Risk Of Type 2 Diabetes Research Articles

Abstract P496: Proteomic BMI Signature and Incidence of Type 2 Diabetes

Background: Obesity exhibits heterogeneity in physiological states and metabolic phenotypes cross individuals. A recent study identified a proteomics signature of obesity which better captures such heterogeneity than classical Body Mass Index (BMI). Aims: We aimed to create a proteomics-inferred BMI signature and investigate whether the proteomic-inferred BMI was associated with incident Type 2 Diabetes (T2D). Methods: This study included 34,317 adults in the UK Biobank who were free of T2D and had complete data on proteomics metrics assessed by antibody-based Olink assay. Sixty-seven pre-identified proteins were available and used to create the proteomic BMI signature. Cox proportional models were used to estimate the association between proteomic BMI signature and incident T2D. Results: The proteomic BMI signature was strongly correlated with actual BMI (Pearson correlation coefficients=0.75, P <0.001). During a mean follow-up of 13.2 years, a total of 1,651 T2D events were documented. We observed that per standard deviation increase in proteomic BMI signature was significantly associated with a 250% higher risk of T2D (HR, 2.50, 95%CI, 2.37, 2.64). Compared with the lowest Quartile, the HR (95%CI) for the Quartile 2 to the Quartile 4 of proteomic BMI signature were 2.06 (1.61, 2.64), 3.56 (2.83, 4.48), and 10.0 (8.08, 12.4), respectively ( P -trend<0.001). Also, we observed that the associations between proteomic BMI signature and incident T2D were stronger in women than men ( P for interaction < 0.001). Compared with the lowest Quartile, the HR (95%CI) for highest Quartile of proteomic BMI signature were 16.63 (9.75, 28.36) for women and 8.06 (6.37, 10.19) for men. Conclusions: Higher proteomics-inferred BMI was significantly associated with higher risk of incident T2D, and such association was stronger in women than men. Our results suggest that proteomic BMI signature may serve as a surrogate metabolic indicator to better understand the mechanism underlying the association of BMI and T2D.

Abstract P432: Validation and Optimization of the American Diabetes Association Score for Undiagnosed Type 2 Diabetes Risk in Hispanic or Latino Adults

Background: The prevalence of type 2 diabetes (T2D) is increasing in Hispanic or Latino adults. The American Diabetes Association (ADA) score to identify current risk of T2D was developed with limited Hispanic or Latino representation. Therefore, we sought to validate the ADA score in a cohort of Hispanic or Latino adults. Methods: At enrollment in the Sangre Por Salud Biobank, 3,625 Hispanic or Latino adults from Phoenix, Arizona completed a baseline questionnaire. Current risk of undiagnosed T2D was based on non-laboratory risk factors and ADA score ≥5 (Table). Participants also completed T2D screening (ie, fasting glucose, 2-hour oral glucose tolerance test, and/or hemoglobin A1c). Undiagnosed T2D was based on 'no self-reported T2D but meeting T2D diagnostic’ criteria. Multivariable logistic regression analyzed associations of ADA risk factors and undiagnosed T2D, and model performance was based on sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: At enrollment, 7.3% of participants had undiagnosed T2D (n=265/3,625). In multivariable analysis, most risk factors described for the ADA score were significantly associated with T2D, except for sex, which showed no association. ADA score ≥5 had sensitivity 50%, specificity 79%, PPV 18%, and NPV 95%. However, ADA score ≥4 had sensitivity 72%, specificity 61%, PPV 14%, and NPV 96%. ADA score ≥4 vs ≥5 identified 22% (n=59) additional cases of undiagnosed T2D. Furthermore, using the revised definition for elevated blood pressure (>120/80 mmHg) vs ≥140/90 mmHg (current ADA score) further improved the ADA score ≥4 (sensitivity 81%; specificity 52%). Other scores had lower performance using both hypertension definitions. Conclusion: In Hispanic or Latino adults, a lower ADA score than currently recommended identified additional cases of undiagnosed T2D. The ADA score requires validation and recalibration, including for the updated hypertension guidelines.

