861 (10.7%) women with and without T2D developed surgical complications, yielding cumulative incidence proportions of 16 (95% c.i. 15 to 17) and 11 (10 to 11)% respectively, and a HR of 1.43 (95% c.i. 1.34 to 1.53). The incidence rate of surgical complications explained by the interaction of T2D with moderate and severe co-morbidity was 21 and 42%, respectively. Women with breast cancer and T2D had a higher risk of complications after primary breast cancer surgery than those without T2D. A synergistic effect of T2D and co-morbidity on surgical complications can explain this association.

Inverse association between total bilirubin and type 2 diabetes in U.S. South Asian males but not females.

United States South Asians constitute a fast-growing ethnic group with high prevalence of type 2 diabetes (T2D) despite lower mean BMI and other traditional risk factors compared to other races/ethnicities. Bilirubin has gained attention as a potential antioxidant, cardio-protective marker. Hence we sought to determine whether total bilirubin was associated with prevalent and incident T2D in U.S. South Asians. We conducted a cross-sectional and prospective analysis of the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study. Total bilirubin was categorized into gender-specific quartiles (Men: <0.6, 0.6, 0.7-0.8, >0.8; Women: <0.5, 0.5, 0.6, >0.6 mg/dl). We estimated odds of type 2 diabetes as well as other cardiovascular (CV) risk factors using multivariable logistic regression. Among a total 1,149 participants (48% female, mean [SD] age of 57 [9] years), 38% had metabolic syndrome and 24% had T2D. Men and women in the lowest bilirubin quartile had 0.55% and 0.17% higher HbA1c than the highest quartile. Men, but not women, in the lowest bilirubin quartile had higher odds of T2D compared to the highest quartile (aOR [95% CI]; Men: 3.00 [1.72,5.23], Women: 1.15 [0.57,2.31]). There was no association between bilirubin and other CV risk factors. Total bilirubin was inversely associated with T2D in SA men but not women. Longitudinal studies are needed to understand temporality of association.

Trends in clinical characteristics, medication use, and glycemic control in insulin-treated patients with type 1 and type 2 diabetes in Finland in 2012-2019: Nationwide real-world evidence study.

To describe the clinical characteristics and medication purchases of insulin-treated adults in Finland at index (January 1, 2012 or first insulin purchase) and December 31, 2019. Additionally, to describe basal insulin (BI) treatment patterns and associated changes in hemoglobin A1c (HbA1c) values. In this descriptive study using nationwide registries, we included adults with at least two reimbursed insulin purchases within 12 months of the first purchase between January 1, 2012 and December 31, 2019. We formed four study groups: type 1 diabetes (T1D) and type 2 diabetes (T2D)-diagnosed people who were further divided into prevalent or naïve users (start of insulin use before or after January 1, 2012). Insulin treatment patterns were estimated from medication purchase data and glycemic control from HbA1c results. Out of 145 020 people included, 34 359 had T1D and 110 661 T2D. By 2019, in parallel with the adaptation of new noninsulin medications, second-generation basal insulin (BI) analogues were adopted by 45.9% and 21.1% of prevalent T1D and T2D users. At index, HbA1c target (≤53 mmol/mol) was reached by 17% and 35% of T2D naïve and prevalent users, respectively, and by 17% of T1D prevalent users. At study end, the target was reached respectively by 41%, 34%, and 22% of insulin users. Insulin initiation improved and discontinuation worsened glycemic control in T2D, with lesser effects seen after treatment gaps or switches between BIs. Our study showed that glycemic control in insulin users has remained stable or improved between 2012 and 2019 despite aging population and in parallel with introduction of new treatment options, providing valuable insight into Finnish national diabetes care.

The development of type 2 diabetes management in people with severe mental illness in the Capital Region of Denmark from 2001 to 2015.

