Incident Type 2 Diabetes Research Articles

Novel Plasma Metabolomic Markers Associated with Diabetes Progression in Older Puerto Ricans.

We assessed longitudinal associations between plasma metabolites, their network-derived clusters, and type 2 diabetes (T2D) progression in Puerto Rican adults, a high-risk Hispanic subgroup with established health disparities. We used data from 1221 participants free of T2D and aged 40–75 years at baseline in the Boston Puerto Rican Health and San Juan Overweight Adult Longitudinal Studies. We used multivariable Poisson regression models to examine associations between baseline concentrations of metabolites and incident T2D and prediabetes. Cohort-specific estimates were combined using inverse-variance weighted fixed-effects meta-analyses. A cluster of 13 metabolites of branched chain amino acids (BCAA), and aromatic amino acid metabolism (pooled IRR = 1.87, 95% CI: 1.28; 2.73), and a cell membrane component metabolite cluster (pooled IRR = 1.54, 95% CI: 1.04; 2.27) were associated with a higher risk of incident T2D. When the metabolites were tested individually, in combined analysis, 5 metabolites involved in BCAA metabolism were associated with incident T2D. These findings highlight potential prognostic biomarkers to identify Puerto Rican adults who may be at high risk for diabetes. Future studies should examine whether diet and lifestyle can modify the associations between these metabolites and progression to T2D.

Is Eating a Greater Diversity of Foods Associated with Lower Incidence of Type 2 Diabetes?: Prospective Analysis of the EPIC-InterAct Case-Cohort Study

ObjectivesHealthy eating includes a diverse diet as this ensures adequate amounts of various nutrients for different metabolic pathways. Dietary diversity may also improve survival and promote metabolic health. However, the impact of dietary diversity on type 2 diabetes (T2D) in heterogenous populations is unknown. We aimed to examine whether greater diversity in total diet and within food groups was related to T2D incidence in multi-country populations. MethodsWe evaluated baseline (1991-1998) self-reported diet data from 23,649 participants (including 10,363 incident events of T2D) from 8 European countries in the EPIC-InterAct study. Incident T2D by 2007 was verified with multiple sources, including objective records in each participating center. We constructed multiple scores for dietary diversity to assess: diversity between food groups (DDS-total5) (range: 0 to 5), and diversity of subtypes of vegetables (DDS-veg) (0 to 4), meats (DDS-meat) (0 to 6), animal protein (DDS-proA) (0 to 8) and plant protein (DDS-proP) (0 to 5). We fitted Prentice-weighted Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) by country and meta-analyzed the country-specific estimates. ResultsIn multivariable-adjusted models, we found a significant association between total dietary diversity (all 5 food groups versus 3 or fewer) and incident T2D (HR 0.86 [95% CI: 0.75–0.98]). Similarly, within the vegetable group and within plant protein group, highest diversity scores were significantly inversely associated with incident T2D (0.90 [0.83–0.98] and 0.78 [0.65–0.93], respectively) compared to lowest scores. Both vegetable diversity and plant-protein diversity were robust to additional statistical adjustment, including food quantity, ratio of saturated to unsaturated fatty acids, prevalent non-communicable diseases and reproductive history. Conversely, greater diversity of animal-protein subtypes was associated with higher T2D incidence, in particular after adjusting for prevalent diseases (1.39 [1.21-1.59]). ConclusionsThis multi-country case-cohort study supports the consumption of diets comprising all 5 food groups as well as diversity of vegetable and plant-protein as a strategy to help prevent diabetes among a European population. Funding SourcesHM is funded by a Canadian Institutes of Health Research Vanier Scholarship.

1184-P: Adolescent Growth Spurt and Type 2 Diabetes Risk in an American Indian Population

Background: Some studies suggest that earlier pubertal development is associated with obesity and metabolic disorders in adulthood, but whether accelerated adolescent linear growth spurt influences type 2 diabetes (T2D) in populations at high risk of diabetes is unclear. Aim: To examine associations of age at initiation of the adolescent growth spurt (i.e., take-off) (ATO) , velocity at take-off (VTO) , and age at peak velocity (APV) with T2D incidence. Methods: Height measurements obtained from a longitudinal study of diabetes in American Indians were used to estimate biological growth parameters using the Preece-Baines growth model I, a parametric model of the human growth curve. Diabetes incidence was analyzed among individuals who had ≥ 4 height examinations at ages 5-17 years and who remained nondiabetic at first examination after age 18. Participants were followed until diabetes developed or last examination. Associations of growth parameters with diabetes incidence were analyzed by Poisson regression. Results: Among 649 originally nondiabetic participants, 135 females and 82 males developed diabetes in a median follow-up of years. With adjustment for age, birth date and maternal diabetes, younger ATO and APV were associated with T2D incidence in males (incidence rate ratio (IRR) =1.75 per year, 95% CI, 1.23, 2.50; and IRR=1.33, 95% CI, 1.01, 1.75, respectively) but not in females (IRR=0.93, 95% CI, 0.75, 1.16; and IRR=1.04, 95% CI, 0.86, 1.26, respectively) . Higher VTO was associated with T2D incidence in males (IRR=1.80 per cm/y, 95% CI, 1.15, 2.81) but not in females (IRR=1.15, 95% CI, 0.88, 1.50) . With further adjustment for adult and childhood BMI and fasting insulin, the associations were attenuated for APV and VTO but remained significant for ATO in males. Conclusion: Our findings suggest that an early and accelerated adolescent growth spurt is a risk factor for T2D, at least in males. These associations are only partially explained by measures of adiposity and insulinemia. Disclosure M.J.Ramirez-luzuriaga: n/a. S.Kobes: None. M.Sinha: None. W.C.Knowler: None. R.L.Hanson: None.