Abstract P131: Individualized Risk Prediction for Type 2 Diabetes: A Secondary Analysis of the Diabetes Prevention Program

Introduction: Type 2 diabetes (T2D) risk prediction models that predict risk with individualized preventive intervention effects can help targeted prevention. Hypothesis: An individualized T2D risk prediction model developed in the Diabetes Prevention Program (DPP) randomized trial that incorporates differential treatment effects based on an individual’s fasting glucose (FG) level and body mass index (BMI) will provide more accurate predictions than a model without individualized treatment effects. Methods: We included 2640 DPP participants randomized to the placebo, metformin, or lifestyle arms. Using 50% of the DPP sample, we developed a non-individualized Cox model predicting T2D risk over 3 years with adjustment for sex, hemoglobin A1c, triglycerides, FG, BMI, and treatment, and an individualized model with adjustment for these variables plus interactions between treatment and age, FG, and BMI. In the remaining 50%, we evaluated the prediction accuracy of both models using the concordance (C)-statistic. We repeated this process 100 times with different random splits. We externally validated models among Multi-Ethnic Study of Atherosclerosis (MESA) adults with prediabetes (n=1067) where model predictions were computed for each intervention scenario and averaged for all participants. Results: Mean (standard deviation) age of participants was 51 (11) years in the DPP and 64 (10) in MESA, with 67% and 54% women, respectively. Mean C-statistics for our individualized and non-individualized prediction models (100 splits) in DPP were 0.71 and 0.70, respectively (table). The individualized model predicted higher benefit of lifestyle intervention at lower BMI levels and higher benefit of both metformin and lifestyle at higher FG. The C-statistic of the individualized model was 0.78 in the MESA validation. Conclusion: Creating individualized estimates of intervention effects can improve accuracy of T2D risk prediction models, allowing patients to make more informed decisions about prevention strategies.

Abstract P429: Coffee Intake is Associated With Enhanced Insulin Sensitivity, Lower Post-Load Glucose Responses, and Lower Truncal Adiposity

Higher coffee consumption has been associated with lower type 2 diabetes (T2D) risk, but the underlying mechanisms remain unclear. We tested the hypothesis that coffee intake is associated with improved glycemia insulin sensitivity, and reduced adiposity. We leveraged data in the VITamin D and OmegA-3 Trial (VITAL), a completed placebo-controlled 5-year trial including 25871 participants. Coffee intake was assessed by a diet questionnaire at baseline and year 2. In the VITAL clinical subcohort (n= 1054), glucose metabolism and insulin resistance were assessed by a 2-hr oral glucose tolerance test, body composition was measured by the dual X-ray absorptiometry, at baseline and year 2. We analyzed the association of coffee intake with glycemic traits and body composition, leveraging repeated assessments using multivariable-adjusted linear mixed models. Secondarily, we tested associations between coffee intake and T2D risk, in 22327 initially T2D-free individuals (482 cases in 5 years of follow-up) using multivariable-adjusted Cox regression. While coffee intake was not associated with fasting glucose or insulin levels, it was significantly associated with lower levels of 2-hr post-load glucose (SD difference per cup increment β = -0.062, P = 0.04) and insulin (β = -0.064, P = 0.02), and a higher metabolic clearance rate of glucose (β= 0.057, P = 0.007) and insulin sensitivity index (β= 0.059, P = 0.02). The associations were consistent for caffeinated and decaffeinated coffee. Further, caffeinated coffee intake was associated with higher body weight (β= 0.018, P = 0.02), but total coffee intake was associated with a lower truncal to limb fat ratio before and after adjusting for BMI (β= -0.057, P = 0.03). We did not observe evidence of association with incident T2D (HR =0.63; 95% CI 0.15-2.50). Higher coffee intake was associated with improved post-load glucose metabolism and insulin sensitivity, and lower truncal adiposity. The figure displays result estimates of linear mixed models. Asterisks represent associations P < 0.05.

Abstract P207: Blood Metabolomic Signatures of 24-hr Urinary Sodium and Potassium Excretion Were Associated With Cardiometabolic Diseases in the Hispanic Community Health Study/Study of Latinos

Background: 24hr urinary sodium (Na) potassium (K) excretions are considered as accurate measures of sodium and potassium intake, but data are limited in large population-based studies due to the difficulties of 24hr urine sample collection. Hypothesis: 24hr urinary Na and K excretion can be predicated by blood metabolomic signatures, which are associated with the risk of cardiometabolic diseases. Methods: We assessed 24hr urinary Na, K excretion and sodium/potassium ratio (Na/K) in 447 apparently healthy individuals from the SOL-Nutrition & Physical Activity Assessment Study (SOLNAS) of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We calculated urinary Na, K excretion, and Na/K metabolite scores by using the Least Absolute Shrinkage and Selection Operator regression on 199 serum metabolites in SOLNAS, and evaluated their associations with incident CVD (heart failure, stroke, myocardial infarction), type 2 diabetes (T2D), and hypertension (HTN) in up to 5738 individuals in HCHS/SOL. Results: There were 41, 22, and 71 metabolites selected to be predictive of urinary Na, K excretion, and Na/K, respectively. Metabolite scores were significantly correlated with measured urinary Na (r=0.35, p < 5e -14 ), K (r=0.58, p< 5e -50 ) excretion and Na/K (r=0.6, p< 5e -50 ). After multivariate adjustment, metabolite scores of urinary Na excretion and Na/K were significantly associated with incident CVD risk (hazard ratio=2.6 for Na and 1.91 for Na/K, per 1 SD increase in score), incident T2D (relative risk [RR]=1.33 for Na and 1.16 for Na/K), and incident HTN (RR=1.53 for Na and 1.35 for Na/K) over a median 7.6 years of follow-up. The metabolite score of urinary K excretion was not associated with CMD risk. Conclusion: In US Hispanics/Latinos, higher levels of 24hr urinary Na excretion and Na/K indicated by blood metabolomics signatures were associated with increased risk of CVD, HTN, and T2D.