Type 2 diabetes (T2D) treatment has changed markedly within the last decades. We aimed to explore whether people with severe mental illness (SMI) have followed the same changes in T2D treatment as those without SMI, as multiple studies suggest that people with SMI receive suboptimal care for somatic disorders. In this registry-based annual cohort study, we explored the T2D treatment from 2001 to 2015 provided in general practices of the Greater Copenhagen area. We stratified the T2D cohorts by their pre-existing SMI status. T2D was defined based on elevated glycated hemoglobin (≥48 mmol/mol) or glucose (≥11 mmol/L) using data from the Copenhagen Primary Care Laboratory Database. Individuals with schizophrenia spectrum disorders (ICD-10 F20-29) or affective disorders (bipolar disorder or unipolar depression, ICD-10 F30-33) were identified based on hospital-acquired diagnoses made within 5 years before January 1 each year for people with prevalent T2D or 5 years before meeting our T2D definition for incident patients. For comparison, we defined a non-SMI group, including people who did not have a hospital-acquired diagnosis of schizophrenia spectrum disorders, affective disorders, or personality disorders. For each calendar year, we assembled cohorts of people with T2D with or without SMI. We used Poisson regression to calculate the rates per 100 person-years of having at least one biochemical test (glycated hemoglobin, low-density lipoprotein cholesterol, estimated glomerular filtration rate, and urine albumin-creatinine ratio), having poor control of these biochemical results, taking glucose-lowering or cardiovascular medications, or experiencing a clinical outcome, including all-cause mortality and cardiovascular mortality. Three outcomes (cardiovascular events, cardiovascular mortality, and all-cause mortality) were additionally examined and adjusted for age and sex in a post hoc analysis. From 2001 to 2015, 66,914 individuals were identified as having T2D. In 2015, 1.5% of the study population had schizophrenia spectrum disorder and 1.4% had an affective disorder. The number of people who used biochemical tests or had poor biochemical risk factor control was essentially unrelated to SMI status. One exception was that fewer LDL cholesterol tests were done on people with affective disorders and schizophrenia spectrum disorders at the beginning of the study period compared to people in the non-SMI group. This difference gradually diminished and was almost nonexistent by 2011. There was also a slightly slower rise in UACR test rates in the SMI groups compared to other people with T2D during the period. Throughout the study period, all groups changed their use of medications in similar ways: more metformin, less sulfonylurea, more lipid-lowering drugs, and more ACEi/ARBs. However, people with schizophrenia disorder consistently used fewer cardiovascular medications. Cardiovascular events were more common in the affective disorder group compared to the non-SMI group from 2009 to 2015 (rate ratio 2015 : 1.36 [95% CI 1.18-1.57]). After adjustment for age and sex, all-cause mortality was significantly higher among people with a schizophrenia spectrum disorder each year from 2003 to 2015 compared to the non-SMI group (rate ratio 2015 : 1.99 [95% CI 1.26-3.12]). Persons with schizophrenia or affective disorders demonstrated the same treatment changes for T2D as those without SMI in general practice. The lower use of most types of cardiovascular medications among people with schizophrenia disorders indicates potential undertreatment of hypertension and dyslipidemia and remains throughout the study period. Cardiovascular events were most common among people with affective disorders, but this was not reflected in a higher proportion using cardiovascular preventive medications. This knowledge should be considered in the management of this vulnerable patient group.

Vaspin: A Novel Biomarker Linking Gluteofemoral Body Fat and Type 2 Diabetes Risk.