142-OR: Global Extended Polygenic Score Predicts Incident Type 2 Diabetes in Women with History of Gestational Diabetes

Around 30-50% of women with history of gestational diabetes (GDM) develop type 2 diabetes (T2D) within years after parturition. However, the role of polygenetic score on prediction of T2D in these women is still unclear. We aimed to investigate the utility of global extended polygenic scores (gePS) in predicting incident T2D using GDM cohorts from 1) UK Biobank (N=941) , 2) Seoul National University Hospital (SNUH, N=357) , and 3) Korean Genome and Epidemiology Study (KoGES, N=379) . We calculated gePS for T2D using Bayesian regression and continuous shrinkage priors, with summary statistics from representative genome-wide association studies in Europeans and East Asians. We performed time-to-event analysis for incident T2D with gePS and assessed improvement of C-statistic when gePS was added to clinical risk factors. In addition, risk of T2D was estimated for those who were in the top percentile of gePS compared to the remainders. The incidence of T2D was 19.8% in UK Biobank, 28.3% in SNUH, and 23.5% in KoGES cohort with median follow-up duration of 28, 4, and 28 years, respectively. The normalized mean PRS for those who developed T2D was higher in each cohort: 0.25±1.vs. -0.06±0.99 in UK Biobank, 0.22±1.vs. -0.09±0.97 in SNUH, and 0.52±0.96 vs. -0.16±0.96 in KoGES (all P<0.01) . When meta-analyzed, adding gePS to clinical risk factors improved the C statistic from 0.715 (95% confidence interval [CI] 0.658-0.766) to 0.743 (95% CI 0.698-0.784) . The standardized gePS was associated with incident T2D in women with history of GDM when the results of the three cohorts were meta-analyzed: hazard ratio 1.68 (95% CI 1.52-1.86, P<0.001) . Furthermore, those who were in the top percentile had 3.52-fold increased risk of T2D: (95% CI 2.68-4.62, P<0.001) . To sum up, genetic information in women with previous GDM pregnancy could be used to identify those who are at high risk of future development of T2D and provide the opportunity for tailored prevention. Disclosure J.Choi: None. H.Lee: None. M.Han: None. D.Choi: None. H.Jang: None. K.Park: None. S.Kwak: None.

Dietary Patterns, Socioeconomic Status, and Risk of Type 2 Diabetes in the Sister Study

ObjectivesHigher diet quality is associated with decreased risk of type 2 diabetes (T2D). Socioeconomic status (SES) has been associated with measures of diet quality. However, few studies have investigated whether the association between diet quality and T2D differs by SES. MethodsWe used prospective cohort data from 41,280 Sister Study participants aged 35 to 74 years who enrolled in 2003–2009 and were followed until September 2017. The alternate Mediterranean diet (aMED), Dietary Approaches to Stop Hypertension (DASH), alternative Healthy Eating Index (aHEI), and Healthy Eating Index 2015 (HEI-2015)] scores were calculated using baseline data from a 110-item Block food frequency questionnaire previously validated in women. SES was evaluated by individual and neighborhood levels. The Area Deprivation Index (ADI), a census-based index was used to define neighborhood SES. Incident T2D was defined based on self-reported physician’s diagnosis of T2D or use of anti-diabetic medications on annual follow-up questionnaires. Multivariable-adjusted hazard ratios (aHRs) and 95% CIs were estimated using Cox proportional hazards models with age as the primary time scale. Effect modification was evaluated by stratification and including an interaction term in statistical models. ResultsInverse associations between dietary pattern scores and incident T2D were observed across all four dietary indices after adjustment for potential confounders (aMED: aHRQ4vsQ1: 0.64, 95% CI: 0.56, 0.72; DASH: aHRQ4vsQ1: 0.55, 95% CI: 0.49, 0.62; aHEI: aHRQ4vsQ1: 0.54, 95% CI: 0.48, 0.61; aHEI-2015: HRQ4vsQ1: 0.61, 95% CI: 0.55, 0.69). The inverse association between all four dietary indices and T2D risk was most pronounced among women with higher education and income. The inverse association between HEI-2015 and T2D risk was strongest among women with lower ADI (low ADI aHRQ4vsQ1: 0.49, 95% CI: 0.39, 0.61; high ADI aHRQ4vsQ1: 0.70, 95% CI: 0.58, 0.85; pinteraction: 0.003). Estimates from aMED, DASH, and aHEI models were similar. ConclusionsOur findings suggest that healthy eating patterns may reduce the risk of T2D and may have a greater impact among participants with higher individual SES and lower neighborhood deprivation. Funding SourcesNational Institute of Environmental Health Sciences T32 from NIH-NIGMS

Estrogen Protects Cardiac Function and Energy Metabolism in Dilated Cardiomyopathy Induced by Loss of Cardiac IRS1 and IRS2.