Abstract MP29: Ready-to-Eat Food Environment and Risk of Incident Type 2 Diabetes: A Prospective Cohort Study

Introduction: Access to environments providing ready-to-eat food has been linked with a higher prevalence of type 2 diabetes (T2D), however, no study has prospectively assessed the food environment with T2D incidence. Hypothesis: We hypothesized that being exposed to ready-to-eat food environments was prospectively associated with a higher risk of developing T2D. Method: The current study included 480,909 participants free of T2D at baseline from the UK Biobank. Individual food environment variables, including pubs or bars, restaurants or cafeterias, and fast-food outlets, were objectively measured within 1 km catchment areas of the residential street of the participants. A composite food environment variable was created as the sum of the density of all three individual food environment variables. Cox proportional hazard model was used to assess the prospective relationship between the ready-to-eat food environments and incident T2D. Results: During a median of 12 years of follow-up, a total of 28,762 T2D cases were documented. Being exposed to a higher density of ready-to-eat food environments was associated with a higher risk of developing T2D ( Table ): HR = 1.22 (95% CI: 1.16-1.27) for comparing the extreme categories of pubs and bars density; HR=1.05 (95% CI: 1.00-1.10) for restaurants and cafeterias, and HR=1.14 (95% CI: 1.09-1.18) for fast-food outlets. Being exposed to the highest density of a composite food environment was associated with a 26% higher risk of developing T2D (HR=1.26, 95% CI: .1.19-1.33). In addition, we found that the higher T2D risk associated with exposure to ready-to-eat food environments was more pronounced among women than men (p-interaction=0.025). Conclusions: Our results indicate that exposure to ready-to-eat food environments is associated with an increased risk of developing T2D.

Abstract P141: T2D-DNA Methylation Score and Changes in Glycemic Traits in Response to Weight-Loss Dietary Interventions: The MACRO Trial

Introduction: Epigenome-wide association studies (EWAS) have identified several CpGs associated with type 2 diabetes (T2D). A previous study has shown that a DNA methylation score provided more comprehensive information related to T2D risk than individual CpGs. However, whether such T2D-DNA methylation score is associated with changes in glycemic traits in response to weight loss dietary interventions remains unknown. Hypothesis: We hypothesized that a T2D-related DNA methylation score was associated with changes in glycemic traits in response to weight-loss dietary interventions; and may modify the effect of the interventions. Method: The current study included 147 participants from the MACRO trial, who were randomly assigned to a low-fat diet or a low-carbohydrate diet. A weighted DNA methylation score was created by 5 CpGs (cg19693031 at TXNIP , cg11024682 at SREBF1 , cg02650017 at PHOSPHO1 , cg18181703 and SOCS3 , and cg06500161 at ABCG1 ) from a previous EWAS at baseline. One-year changes in glycemic traits were calculated. Results: We found that a higher DNA methylation score was significantly associated with greater reductions in glucose (β: -3.20, SE: 1.08, p=0.003), insulin (β: -2.29, SE: 0.86, p=0.009), and homeostasis model assessments of insulin resistance (HOMA-IR, β: -0.86, SE: 0.30, p=0.005). The DNA methylation score was more strongly associated with changes in glycemic traits than any individual CpG sites ( Figure ). In addition, DNA methylation score significantly interacted with dietary interventions (low-fat vs. low-carbohydrate). The beneficial associations appeared to be stronger among participants with the low-carbohydrate diet (p-interaction=0.009 for glucose, 0.003 for insulin, and 0.004 for HOMA-IR). Conclusions: Our data indicate that a higher DNA methylation score was significantly associated with greater reductions in glycemic traits in response to weight-loss dietary interventions; such beneficial associations were stronger among those who consumed a low-carbohydrate diet.

Clinical features of early-onset type 2 diabetes and its association with triglyceride glucose-body mass index: a cross-sectional study.