To determine whether adiposity depots modulate vaspin levels and whether vaspin predicts type 2 diabetes (T2D) risk, through epidemiological and genetic analyses. We assessed the relationship of plasma vaspin concentration with incident and prevalent T2D and adiposity-related variables in 1) the Prospective Urban and Rural Epidemiology (PURE) biomarker substudy (N = 10,052) and 2) the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial (N = 7,840), using regression models. We then assessed whether vaspin is causally associated with T2D and whether genetic variants associated with MRI-measured adiposity depots modulate vaspin levels, using two-sample Mendelian randomization (MR). A 1-SD increase in circulating vaspin levels was associated with a 16% increase in incident T2D in the PURE cohort (hazard ratio 1.16; 95% CI 1.09-1.23; P = 4.26 × 10-7) and prevalent T2D in the ORIGIN cohort (odds ratio [OR] 1.16; 95% CI 1.07-1.25; P = 2.17 × 10-4). A 1-unit increase in BMI and triglyceride levels was associated with a 0.08-SD (95% CI 0.06-0.10; P = 2.04 × 10-15) and 0.06-SD (95% CI 0.04-0.08; P = 4.08 × 10-13) increase, respectively, in vaspin in the PURE group. Consistent associations were observed in the ORIGIN cohort. MR results reinforced the association between vaspin and BMI-adjusted T2D risk (OR 1.01 per 1-SD increase in vaspin level; 95% CI 1.00-1.02; P = 2.86 × 10-2) and showed that vaspin was increased by 0.10 SD per 1-SD decrease in genetically determined gluteofemoral adiposity (95% CI 0.02-0.18; P = 2.01 × 10-2). No relationships were found between subcutaneous or visceral adiposity and vaspin. These findings support that higher vaspin levels are related to increased T2D risk and reduced gluteofemoral adiposity, positioning vaspin as a promising clinical predictor for T2D.

Abstract 16868: Genetic Regulation of Branched-Chain Amino Acid Levels Does Not Increase Type 2 Diabetes Risk

Introduction: The branched-chain amino acids (BCAAs) valine, leucine, and isoleucine are associated with incident type 2 diabetes (T2D). Prior genetic studies have provided conflicting results as to whether the BCAAs are causally related to T2D but are limited by a small number of genetic instruments associated with BCAA levels. Hypothesis: We hypothesized that polygenic predictors that capture a broad set of genetic mechanisms regulating BCAA levels would clearly define the etiological relationship with T2D. Methods: We constructed and validated instrumental variables for each BCAA using well-powered datasets and tested their association with T2D using two-sample inverse variance weighted (IWV) Mendelian randomization (MR). Sensitivity analyses were performed to ensure the accuracy of the findings. We also tested whether instrumental variables for T2D, fasting insulin, and body mass index (BMI) were associated with BCAA levels. Finally, logistic regression was used to test whether a polygenic risk score (PRS) for T2D was associated with measured BCAA levels among 1220 participants in the Framingham offspring study (FOS) without prevalent T2D. Results: There were no significant associations with T2D for valine (beta=0.17 change in log-odds per standard deviation change in valine, [95% CI, -0.28 - 0.62], p=0.45), leucine (beta=0.19 [-0.30 - 0.68] p=0.45) or isoleucine (beta=0.02 [-0.54 - 0.59], p=0.94). In contrast, T2D was associated with each BCAA (valine: beta=0.08 per standard deviation change in levels per log-odds change in type 2 diabetes, [0.05 - 0.10], p=1.8x10 -9 ), (leucine: beta= 0.06 [0.04 - 0.09], p=4.5x10 -8 ) and isoleucine (beta= 0.06 [0.04 - 0.08], p=2.8x10 -8 ). The T2D associations were replicated in an independent population but not in a second population where T2D cases were removed. Similarly, a T2D PRS was associated with measured BCAA levels in the FOS study but not when incident T2D cases were removed. Positive associations were seen for fasting insulin and BMI, and the BCAAs by MR, and, in multivariable MR analyses, T2D and fasting insulin had independent associations with each BCAA. Conclusions: These data suggest that BCAAs are not mediators of T2D risk but may rather serve as biomarkers of T2D and higher insulin levels.