Type 2 diabetes (T2D) is a high-risk factor for incident of cardiovascular diseases. Women at young ages show a reduced incidence of both T2D and cardiovascular diseases compared with men, but these disparities disappear in postmenopausal women versus age-matched men. Thus, ovaries and ovarian hormones, such as estrogen, are expected to protect from T2D and cardiovascular diseases. In this study, we aimed to investigate the role of ovaries and ovarian hormone estrogen in cardiac function and energy metabolism using the cardiac IRS (insulin receptor substrate) 1 and IRS2 double genes knockout mice that mimic cardiac insulin resistance. Control and heart-specific IRS1/2 double genes knockout mice were treated with placebo or 17β-estradiol (E2) pellets, respectively, through subcutaneous implantation. Female mice were subjected to a bilateral ovariectomy surgery to remove endogenous E2. The cardiac function and energy metabolism were determined using echocardiography and indirect calorimeter, respectively. All male heart-specific IRS1/2 double genes knockout mice died of heart failure at 6 to 8 weeks as we previously described (Qi et al), but all female heart-specific IRS1/2 double genes knockout mice survived >1 year. Removal of ovaries in heart-specific IRS1/2 double genes knockout female mice resulted in cardiac dysfunction, and ultimately animal death. However, E2 supplementation prevented the dilated cardiomyopathy, improved cardiac function and energy metabolism, and enhanced lifespan in both male and ovariectomy female mice deficient for cardiac IRS1 and IRS2 genes, largely owing to the activation of Akt (protein kinase B)-Foxo1 (O1 class of forkhead/winged helix transcription factor) signaling cascades. These results show that estrogen protects mice from cardiac insulin resistance-induced diabetic cardiomyopathy. This may provide a fundamental mechanism for the gender difference for the incidence of both T2D and cardiovascular diseases. This study highlights that estrogen signaling could be a potential target for improving cardiac function and energy metabolism in humans with T2D.

Youth‐onset type 2 diabetes in Israel: A national cohort

Prevalence of youth-onset type 2 diabetes (T2D) has increased worldwide, paralleling the rise in pediatric obesity. Occurrence and clinical manifestations vary regionally and demographically. We assessed the incidence, and clinical and demographic manifestations of youth-onset T2D in Israel. In a national observational study, demographic, clinical, and laboratory data were collected from the medical records of children and adolescents, aged 10-18 years, diagnosed with T2D between the years 2008 and 2019. The incidence of youth-onset T2D in Israel increased significantly from 0.63/100,000 in 2008 to 3.41/100,000 in 2019. The study cohort comprised 379 individuals (228 girls [59.7%], 221 Jews [58.3%], mean age 14.7± 1.9 years); 73.1% had a positive family history of T2D. Mean body mass index (BMI) z-score was 1.96 ± 0.7, higher in Jews than Arabs. High systolic (≥ 130 mmHg) and diastolic blood pressure (≥ 85 mmHg) were observed in 33.7% and 7.8% of patients, respectively; mean glycosylated hemoglobin (A1c) level at diagnosis was 8.8± 2.5%. Dyslipidemia, with high triglyceride (>150 mg/dl) and low HDL-c (<40 mg/dl) levels, was found in 45.6% and 56.5%, respectively. Microalbuminuria and retinopathy were documented at diagnosis, 15.2% and 1.9%, respectively) and increased (36.7% and 4.6%, respectively) at follow-up of 2.9± 2.1 years. Criteria of metabolic syndrome were met by 224 (62.2%) patients, and fatty liver documented in 65%, mainly Jews. Psychosocial comorbidity was found in 31%. Treatment with metformin (45.6%), insulin (20.6%), and lifestyle modification (18%) improved glycemic control. Youth-onset T2D in Israel has increased significantly and presents a unique profile.

1234-P: Serum Fatty Acid Composition as a Biomarker of Diabetes Development: Tokushima Cohort Study