The incidence of early-onset type 2 diabetes (T2D) has increased significantly, with insulin resistance (IR) and obesity being the main drivers of its onset. This study aims to investigate the clinical characteristics of early-onset T2D and its association with triglyceride glucose body mass index (TyG-BMI), an emerging surrogate of IR. A total of 1000 adults newly diagnosed with T2D were enrolled and divided into early-onset T2D (18~40 years, N=500) and late-onset T2D groups (≥40 years, N=500). Independent t and chi-squared tests were used to compare the characteristics of the two groups, and logistic regression analysis, trend tests, restricted cubic spline curves (RCSs), and receiver operating characteristic (ROC) curves were used to identify the relationship between TyG-BMI and early-onset T2D. Patients with early-onset T2D were more likely to have a higher body mass index (BMI), hemoglobin A1C (HbA1c), fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), serum uric acid (SUA), triglyceride glucose index (TyG), and TyG-BMI (P < 0.05). A higher TyG-BMI was associated with an increased risk of early-onset T2D (P < 0.001). The RCSs showed a nonlinear relationship between TyG-BMI and early-onset T2D, and the slope of the curve increased with an increase in TyG-BMI (P for nonlinearity < 0.001). In the subgroup analysis, additive interactions between TyG-BMI and the risk of early-onset T2D were observed for sex, family history of diabetes, BMI, fatty liver, and hypertension (P < 0.001). ROC curve showed that the area under the curve of TyG-BMI was 0.6781, which was larger than its main components (TyG, BMI, FPG, TG). The best cutoff value was 254.865, the sensitivity was 74.6%, and the specificity was 53.6%. Patients with early-onset T2D are characterized by severe IR, metabolic disorders, and being overweight/obese and an increase in TyG-BMI is independently associated with an increased risk of early-onset T2D.

Vitamin D and risk of developing type 2 diabetes in the SUN project: a prospective cohort study

PurposeVitamin D deficiency has been associated with multiple chronic diseases, including metabolic disorders such as insulin resistance and type 2 diabetes (T2D). The aim of the study was to analyze the association between validated predicted serum vitamin D status and the risk of developing T2D in a large prospective cohort based on a Mediterranean population.MethodsThe SUN project is a prospective and dynamic Spanish cohort that gathers university graduates who have answered lifestyle questionnaires, including a validated Food Frequency Questionnaire. The association between predicted serum vitamin D and the risk of T2D was assessed through Cox regression models according to quartiles (Q) of predicted vitamin D at baseline. The models were adjusted for potential confounders and sensitivity analyses were performed to ensure the robustness of our findings.ResultsOur study included a total of 18,594 participants and after a total follow-up of 238,078 person-years (median follow-up of 13.5 years), 209 individuals were diagnosed with incident T2D. We found a significant inverse association between predicted levels of serum vitamin D and the risk of developing T2D, after adjusting for potential confounders and performing different sensitivity analyses (hazard ratio Q4 vs. Q1: 0.48, 95% CI 0.26–0.88; p for trend = 0.032).ConclusionThe outcomes suggest that higher levels of vitamin D at baseline may be associated with a reduced risk of developing T2D.

A multi-ancestry genome-wide association study in type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease caused by destruction of the pancreatic β-cells. Genome-wide association (GWAS) and fine mapping studies have been conducted mainly in European ancestry (EUR) populations. We performed a multi-ancestry GWAS to identify SNPs and HLA alleles associated with T1D risk and age at onset. EUR families (N = 3223), and unrelated individuals of African (AFR, N = 891) and admixed (Hispanic/Latino) ancestry (AMR, N = 308) were genotyped using the Illumina HumanCoreExome BeadArray, with imputation to the TOPMed reference panel. The Multi-Ethnic HLA reference panel was utilized to impute HLA alleles and amino acid residues. Logistic mixed models (T1D risk) and frailty models (age at onset) were used for analysis. In GWAS meta-analysis, seven loci were associated with T1D risk at genome-wide significance: PTPN22, HLA-DQA1, IL2RA, RNLS, INS, IKZF4-RPS26-ERBB3, and SH2B3, with four associated with T1D age at onset (PTPN22, HLA-DQB1, INS, and ERBB3). AFR and AMR meta-analysis revealed NRP1 as associated with T1D risk and age at onset, although NRP1 variants were not associated in EUR ancestry. In contrast, the PTPN22 variant was significantly associated with risk only in EUR ancestry. HLA alleles and haplotypes most significantly associated with T1D risk in AFR and AMR ancestry differed from that seen in EUR ancestry; in addition, the HLA-DRB1*08:02-DQA1*04:01-DQB1*04:02 haplotype was 'protective' in AMR while HLA-DRB1*08:01-DQA1*04:01-DQB1*04:02 haplotype was 'risk' in EUR ancestry, differing only at HLA-DRB1*08. These results suggest that much larger sample sizes in non-EUR populations are required to capture novel loci associated with T1D risk.