Health inequalities in type 2 diabetes: contributions of exposures in the residential environment

Abstract Background People with lower socioeconomic position (SEP) have higher risk of type 2 diabetes (T2D). Besides genetic predisposition, the exposome shapes this risk. This includes exposures in the residential environment. We explored the relationships between SEP, the residential food environment, walkability, greenspace, and T2D. Methods Cross-sectional and longitudinal data from 9188 participants were analyzed. Prevalent T2D was measured by an oral glucose tolerance test. Incident T2D was self-reported in annual follow-up questionnaires. Education, income, and occupation were measured as indicators of SEP. The residential environment was operationalized by address level Food Environment Healthiness Index (FEHI), number of fast-food outlets (FF), walkability index (WI), and proportion of greenspace (GS). Logistic regression and survival analyses were used to model the associations between SEP, the environment and T2D. The proportion of mediation of the association between SEP and T2D was estimated in a causal mediation analysis using a simulation approach. Results Over a median follow-up of 6.2 years, 207 incident cases were identified. Lower SEP was associated with higher risk of T2D. Hazard ratios (HR) were 2.0 (95%CI 1.6-2.6), 1.8 (1.4-2.3) and 1.8 (1.2-2.6) for an interquartile range decrease (IQR) of education, income, and occupation, respectively. HRs for IQR changes of the environmental factors were: FEHI 1.2 (1.0-1.4), FF 0.9 (0.8-1.0), WI 1.2 (1.0-1.6) and GS 1.2 (1.0-1.4). Regression on prevalent T2D yielded similar results. Lower SEP was associated with a less healthy environment (e.g., FEHI -0.08 (-0.10--0.06) for education). Environmental exposures mediated between 0.3% (-8.6-8.6) and 8.5% (2.3-27.4) of the longitudinal associations. Conclusions Lower SEP was associated with prevalent and incident T2D. People with lower SEP lived in a slightly less healthy residential environment. Some of the SEP-T2D association could be mediated by the environment. Key messages • A less healthy residential food environment, lower walkability and less green space might mediate some of the association between SEP and T2D. • More research is needed to clarify the extent to which environmental pathways contribute to health inequalities.

A Type 1 Diabetes Polygenic Score Is Not Associated With Prevalent Type 2 Diabetes in Large Population Studies.

Both type 1 diabetes (T1D) and type 2 diabetes (T2D) have significant genetic contributions to risk and understanding their overlap can offer clinical insight. We examined whether a T1D polygenic score (PS) was associated with a diagnosis of T2D in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. We constructed a T1D PS using 79 known single nucleotide polymorphisms associated with T1D risk. We analyzed 13 792 T2D cases and 14 169 controls from CHARGE cohorts to determine the association between the T1D PS and T2D prevalence. We validated findings in an independent sample of 2256 T2D cases and 27 052 controls from the Mass General Brigham Biobank (MGB Biobank). As secondary analyses in 5228 T2D cases from CHARGE, we used multivariable regression models to assess the association of the T1D PS with clinical outcomes associated with T1D. The T1D PS was not associated with T2D both in CHARGE (P = .15) and in the MGB Biobank (P = .87). The partitioned human leukocyte antigens only PS was associated with T2D in CHARGE (OR 1.02 per 1 SD increase in PS, 95% CI 1.01-1.03, P = .006) but not in the MGB Biobank. The T1D PS was weakly associated with insulin use (OR 1.007, 95% CI 1.001-1.012, P = .03) in CHARGE T2D cases but not with other outcomes. In large biobank samples, a common variant PS for T1D was not consistently associated with prevalent T2D. However, possible heterogeneity in T2D cannot be ruled out and future studies are needed do subphenotyping.

Glucose-lowering drug use in migrants and native Danes with type 2 diabetes: Disparities in combination therapy and drug types.