Few prospective cohort studies still exist on the association between serum fatty acid (FA) proportions and the enzymes involved in their synthesis and the onset of type 2 diabetes (T2D) . Thus, the aim of the present study was to investigate whether or not serum FA proportions or FA ratios, which reflect desaturase activities, are associated with the incidence of T2D. Here we analyzed data of a prospective cohort study, which was conducted during 2010-20in Japan. A total of 872 male workers without diabetes aged over 20 years were followed up prospectively. Diabetes was defined as having either: 1) fasting plasma glucose ≥ 126 mg/dl, 2) HbA1c ≥ 6.5%, 3) medication for hyperglycemia or 4) postprandial plasma glucose ≥ 200 mg/dl during the follow-up period. We measured serum FA levels and estimated the activity of ⊿5desaturase (D5D) by calculating the ratio of serum arachidonic acid to dihomo-γ-linolenic acid (DGLA) . The subjects were also divided into two groups by the cutoff point of waist circumference (WC) ≥ 90 cm. In multivariate analysis, the HR of developing diabetes was 2.81 [95%CI: 1.to 7.15, P=0.03] in the highest quartile of serum DGLA proportion and 0.28 [95%CI: 0.to 0.90, P=0.03] in the highest quartile of D5D, compared with their lowest quartiles, respectively. In stratified analysis, the multivariate adjusted risk of diabetes was higher in participants with low D5D/low WC (2.56 [0.96 to 6.82]) or high D5D/high WC (2.77 [0.68 to 11.32]) , and was significantly higher in participants with low D5D/high WC (6.30 [1.95 to 20.33, P=0.002]) than in participants with high D5D/low WC. Our findings suggest that the combination of increased serum DGLA proportion and attenuated D5D activity is a risk factor for the incidence of diabetes in male Japanese, especially in those with WC ≥ 90 cm. Thus, the significance of serum FA measurements in predicting T2D is suggested. Disclosure A.Hata: None. N.Aki: None. T.Ichihara: None. A.Tamura: None. T.Minagawa: None. Y.Kuwamura: None. M.Funaki: Board Member; Mechanogenic, Inc. Funding Grants-in-aid for research from Tokushima Prefecture Local Government

1271-P: The Gut Microbiota Related Genetic Variant at ABO Locus, Circulating Metabolome, and Type 2 Diabetes Risk: Prospective Study in UK Biobank

Background: Gut microbiota has been implicated in the development of type 2 diabetes (T2D) . A recent genome-metagenome-wide study identified that genetic variants at the ABO locus (SNPs rs3758348, rs8176632, rs602662, and rs601338) were associated with the abundance of the gut microbiome. This study aimed to investigate whether the gut microbiota-related genetic variants at the ABO locus were associated with T2D and blood metabolome. We also analyzed the associations of the gut microbiota-related Metabolomic Risk Score (MRS) with incident T2D. Methods: A total of 456,274 participants who are free of T2D at baseline and have available data on genetic variants from the UK Biobank population were included in this study. Plasma metabolome was profiled by a high-throughput NMR-based metabolic biomarker profiling platform among 109,0 participants. The MRS score was constructed with genetic variant-associated metabolites. Results: We observed that the gut microbiota-related variant rs3758348 was significantly associated with T2D in the fully adjusted model (hazard ratio [HR] per copy of the C allele 1.06; [95% CI, 1.02-1.10]; P=0.0012 for trend) . We found that a total of 91 metabolites were significantly associated with rs3758348 (false discovery rate &amp;lt; 0.05) . Using elastic net regularized regressions, we generated a weighted MRS applying the 91 metabolites to predict the incidence risk of T2D. In multivariable Cox regressions, the weighted MRS showed a significant association with T2D incidence after adjusting for age, sex, BMI, alcohol status, smoking status, physical activity, and diet quality score (HR=1.49 [95% CI, 1.41-1.59], P&amp;lt;0.0001) . Conclusion: Our study indicates that the gut microbiota-related genetic variant and metabolomic profile significantly predict T2D risk, independent of traditional risk factors. Disclosure R.Tang: None. X.Wang: None. H.Ma: None. X.Li: None. Y.Heianza: None. L.Qi: None. Funding National Heart, Lung, and Blood Institute (HL071981, HL034594, HL126024) , the National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, DK100383) , the Fogarty International Center (TW010790) , and Tulane Research Centers of Excellence Awards.

Trait-anger, hostility, and the risk of incident type 2 diabetes and diabetes-related complications: a systematic review of longitudinal studies

IntroductionThere is a well-established association between anger, hostility, and an increased risk of cardiovascular disease. Emerging evidence also suggests associations between anger/hostility and type 2 diabetes (T2D), though evidence from longitudinal studies has not yet been synthesized.ObjectivesTo systematically review findings from existing prospective cohort studies on trait anger/hostility and the risk of T2D and diabetes-related complications.MethodsElectronic searches of MEDLINE (PubMed), PsychINFO, Web of Science, and CINAHL were performed for articles/abstracts published up to December 15, 2020. Peer-reviewed longitudinal studies conducted with adult samples, with effect estimates reported for trait anger or hostility and incident T2D or diabetes-related complications, were eligible for inclusion. Risk of bias/study quality was assessed. The review protocol was published a priori in PROSPERO (CRD42020216356) and was in keeping with PRISMA guidelines. Screening for eligibility, data extraction, and quality assessment was conducted by two independent reviewers.ResultsFour studies with a total of 155,146 participants met the inclusion criteria. A narrative synthesis of extracted data was conducted according to the Synthesis Without Meta-Analysis guidelines. While results were mixed, our synthesis suggested a positive association between high trait-anger/hostility and increased risk of incident T2D. No longitudinal studies were identified relating to anger/hostility and incident diabetes-related complications. Geographical locations of the study samples were limited to the USA and Japan.ConclusionsFurther research is needed to investigate whether trait-anger/hostility predicts incident type 2 diabetes after adjustments for potential confounding factors. Longitudinal studies are needed to investigate trait-anger/hostility and the risk of diabetes-related vascular complications.DisclosureNo significant relationships.