Habitual Short Sleep Duration, Diet, and Development of Type 2 Diabetes in Adults

Understanding the interplay between sleep duration, dietary habits, and the risk of developing type 2 diabetes (T2D) is crucial for public health and diabetes prevention strategies. To investigate the associations of type of diet and duration of sleep with the development of T2D. Data derived from the UK Biobank baseline investigation (2006-2010) were analyzed for this cohort study between May 1 and September 30, 2023. The association between sleep duration and healthy dietary patterns with the risk of T2D was investigated during a median (IQR) follow-up of 12.5 (11.8-13.2) years (end of follow-up, September 30, 2021). For the analysis, 247 867 participants were categorized into 4 sleep duration groups: normal (7-8 hours per day), mild short (6 hours per day), moderate short (5 hours per day), and extreme short (3-4 hours per day). Their dietary habits were evaluated based on population-specific consumption of red meat, processed meat, fruits, vegetables, and fish, resulting in a healthy diet score ranging from 0 (unhealthiest) to 5 (healthiest). Cox proportional hazards regression analysis was used to calculate hazard ratios (HRs) and 95% CIs for the development of T2D across various sleep duration groups and healthy diet scores. The cohort comprised 247 867 participants with a mean [SD] age of 55.9 [8.1] years, of whom 52.3% were female. During the follow-up, 3.2% of participants were diagnosed with T2D based on hospital registry data. Cox regression analysis, adjusted for confounding variables, indicated a significant increase in the risk of T2D among participants with 5 hours or less of daily sleep. Individuals sleeping 5 hours per day exhibited a 1.16 adjusted HR (95% CI, 1.05-1.28), and individuals sleeping 3 to 4 hours per day exhibited a 1.41 adjusted HR (95% CI, 1.19-1.68) compared with individuals with normal sleep duration. Furthermore, individuals with the healthiest dietary patterns had a reduced risk of T2D (HR, 0.75 [95% CI, 0.63-0.88]). The association between short sleep duration and increased risk of T2D persisted even for individuals following a healthy diet, but there was no multiplicative interaction between sleep duration and healthy diet score. In this cohort study involving UK residents, habitual short sleep duration was associated with increased risk of developing T2D. This association persisted even among participants who maintained a healthy diet. To validate these findings, further longitudinal studies are needed, incorporating repeated measures of sleep (including objective assessments) and dietary habits.

Multi-ancestry polygenic mechanisms of type 2 diabetes.

Type 2 diabetes (T2D) is a multifactorial disease with substantial genetic risk, for which the underlying biological mechanisms are not fully understood. In this study, we identified multi-ancestry T2D genetic clusters by analyzing genetic data from diverse populations in 37 published T2D genome-wide association studies representing more than 1.4 million individuals. We implemented soft clustering with 650 T2D-associated genetic variants and 110 T2D-related traits, capturing known and novel T2D clusters with distinct cardiometabolic trait associations across two independent biobanks representing diverse genetic ancestral populations (African, n = 21,906; Admixed American, n = 14,410; East Asian, n =2,422; European, n = 90,093; and South Asian, n = 1,262). The 12 genetic clusters were enriched for specific single-cell regulatory regions. Several of the polygenic scores derived from the clusters differed in distribution among ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a body mass index (BMI) of 30 kg m-2 in the European subpopulation and 24.2 (22.9-25.5) kg m-2 in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg m-2 in the East Asian group. Thus, these multi-ancestry T2D genetic clusters encompass a broader range of biological mechanisms and provide preliminary insights to explain ancestry-associated differences in T2D risk profiles.

Tailoring of Health-Promotion Video Messaging for Reproductive-Aged Women at Risk for Developing Cardiometabolic Disease: Qualitative Focus-Groups Study.