To examine disparities in glucose-lowering drug (GLD) usage between migrants and native Danes with type 2 diabetes (T2D). In a nationwide, register-based cross-sectional study of 253 364 individuals with prevalent T2D on December 31, 2018, we examined user prevalence during 2019 of (i) GLD combination therapies and (ii) individual GLD types. Migrants were grouped by origin (Middle East, Europe, Turkey, Former Yugoslavia, Pakistan, Sri Lanka, Somalia, Vietnam), and relative risk (RR) versus native Danes was computed using robust Poisson regression to adjust for clinical and socioeconomic characteristics. In 2019, 34.7% of native Danes received combination therapy, and prevalence was lower in most migrant groups (RR from 0.78, 95% confidence interval CI 0.71-0.85 [Somalia group] to 1.00, 95% CI 0.97-1.04 [former Yugoslavia group]). Among native Danes, the most widely used oral GLD was metformin (used by 62.1%), followed by dipeptidyl peptidase-4 inhibitors (13.3%), sodium-glucose cotransporter-2 inhibitors (11.9%) and sulphonylureas (5.2%), and user prevalence was higher in most migrant groups (RR for use of any oral GLD: 0.99, 95% CI 0.97-1.01 [Europe group] to 1.09, 95% CI 1.06-1.11 [Sri Lanka group]). Furthermore, 18.7% of native Danes used insulins and 13.3% used glucagon-like peptide-1 receptor agonists (GLP-1RAs), but use was less prevalent in migrants (RR for insulins: 0.66, 95% CI 0.62-0.71 [Sri Lanka group] to 0.94, 95% CI 0.89-0.99 [Europe group]; RR for GLP-1RAs: 0.29, 95% CI 0.22-0.39 [Somalia group] to 0.95, 95% CI 0.89-1.01 [Europe group]). Disparities in GLD types and combination therapy were evident between migrants and native Danes. Migrants were more likely to use oral GLDs and less likely to use injection-based GLDs, particularly GLP-1RAs, which may contribute to complication risk and mortality among this group.

63-OR: The Contribution of Social-Needs Factors to Racial Differences in Type 2 Diabetes

Studies have attributed gaps in type 2 diabetes (T2D) between Black/African-American (BAA) and White adults to socioeconomic factors. We quantified the contribution of social risk factors to racial gaps in T2D in 6 Kaiser Permanente health systems across the U.S. We utilized data collected from the National KP Social Needs Survey conducted in 2020 among 10,226 health system members. We linked survey data to electronic health record data. Exposures included financial strain, food insecurity, and housing instability in the past year. The outcome, prevalent T2D, was defined as either a diagnosis of T2D or medication fills for antidiabetic medications. Self-reported BAA and White race were used to stratify data. Other covariates included demographics, insurance type, clinical measures, and comorbidities. Cross-sectional logistic regression models assessed the odds of T2D by race and the Oaxaca-Blinder decomposition method calculated the percent contribution of all variables to the racial difference in T2D. All statistical analysis were weighted to account for the complex survey design. Our final analysis included 1,223 BAA and 3,372 White survey participants. BAA participants were more likely to be younger, female, report more social risk factors, and have a greater burden of comorbidities. The prevalence of T2D was 22% in BAA patients and 11% in White patients. The covariates in the Oaxaca-Blinder analysis explained 43% of the 11% overall difference in T2D prevalence between BAA and White patients. Of this explained difference, the combined variable of financial strain, food insecurity, or housing instability significantly contributed to the racial gap in T2D by 11%. Our results demonstrated, that if social risk factors of BAA patients were equal to White patients, the racial difference in T2D would be reduced by 11% in our population with access to health care. However, the impact is relatively small and other social factors (e.g. discrimination) will be important to explore using this methodology. Disclosure S. Vupputuri: None. S. Kim: None. M. Clennin: None. L. Cromwell: None. S.L. Daugherty: None. Funding Kaiser Permanente Social Needs Network for Evaluation and Translation

209-LB: Discovery Metabolomics across a Population Scale Study Identifies a Community of Glycerolipids Associated with Incident Type 2 Diabetes