1122-P: Subgroup Analysis to Evaluate Individuals at Risk for Incident Diabetes

Since type 2 diabetes (T2D) is a heterogenous disease, treatment of T2D appears to be better personalized depending on their underlining conditions. A recent attempt to classify adult-onset DM based on only 6 DM related variables (GAD antibodies, age at diagnosis, BMI, HbA1c, and HOMA2 indices) , showed that DM can be classified into 5 clusters, among them 4 represent T2D (Lancet Diabetes Endocrinol. 2018;6:361) . We here classified non-diabetic population to find risk cluster for incident DM, or to extend strategies for prevention of T2D. The participants were recruited from Iwaki study, a health promotion study of Japanese people. Among 1167 participants in 2014 (baseline) , 868 non-diabetic individuals who attended at least one time in 2015 to 20were included in this prospective study. A hierarchical cluster analysis was performed based on 5 variables (age, BMI, HbA1c, HOMA2-β, and HOMA2-IR) . The hazard ratios (HRs) for incident T2D of clusters observed were examined using Cox proportional hazards model. Traits (mean) of 5 clusters observed were as follows: age (clusters; 1: 60.1, 2: 58.7, 3: 63.6, 4: 36.1, 5: 48.3) , BMI (1: 20.8, 2: 24.2, 3: 22.9, 4: 20.7, 5: 27.7) , HbA1c (1: 5.54, 2: 5.67, 3: 6.01, 4: 5.41, 5: 5.73) , HOMA2-β (1: 82.8, 2: 101.8, 3: 78.5, 4: 101.4, 5: 143.1) , and HOMA2-IR (1: 0.53, 2: 0.79, 3: 0.73, 4: 0.57, 5: 1.16) . The HR for incident T2D was significantly higher in cluster 3 than in clusters 1, 2, and 4, even after adjustment for age and sex (HR (p) : 5.00 (0.005) , 4.90 (0.005) , and 10.4 (0.048) , respectively) . Accordingly, cluster 3 had significantly higher age and HbA1c than other clusters, lower HOMA2-β than clusters 2, 4, and 5, and lower HOMA2-IR and BMI than clusters 2 and 5. In summary, cluster analysis of a general non-diabetic population revealed a risk cluster for incident T2D, and, thus, individuals with characteristics representing the cluster (less insulin resistant but decreased insulin secretion, older age, and poor metabolic control) should be a target for prevention of incident T2D. Disclosure R.Ito: None. M.Daimon: None. S.Mizushiri: None. S.Ono: None. Y.Nishiya: None. A.Tamura: None. M.Murabayashi: None. A.Kamba: None.

1185-P: Low Birth Weight Is Associated with a Nongenetic Higher Incidence Rate of Type 2 Diabetes

Background: Low birth weight, indictive of a poor fetal environment, is a risk factor for type 2 diabetes (T2D) . Most previous studies were based on cross sectional prevalence data and not designed to study the timing of onset of T2D in relation to birth weight (BW) . Furthermore, earlier studies have not adjusted for common genetic variation influencing BW. We aimed to examine associations of BW with age-specific incidence of T2D using BW polygenetic risk scores (BWPRS) to adjust for genetic confounding. Methods: Adults (30-60 years) enrolled in the Inter99 cohort from 1999-20with information on BW from original birth records, and without diabetes at baseline were eligible. Birth records were linked with individual-level data on T2D incidence from the Danish Diabetes Register and key covariates from the Inter99 study. Incidence rates of T2D as a function of age, sex and BW were modelled using Poisson regression and adjusted for adult BMI, socioeconomic status, maternal history of diabetes and BWPRS. Results: Among 4584 participants there were 438 incident cases of T2D during a mean follow-up of 18 years. BW was inversely associated with T2D with a higher incidence in men. T2D incidence increased with age and the rate of increase was higher in persons with lower BW compared with higher BW in a dose-response manner. Conclusion: A lower birth weight is associated with a greater increase in incidence rate of T2D in a non-genetic manner. Disclosure R.Wibaek: Stock/Shareholder; Novo Nordisk A/S. G.S.Andersen: Stock/Shareholder; Novo Nordisk A/S. A.Linneberg: None. N.Grarup: None. T.Hansen: None. C.Brøns: Stock/Shareholder; Novo Nordisk. D.Vistisen: Research Support; Bayer AG, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi, Stock/Shareholder; Novo Nordisk A/S. A.A.Vaag: Stock/Shareholder; AstraZeneca. Funding Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation (NNF17SA0031406)

1-LB: Trends in Incidence and Age at Diagnosis of Youth-Onset Type 2 Diabetes, 2002–2018—The SEARCH for Diabetes in Youth Study