Targeting reproductive-aged women at high risk for type 2 diabetes (T2D) provides an opportunity for prevention earlier in the life course. A woman's experiences during her reproductive years may have a large impact on her future risk of T2D. Her risk is 7 to 10 times higher if she has had gestational diabetes (GDM). Despite these risks, T2D is preventable. Evidence-based programs, such as the National Diabetes Prevention Program (DPP), can reduce the risk of developing T2D by nearly 60%. However, only 0.4% of adults with prediabetes have participated in the DPP to date and reproductive-aged women are 50% less likely to participate than older women. In prior work, our team developed a mobile 360° video to address diabetes risk awareness and promote DPP enrollment among at-risk adults; this video was not designed, however, for reproductive-aged women. This study aims to obtain feedback from reproductive-aged women with cardiometabolic disease risk about a 360° video designed to promote enrollment in the DPP, and to gather suggestions about tailoring video messages to reproductive-aged women. Focus groups and a qualitative descriptive approach were used. Women with at least 1 previous pregnancy, aged 18 to 40 years, participated in one of three focus groups stratified by the following health risks: (1) a history of GDM or a hypertensive disorder of pregnancy, (2) a diagnosis of prediabetes, or (3) a BMI classified as obese. Focus-group questions addressed several topics; this report shared findings regarding video feedback. The 3 focus-group discussions were conducted via Zoom and were recorded and transcribed for analysis. Deductive codes were used to identify concepts related to the research question and inductive codes were created for novel insights shared by participants. The codes were then organized into categories and themes. The main themes identified were positive feedback, negative feedback, centering motherhood, and the importance of storytelling. While some participants said the video produced a sense of urgency for health-behavior change, all participants agreed that design changes could improve the video's motivating effect on health-behavior change in reproductive-aged women. Participants felt a tailored video should recognize the complexities of being a mother and how these dynamics contribute to women's difficulty engaging in healthy behaviors without stirring feelings of guilt. Women desired a video with a positive, problem-solving perspective, and recommended live links as clickable resources for practical solutions promoting health behavior change. Women suggested using storytelling, both to describe how complications experienced during pregnancy impact long-term health and to motivate health behavior change. Reproductive-aged women require tailored lifestyle-change messaging that addresses barriers commonly encountered by this population (eg, parenting or work responsibilities). Moreover, messaging should prioritize a positive tone that harnesses storytelling and human connection while offering realistic solutions.

Plasma calprotectin and new-onset type 2 diabetes in the general population: a prospective cohort study.

Systemic inflammation plays a pivotal role in the development of type 2 diabetes (T2D). Here we hypothesized that circulating levels of calprotectin, a myeloid cell-derived biomarker of inflammation, is associated with the development of new-onset T2D in the general population. A total of 4,815 initially non-diabetic participants of the Prevention of Renal and Vascular ENd-stage Disease (PREVEND), a prospective population-based cohort study, were assessed for plasma levels of calprotectin at baseline. Circulating levels of calprotectin were investigated for potential associations with the risk of new-onset T2D, defined as a fasting plasma glucose level ≥7.0 mmol/l, a random plasma glucose level ≥11.1 mmol/l, a self-reported physician-based diagnosis of T2D, the use of glucose-lowering drugs, or any combinations thereof. Median plasma calprotectin levels were 0.49 [0.35-0.69] mg/l. Plasma calprotectin levels were significantly associated with the risk of new-onset T2D (hazard ratio [HR] per doubling 1.42 [95% confidence interval: 1.22-1.66], P<0.001). The association remained independent of adjustment for age and sex (HR 1.34 [95%CI: 1.14-1.57], P<0.001), but not after further adjustment for potentially confounding factors (HR 1.11 [95% CI: 0.90-1.37], P=0.326), with adjustment for hyperlipidemia and high-sensitivity C-reactive protein explaining the loss of significance. Stratified analyses showed significant effect modification by hypertension, history of cardiovascular disease and HOMA-IR (Pinteraction≤0.001 for each), with higher HRs in individuals without hypertension, without history of cardiovascular disease and with below-median HOMA-IR. Elevated plasma levels of calprotectin are associated with a higher risk of developing T2D in the general population and may represent a moveable inflammatory biomarker. This association, however, does not represent a direct effect, and seems dependent on hyperlipidemia and systemic inflammation.

Causal effects of inflammatory bowel disease on risk of type 2 diabetes: a two-sample multivariable Mendelian randomization study.