It is well appreciated that changes in metabolic pathways precede the development of overt type 2 diabetes (T2D), but a systematic and unbiased evaluation of such metabolic changes is lacking. Here, we applied a novel high-throughput untargeted liquid chromatography-mass spectrometry (LC-MS) method to the FINRISK 2002 cohort (n=8014) to identify plasma metabolite predictors of incident T2D. We analyzed LC-MS data consisting of 14,615 metabolite features from individuals without prevalent T2D to discover 171 that predicted T2D incidence at a threshold of P&amp;lt;10-6 (Cox regression). To identify discrete molecular pathways, we performed Gaussian graphical modeling to create a network of all detected metabolite features finding that the T2D predictor metabolites were enriched in 11 distinct metabolite communities containing between 6 and 48 interconnected metabolites. Here we highlight one community consisting of 26 plasma diacylglycerols (DAGs) and closely related metabolites. One member of this community, a DAG with carbon:unsaturated bond sum composition of 36:4, predicted T2D incidence (HR = 1.22, p = 7.6×10-10) independently of insulin, glucose and HbA1c, but not 2-hour glucose as measured by OGTT. Thus, this metabolite is a novel predictor of incident T2D that can capture the metabolic dysregulation identifiable by OGTT. In summary, we have identified multiple communities of T2D metabolite biomarkers, representative of distinct pathways that are dysregulated preceding T2D, with potentially clinical useful properties. Disclosure A. Begzati: None. K. P. Godinez Macias: None. J. Watrous: None. T. Long: None. E. Kantz: None. J. Tuomilehto: Stock/Shareholder; Orion pharma. A. S. Havulinna: None. T. Niiranen: Speaker's Bureau; AstraZeneca, Servier Laboratories. P. Jousilahti: None. V. Salomaa: Research Support; Bayer Inc. T. Ideker: None. M. Jain: Employee; Sapient Bioanalytics. A. R. Majithia: None. Funding National Institutes of Health (5R01DK129840-02)

1468-P: Integrating Whole-Genome Sequence Analysis and eQTL Data from the TOPMed Program Improves Understanding of Type 2 Diabetes Risk Loci in Diverse Populations

Type 2 diabetes (T2D) has been well characterized by genetic studies with over 550 risk loci identified in mostly European populations. To better understand the genetic basis of T2D in diverse ancestries, we performed a whole genome sequence association analysis with T2D and related traits of fasting insulin (FI), glucose (FG) and hemoglobin A1c (HbA1c). We then used the colocalization method COLOC to evaluate if the risk locus and expression quantitative trait loci (eQTL) region shared a variant. Four relevant eQTL specific to tissues or cell types were obtained from the NHLBI Trans Omics for Precision Medicine (TOPMed) program, including 6,602 samples for whole blood, 1,265 for peripheral blood mononuclear cells (PBMC), 368 for T cells, and 352 for monocytes. A signal was considered colocalized if the posterior probability of colocalization (PP.coloc) was &amp;gt;0.5. Our analysis included 21,913 prevalent T2D cases, 61,036 controls, and up to 50,201 non-T2D individuals with FG, FI or HbA1c from African, Atlantic Islander, East Asian, European, Hispanic, and Samoan groups. Single variant analysis identified 35 variants in known regions that were significantly associated with T2D or related traits (P &amp;lt; 4.00 × 10−9). Among these regions, we detected six genes (SLC2A2, NKX6-3, KCNQ1, HBB, FN3K, and G6PD) having colocalizing signals in at least one relevant tissue or cell type. For example, variant rs1050828 near G6PD on chromosome X was strongly associated with HbA1c (P &amp;lt;1.0×10−200). Colocalization analysis revealed that rs1050828 also affected the gene expression in various tissues or cell types, including BCAP31 in whole blood, TKTL1 in PBMC, MPP1 in T cell, and RENBP in monocytes. This novel finding, obtained using TOPMed eQTL data from multiple cohorts, suggests a link between risk-associated variation and effector genes, providing insight into potential causal genes and regulatory variants at T2D risk loci in diverse populations. Disclosure N.Wang: None. D.A.Dicorpo: None. Y.Zhang: None. J.Wessel: None. A.Manning: None. Topmed diabetes working group: n/a. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UM1DK078616, R01HL151855)