The SEARCH study ascertained individuals with type 2 diabetes (T2D) diagnosed at &amp;lt;20 years of age at 5 study centers in the US from 2002 to 2018 and calculated annual incidence as number of cases divided by the population &amp;lt;20 years in the catchment area (∼5 million annually based on US Census or health-plan member counts) . We estimated incidence trends using a generalized autoregressive (2-year) moving average model. From annual incidence, we calculated peak age at T2D diagnosis overall population and within period, sex, race and ethnicity strata. Incidence increased from 2002-2009 to 2010-2018 (p&amp;lt;0.0001) ; however, the peak age at diagnosis did not change (16 years; Figure) . Across all years, the peak age at diagnosis was similar between females (16 years [95% CI 15-18]) and males (16 years [16-18]) . The peak age at diagnosis was younger for non-Hispanic Black youth (NHB; 13 years) , while similar for American Indian (AI) , Asian and Pacific Islander (API) , Hispanic (HISP) , and non-Hispanic White (NHW) youth (16 years; Figure) . These data indicate continued increases in T2D incidence across ages associated with the pubertal transition, with a rapid decline following the incidence peak. They also highlight an earlier T2D onset among NHB youth. These results highlight the need for pre-pubertal or early pubertal intervention to mitigate risk of youth-onset T2D. Disclosure K. A. Sauder: None. A. Bellatorre: None. J. M. Lawrence: None. J. Divers: None. E. T. Jensen: Consultant; Regeneron Pharmaceuticals Inc. L. E. Wagenknecht: None. A. D. Liese: None. D. Dabelea: None. S. M. Marcovina: None. C. Pihoker: None. K. Reynolds: Research Support; Amgen Inc., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation. A. S. Shah: None. L. M. Dolan: None. Funding Centers for Disease Control and Prevention and National Institutes of Health

159-LB: The Lipidomic Signature of Prediabetes among the Oldest Old—The Long Life Family Study

The epidemiology of prediabetes and its metabolomic features remain poorly characterized in the oldest old. Therefore, we characterized the serum lipidome in 635 nonagenarians and centenarians without type 2 diabetes (T2D) from the Long Life Family Study, a multicenter study of 583 families with a clustering of exceptional longevity. Despite a low T2D prevalence and incidence in the LLFS cohort, 361 (56.9%) of participants aged 90+ years had prediabetes at study entry based on either glycated hemoglobin or fasting serum glucose levels. We used LC/MS to initially assess 193 lipid metabolites in fasting serum in those with and without prediabetes. We tested the association of log transformed lipid metabolites with prediabetes using logistic regression with the Benjamini-Hochberg false-discovery rate method (FDR&amp;lt;0.05) , while adjusting for age, sex, fasting time, field center, and familial relatedness. 17 out of 193 annotated lipid metabolites were associated with prevalent prediabetes, with the strongest association found for phosphatidylethanolamine (PE 40:7) , which remained significant after additional adjustment for BMI (odds ratio (OR) =2.83; 95% confidence interval (CI) : 1.7-4.7) . Phosphatidylethanolamine might have proinflammatory properties and act as a positive modulator of membrane disruption induced by islet amyloid polypeptide, an amyloidogenic protein involved in T2D. Our data suggest that among the oldest old with exceptional longevity prediabetes burden is high, and that the phosphatidylethanolamine pathway might have an important role in the development of prediabetes. Future untargeted metabolomic analyses will investigate potential biomarkers that predict the transition from prediabetes to diabetes among the oldest old in this unique family study of healthy aging and exceptional longevity. Disclosure I. Miljkovic: None. R. Cvejkus: None. P. An: None. B. Thyagarajan: n/a. J. Mengel-from: None. M. Feitosa: None. A. N. Benbourenane: None. J. M. Zmuda: None. Funding National Institute of Health (U01AG023746)

Associations between exploratory dietary patterns and incident type 2 diabetes: a federated meta-analysis of individual participant data from 25 cohort studies

PurposeIn several studies, exploratory dietary patterns (DP), derived by principal component analysis, were inversely or positively associated with incident type 2 diabetes (T2D). However, findings remained study-specific, inconsistent and rarely replicated. This study aimed to investigate the associations between DPs and T2D in multiple cohorts across the world.MethodsThis federated meta-analysis of individual participant data was based on 25 prospective cohort studies from 5 continents including a total of 390,664 participants with a follow-up for T2D (3.8–25.0 years). After data harmonization across cohorts we evaluated 15 previously identified T2D-related DPs for association with incident T2D estimating pooled incidence rate ratios (IRR) and confidence intervals (CI) by Piecewise Poisson regression and random-effects meta-analysis.Results29,386 participants developed T2D during follow-up. Five DPs, characterized by higher intake of red meat, processed meat, French fries and refined grains, were associated with higher incidence of T2D. The strongest association was observed for a DP comprising these food groups besides others (IRRpooled per 1 SD = 1.104, 95% CI 1.059–1.151). Although heterogeneity was present (I2 = 85%), IRR exceeded 1 in 18 of the 20 meta-analyzed studies. Original DPs associated with lower T2D risk were not confirmed. Instead, a healthy DP (HDP1) was associated with higher T2D risk (IRRpooled per 1 SD = 1.057, 95% CI 1.027–1.088).ConclusionOur findings from various cohorts revealed positive associations for several DPs, characterized by higher intake of red meat, processed meat, French fries and refined grains, adding to the evidence-base that links DPs to higher T2D risk. However, no inverse DP–T2D associations were confirmed.