This study aimed to explore the causal association between inflammatory bowel disease (IBD) and the risk of type 2 diabetes (T2D) based on a two-sample Mendelian randomization (MR) study. Summary single nucleotide polymorphism (SNP)-phenotype association data were obtained from published two genome-wide association studies (GWAS) including SNPs related to IBD, UC, or CD in European participants (n = 71,997) and East Asian participants (n = 16,805). Two GWAS including SNPs associated with T2D included 655,666 Europeans and 433,540 East Asians. A series of screening processes were performed to select qualified instrumental SNPs strongly related to exposure. We applied the inverse variance weighted (IVW), the MR-Egger regression, and the weighted median to estimate the causal effects of IBD, ulcerative colitis (UC) or Crohn' disease (CD) on T2D. Cochran's Q test was conducted to evaluate the statistical heterogeneity between SNPs in the IVW method. The leave-one-out analysis was employed to assess whether the results were caused by any single SNP associated with IBD, UC, or CD. Odds ratio (OR) and 95% confidence interval (CI) were calculated. The IVW results demonstrated that IBD could increase the risk of T2D in the European population (OR = 1.0230, 95%CI: 1.0073-1.0390). UC was positively associated with the risk of T2D according to the weighted median (OR = 1.0274, 95%CI: 1.0009-1.0546) and IVW (OR = 1.0244, 95%CI: 1.0071-1.0421) results in the European population. The IVW results indicated that the CD was positively associated with the risk of T2D in the European population (OR = 1.0187, 95%CI: 1.0045-1.0330). In the East Asian population, there are no associations between the IBD, UC, or CD and the risk of T2D (all P > 0.05). MVMR results revealed that the causal effect UC on T2D was still statistically significant after including body mass index (BMI) or low-density lipoprotein (LDL). IBD, UC, or CD had causal effects on the risk of T2D in the European population, which might provide evidence for the prevention of T2D in patients with IBD, UC, or CD.

White blood cells and type 2 diabetes: A Mendelian randomization study.

Observational studies have demonstrated an association between white blood cells (WBC) subtypes and type 2 diabetes (T2D) risk. However, it is unknown whether this relationship is causal. We used Mendelian randomization (MR) to investigate the causal effect of WBC subtypes on T2D and glycemic traits. The summary data for neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts were extracted from a recent genome-wide association study (n = 173,480). The DIAGRAM and MAGIC consortia offered summary data pertaining to T2D and glycemic characteristics, including fasting glucose (FG) (n = 133,010), glycosylated hemoglobin (HbA1c) (n = 46,368), and homeostatic model assessment-estimated insulin resistance (HOMA-IR) (n = 37,037). A series of MR analyses (univariable MR, multivariable MR, and reverse MR) were used to investigate the causal association of different WBC subtypes with T2D and glycemic traits. Using the inverse-variance weighted method, we found one standard deviation increases in genetically determined neutrophil [odd ratio (OR): 1.086, 95% confidence interval (CI): 0.877-1.345], lymphocyte [0.878 (0.766-1.006)], monocyte [1.010 (0.906-1.127)], eosinophil [0.995 (0.867-1.142)], and basophil [0.960 (0.763-1.207)] were not causally associated with T2D risk. These findings were consistent with the results of three pleiotropy robust methods (MR-Egger, weighted median, and mode-based estimator) and multivariable MR analyses. Reverse MR analysis provided no evidence for the reverse causation of T2D on WBC subtypes. The null causal effects of WBC subtypes on FG, HbA1c, and HOMA-IR were also identified. WBCs play no causal role in the development of insulin resistance and T2D. The observed association between these factors may be explained by residual confounding.

The association of dietary total flavonoids and their subclasses with the risk of type 2 diabetes: a prospective cohort study.

Data from mechanistic studies suggest flavonoids may benefit glucose metabolism, but their associations with type 2 diabetes (T2D) remain unclear. This study examined the prospective associations of dietary intake of total, classes, and individual flavonoids, as well as their source foods, with T2D in the CArdioVascular disease Association Study (CAVAS). A total of 16,666 Korean men and women were enrolled at baseline, and 953 were newly diagnosed with T2D over a median follow-up of 5.96years. Intake of flavonoids was cumulatively averaged using all food frequency questionnaires before the censoring events. A Poisson regression model was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Women with higher total flavonoid, flavonol, isoflavone, and proanthocyanidin intake had a lower risk of T2D (fourth vs. first quartile, IRR 0.62; 95% CI 0.44-0.89; P for linearity and non-linearity < 0.05 for total flavonoids), while in men, flavanones, anthocyanins, and proanthocyanidins, but not total flavonoids, were inversely associated with T2D risk (all P interaction for sex > 0.05). The key source foods contributing to flavonoid intake were also different between men and women, except for apples: tangerines and strawberries in men and green leafy vegetables and soy products in women. A higher intake of total flavonoids, particularly from vegetables, soybeans, and apples, may be associated with lower risk of T2D in women. However, flavonoids from fruits, rather than total flavonoids, may be inversely associated in men. The association between flavonoid intake and the risk of T2D may be contingent upon the dietary sources of flavonoids consumed.

Creatine Acts as a Mediator of the Causal Effect of Obesity on Puberty Onset in Girls: Evidence from Mediation Mendelian Randomization Study.

Epidemiological studies have linked obesity to the onset of puberty, while its causality and the potential metabolite mediators remain unclear. We employed a two-sample Mendelian randomization (MR) design to evaluate the causal effects of obesity on puberty onset and its associated diseases including type 2 diabetes (T2D) and cardiovascular diseases (CVDs). The potential mediators in this pathway were further explored using a two-step MR design. The robustness of our findings was evaluated using sensitivity analyses. Our MR results revealed that childhood obesity/BMI were causally associated with an increased Tanner stage in girls, younger age at menarche, and increased risk of adulthood T2D and CVD. However, neither childhood BMI nor obesity had a causal effect on the Tanner stage in boys. Mediation analysis further indicated that increased creatine served as a mediator for the causal pathway from childhood obesity/BMI to the Tanner stage of girls, while early puberty onset in girls played a mediating role in the pathway linking childhood obesity to increased risk of adulthood T2D and CVD. This study indicated that the risk of early puberty onset in girls and its associated health issues can be potentially reduced by preventing childhood obesity. The involvement of creatine in this process needs to be further validated and explored.

Microvascular disease not type 2 diabetes is associated with increased cortical porosity: A study of cortical bone microstructure and intracortical vessel characteristics

IntroductionFracture risk is elevated in type 2 diabetes (T2D) despite normal or even high bone mineral density (BMD). Microvascular disease (MVD) is a diabetic complication, but also associated with other diseases, for example chronic kidney disease. We hypothesize that increased fracture risk in T2D could be due to increased cortical porosity (Ct.Po) driven by expansion of the vascular network in MVD. The purpose of this study was to investigate associations of T2D and MVD with cortical microstructure and intracortical vessel parameters. MethodsThe study group consisted of 75 participants (38 with T2D and 37 without T2D). High-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) of the ultra-distal tibia were performed to assess cortical bone and intracortical vessels (outcomes). MVD was defined as ≥1 manifestation including neuropathy, nephropathy, or retinopathy based on clinical exams in all participants. Adjusted means of outcomes were compared between groups with/without T2D or between participants with/without MVD in both groups using linear regression models adjusting for age, sex, BMI, and T2D as applicable. ResultsMVD was found in 21 (55 %) participants with T2D and in 9 (24 %) participants without T2D. In T2D, cortical pore diameter (Ct.Po.Dm) and diameter distribution (Ct.Po.Dm.SD) were significantly higher by 14.6 μm (3.6 %, 95 % confidence interval [CI]: 2.70, 26.5 μm, p = 0.017) and by 8.73 μm (4.8 %, CI: 0.79, 16.7 μm, p = 0.032), respectively. In MVD, but not in T2D, cortical porosity was significantly higher by 2.25 % (relative increase = 12.9 %, CI: 0.53, 3.97 %, p = 0.011) and cortical BMD (Ct.BMD) was significantly lower by −43.6 mg/cm3 (2.6 %, CI: −77.4, −9.81 mg/cm3, p = 0.012). In T2D, vessel volume and vessel diameter were significantly higher by 0.02 mm3 (13.3 %, CI: 0.004, 0.04 mm3, p = 0.017) and 15.4 μm (2.9 %, CI: 0.42, 30.4 μm, p = 0.044), respectively. In MVD, vessel density was significantly higher by 0.11 mm−3 (17.8 %, CI: 0.01, 0.21 mm−3, p = 0.033) and vessel volume and diameter were significantly lower by −0.02 mm3 (13.7 %, CI: −0.04, −0.004 mm3, p = 0.015) and − 14.6 μm (2.8 %, CI: −29.1, −0.11 μm, p = 0.048), respectively. ConclusionsThe presence of MVD, rather than T2D, was associated with increased cortical porosity. Increased porosity in MVD was coupled with a larger number of smaller vessels, which could indicate upregulation of neovascularization triggered by ischemia. It is unclear why higher variability and average diameters of pores in T2D were accompanied by larger vessels.

Experiences and Outcomes of Indigenous Patients Undergoing Bariatric Surgery: a Mixed-Method Scoping Review.

Obesity and type 2 diabetes (T2D) are growing global health concerns. Evidence suggests that Indigenous peoples are at higher lifetime risk of obesity and its associated conditions. Obesity increases the risk of T2D, cardiovascular disease, and all-cause mortality. Bariatric surgery is the most sustained and effective intervention for treating obesity-associated medical problems. This review aims to explore the experiences and outcomes of Indigenous peoples undergoing bariatric surgery in Canada, the USA, Australia, and New Zealand (CANZUS). Analysis of quantitative data revealed that Indigenous patients had fewer bariatric procedures, poorer clinic attendance, similar weight loss outcomes and slightly higher post-operative complication rates. Qualitative data analysis revealed that Indigenous patients living with obesity have a desire to improve their health and quality of life.