1209-P: Genetic Subtypes of Prediabetes, Healthy Lifestyle, and Risk of Type 2 Diabetes in U.S. Hispanics

Prediabetes is a heterogenous metabolic condition. We calculated 5 pathway-based partitioned polygenetic risk scores (pPRS: beta-cell, proinsulin, obesity, lipodystrophy and liver/lipid scores) based on 94 type 2 diabetes (T2D) -associated variants in 3677 individuals with prediabetes from the Hispanic Community Health Study/Study of Latinos. Based on these 5 pPRS, we identified 6 subtypes of prediabetes (n=488∼742 in each cluster) with different pPRS patterns by consensus clustering (Fig 1A) . Phenotypic patterns were consistent with pPRS patterns in these subtypes (Fig 1B; e.g., Cluster 1 had much lower beta-cell score, higher obesity and liver/lipid scores, and higher HOMA-B, BMI and HOMA-IR compared to other clusters) . These subtypes had similar levels of fasting glucose, HbA1c and 2h glucose at baseline but different risk of incident T2D over 6 years (Fig 1C) . Individuals in Cluster 6 featured with a very low proinsulin score had the highest risk of T2D (RR=1.42 [95% CI 1.13, 1.80] compared to Cluster 1) . We examined the association between a lifestyle score, using BMI, alcohol intake, smoking, physical activity and diet, and risk of T2D across 6 subtypes and found significant associations only in Cluster 1 (RR=0.76 [0.62, 0.93]) and Cluster 5 (RR=0.79 [0.67, 0.92]) . In US Hispanics, we identified 6 genetic subtypes of prediabetes which may differ in the development of T2D and benefits from healthy lifestyle. Disclosure Y.Li: None. T.Wang: None. J.D.Kaufman: None. R.Kaplan: None. Q.Qi: None. G.Chen: None. J.Moon: None. D.Sotres-alvarez: None. M.L.Daviglus: None. A.Pirzada: n/a. J.Mattei: None. K.M.Perreira: None. S.Wasserthei-smoller: None.

190-LB: Vaspin—A Novel Predictor of Type 2 Diabetes Risk

Vaspin (visceral adipose tissue-derived serpinA12) is an adipokine suspected to be involved in type 2 diabetes (T2D) pathogenesis, linking obesity and T2D. We sought to assess epidemiological and genetic associations of vaspin with T2D and related variables. We assessed the relationship of body-mass index (BMI) and waist-hip ratio (WHR) and plasma vaspin concentration, along with the relationship between plasma vaspin and adiposity-related variables and T2D in (i) a case-cohort within the Prospective Urban and Rural Epidemiology (PURE) prospective multi-country study (N=10,052) , and (ii) the Outcome Reduction with Initial Glargine Intervention (ORIGIN) Trial (N=7,840) of participants with dysglycemia. We next investigated the predictive value of vaspin for T2D risk. All models adjusted for age, sex, and ethnicity. Using two-sample Mendelian randomization (MR) , we analyzed if genetically higher vaspin is causal for T2D. The MR analysis used 34 independent genetic variants (linkage disequilibrium r2&amp;lt;0.1) associated with vaspin concentration in PURE (N=3,513) , estimating their effect on BMI-adjusted T2D risk in the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium (N=898,130) . In PURE, a 1 unit increase in BMI and WHR was associated with a 0.01 SD (95% CI 0.01 - 0.02; P = 2.04x10−15) and 0.45 SD (95% CI, 0.21 - 0.70; P = 2.87 × 10−4) increase in plasma vaspin respectively. A 1 SD increase in plasma vaspin was associated with higher triglycerides (0.09 mmol/L; 95% CI, 0.07 - 0.12, P = 4.08x10−13) . Directionally-consistent associations were observed in ORIGIN. A 1 SD increase in plasma vaspin was associated with a 19% increase in incident T2D risk in PURE (HR, 1.19; 95% CI, 1.12 - 1.26; P = 6.36x10−8) and a 16% increase in prevalent T2D in ORIGIN (OR, 1.16; 95% CI, 1.07 - 1.25; P = 2.17x10−4) . Sensitivity analyses showed vaspin's specificity for T2D. Genetically-higher vaspin was associated with increased BMI-adjusted T2D risk (OR, 1.02; 95% CI, 1.00 - 1.03; P = 5.46x10−3) . Our data suggests that vaspin is a predictor for T2D risk, a modest causal factor for T2D development, and might represent a potential T2D therapeutic target. Disclosure H. Wang: None. M. Chong: None. N. Perrot: None. J. Feiner: None. S. Hess: Employee; Sanofi. S. Yusuf: None. H. C. Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk, Sanofi. G. Pare: Advisory Panel; Amgen Inc., Bayer AG, Sanofi, Research Support; Bayer AG. M. Pigeyre: n/a. Funding PURE biomarker study was sponsored by Bayer and CIHR. Origin (NCT00069784) and the biomarker-substudy in Origin were sponsored by Sanofi and CIHR.

Fractures in type 2 diabetes confer excess mortality: The Dubbo osteoporosis epidemiology study.

Diabetes and fractures are both associated with increased mortality, however the effect of the combination is not well-established. We examined the mortality risk following all types of fractures in type 2 diabetes (T2D). In the Dubbo Osteoporosis Epidemiology Study (1989-2017), participants were grouped according to T2D and/or incident fracture. Study outcome was all-cause mortality. First incident radiological fragility fracture and incident T2D diagnosis were time-dependent variables. Cox's proportional hazards models quantified mortality risk associated with T2D and incident fracture overall, as well as by fracture site, T2D duration and T2D medication type. In 3618 participants (62% women), 272 had baseline and 179 developed T2D over median 13.0 years (IQR 8.2-19.6). 796 women (56 with T2D) and 240 men (25 with T2D) sustained a fracture. Compared to those without T2D or fracture, mortality risk increased progressively, in T2D without fracture, then no T2D with fracture, and was highest in those with T2D with fracture (adjusted hazard ratio (aHR) (95% CI) for women 2.62 (1.75-3.93) and men 2.61 (1.42-4.81)). Within T2D participants, incident fracture was associated with increased mortality (aHR for women 1.87 (1.10-3.16) and men 2.83 (1.41-5.68)), especially following hip/vertebral fractures in men (aHR 2.97 (1.29-6.83)) and non-hip non-vertebral fractures in women (aHR 2.42 (1.24-4.75)), and in T2D duration >5 years. Any fracture in T2D conferred significant excess mortality. Individuals with T2D should be carefully monitored post-fracture, especially if T2D >5 years. Optimising fracture prevention and post-fracture management in T2D is critical and warrants further studies.

Association of alcohol drinking with incident type 2 diabetes and pre-diabetes: The Guangzhou Biobank Cohort Study.

We examined associations of baseline alcohol drinking with incident type 2 diabetes (T2D) or impaired fasting glucose (IFG), and explore whether the associations were modified by genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2) and alcohol dehydrogenase-1B (ADH1B). All participants were aged 50+ (mean=60.45; standard deviation=6.88) years. Information of alcohol consumption was collected at baseline from 2003 to 2008. Incident T2D was defined as fasting glucose ≥7.0mmol/L or post-load glucose ≥11.1mmol/L at follow-up examination (2008-2012), self-reported T2D and/or initiation of hypoglycaemia medication or insulin during follow-up. Impaired fasting glucose was defined as fasting glucose ≥5.6mmol/L and <7mmol/L. Of 15,716 participants without diabetes and 11,232 participants without diabetes and IFG at baseline, 1624 (10.33%) developed incident T2D and 1004 (8.94%) developed incident IFG during an average 4years of follow-up. After multivariable adjustments, compared with never drinking, occasional or moderate alcohol drinking was not associated with risk of incident hyperglycaemia (T2D+IFG) (odds ratio (OR)=1.10, 95% confidence interval (CI) 0.95-1.27, and 0.90 (0.69-1.18), respectively), whereas heavy alcohol drinking was associated with a higher risk of incident hyperglycaemia (T2D+IFG) (OR=1.82, 95% CI 1.24-2.68). No interactions of sex, overweight/obesity and genetic polymorphisms of ADH1B/ALDH2 genes with alcohol drinking on incident T2D and/or IFG were found (P for interaction from 0.12 to 0.85). Our results support a detrimental effect of heavy alcohol use on IFG and T2D. No protective effect was found for those carrying lower risk alleles for ADH1B/ALDH2 genes.

Prospective association between dietary pesticide exposure profiles and type 2 diabetes risk in the NutriNet-Santé cohort

BackgroundStudies focusing on dietary pesticides in population-based samples are scarce and little is known about potential mixture effects. We aimed to assess associations between dietary pesticide exposure profiles and Type 2 Diabetes (T2D) among NutriNet-Santé cohort participants.MethodsParticipants completed a Food Frequency Questionnaire at baseline, assessing conventional and organic food consumption. Exposures to 25 active substances used in European Union pesticides were estimated using the Chemisches und Veterinäruntersuchungsamt Stuttgart residue database accounting for farming practices. T2D were identified through several sources.Exposure profiles were established using Non-Negative Matrix Factorization (NMF), adapted for sparse data. Cox models adjusted for known confounders were used to estimate hazard ratios (HR) and 95% confidence interval (95% CI), for the associations between four NMF components, divided into quintiles (Q) and T2D risk.ResultsThe sample comprised 33,013 participants aged 53 years old on average, including 76% of women. During follow-up (median: 5.95 years), 340 incident T2D cases were diagnosed.Positive associations were detected between NMF component 1 (reflecting highest exposure to several synthetic pesticides) and T2D risk on the whole sample: HRQ5vsQ1 = 1.47, 95% CI (1.00, 2.18). NMF Component 3 (reflecting low exposure to several synthetic pesticides) was associated with a decrease in T2D risk, among those with high dietary quality only (high adherence to French dietary guidelines, including high plant foods consumption): HRQ5vsQ1 = 0.31, 95% CI (0.10, 0.94).ConclusionsThese findings suggest a role of dietary pesticide exposure in T2D risk, with different effects depending on which types of pesticide mixture participants are exposed to. These associations need to be confirmed in other types of studies and settings, and could have important implications for developing prevention strategies (regulation, dietary guidelines).Trial RegistrationThis study is registered in ClinicalTrials.gov (NCT03335644).