Risk Of Type 2 Diabetes Research Articles

Genetics of C-peptide and Age at Diagnosis in Type 1 Diabetes

Identified genetic loci for C-peptide and age at diagnosis (AAD) in individuals with type 1 diabetes (T1D) explain only a small proportion of their variation. Here, we aimed to perform large metagenome-wide association studies (GWAS) of C-peptide and AAD in T1D; and to identify the HLA allele/haplotypes associated with C-peptide and AAD. 7,252 and 7,923 European individuals with T1D were included in C-peptide and AAD GWAS, respectively. HLA-DQB1*06:02 which is strongly protective against T1D was associated with higher C-peptide. HLA-DQB1*03:02, HLADRB1*03:01 and HLA-A*24:02 which increase T1D risk were independently associated with younger AAD. HLA-DR3-DR4 haplotype combination, the strongest T1D susceptibility factor, was associated with younger AAD. Outside HLA region, rs115673528 on Chr5 (GABRG2) was associated with C-peptide, and an indel, rs111970692, on Chr15 within CTSH, a known T1D locus, was associated with AAD. Genetically predicted CTSH expression, methylation and protein levels were associated with AAD; Mendelian randomization analysis suggested that higher levels of procathepsin H reduce AAD. In conclusion, some HLA allele/haplotypes associated with T1D also contribute to variability of C-peptide and AAD. Outside HLA, T1D loci are generally not associated with C-peptide or AAD. CTSH could be a potential therapeutic target to delay development/progression of type 1 diabetes.

The mediatory role of androgens on sex differences in glucose homeostasis and incidence of type 2 diabetes: the KORA study.

Sex differences exist in type 2 diabetes (T2D), and androgens have been implicated in the etiology of T2D in a sex-specific manner. We therefore aimed to investigate whether androgens play a role in explaining sex differences in glucose homeostasis and incidence of T2D. We used observational data from the German population-based KORA F4 study (n = 1975, mean age: 54 years, 41% women) and its follow-up examination KORA FF4 (median follow-up 6.5 years, n = 1412). T2D was determined through self-reporting and confirmed by contacting the physicians and/or reviewing the medical charts. Multivariable linear and logistic regression models were employed to explore associations. Mediation analyses were performed to assess direct effects (DE) and indirect effects (IE), and the mediating role of androgens (total testosterone (TT), dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAs)) in the association between sex (women vs. men) and glucose- and insulin-related traits (cross-sectional analysis) and incidence of T2D (longitudinal analysis). After adjustment for confounders, (model 1: adjusted for age; model 2: model 1 + smoking + alcohol consumption + physical activity), women had lower levels of TT, DHEAs, fasting glucose levels, fasting insulin levels, 2h-glucose levels and HOMA-IR, compared to men. An inverse association was observed for TT and glucose- and insulin-related traits in men, while a positive association was observed for TT and fasting glucose levels in women. We found a mediatory role of TT on the association of sex with fasting glucose levels (IE: β = 3.08, 95% CI: 2.04, 4.30), fasting insulin levels (IE: β = 0.39, 95% CI:0.30, 0.47), 2h-glucose levels (IE: β = 12.77, 95% CI: 9.01, 16.03) and HOMA-IR (IE: β = 0.41, 95% CI: 0.33, 0.50). Also, the inconsistent mediatory role of TT was seen on the association of sex with incidence of T2D (DE: 0.12, 95% CI: 0.06, 0.20 and IE: OR = 7.60, 95% CI: 3.43, 24.54). The opposing DE and IE estimates suggest that the association between sex and either glucose homeostasis or the incidence of T2D may differ when TT is considered as a potential mediator, with higher TT levels being beneficial for glucose metabolism or incidence of T2D in men, while in women, detrimental. No mediatory role was observed for either DHEA or DHEAs on glucose homeostasis or the incidence of T2D. The dimorphic mediatory role of TT highlights its complex role in metabolic health, contributing differently to the glucose dysregulation and risk of T2D in men and women.

Low-frequency variants in genes involved in glutamic acid metabolism and γ-glutamyl cycle and risk of coronary artery disease in type 2 diabetes.

A common genetic variant at the glutamate-ammonia ligase (GLUL) locus has been previously associated with an increased risk of coronary artery disease (CAD) as well as alterations of glutamic acid metabolism and the γ-glutamyl cycle in individuals with type 2 diabetes (T2D). Here we investigated whether less frequent variants in GLUL and 15 additional genes in these pathways are associated with differences in CAD risk in T2D. Coding sequences and regulatory elements of these genes were sequenced in 2,394 individuals with T2D from three CAD case/control sets. Ninety-six variants with minor allele frequency [MAF]< 0.05 were identified as being nominally associated with CAD status. One of these variants (rs62447457, MAF 0.025), placed in a non-coding region flanking the γ-glutamylcyclotransferase (GGCT) gene, showed nominal evidence of replication in two other cases-control sets (n = 1,132), with summary OR of 0.54 (p = 2.5 × 10-4). Another variant (rs145322388, MAF = 0.039), flanking the dipeptidase 2 (DPEP2) gene, showed association with CAD status across discovery and replications sets (summary OR 0.61, p = 2.5 × 10-4). A third variant (rs1238275622, MAF 0.004), flanking the GLUL gene, was associated with increased risk of CAD (summary OR 1.84, p-value 2.1 × 10-3). Based on their Regulome scores (2b, 2a, and 3a, respectively), all three variants are very likely to have regulatory functions. In summary, we have identified low-frequency variants associated with CAD in T2D at two loci involved in glutamic acid metabolism and the γ-glutamyl cycle. These findings provide further evidence for a role of these pathways in the link between T2D and CAD.

Abstract 4135352: Neighborhood-level Determinants and Disparities in Incident Type 2 Diabetes in a Population-Based Cohort, 2015–2020

Introduction: Living in an area with high Area Deprivation Index (ADI) is linked to worse cardiovascular disease (CVD) outcomes. However, the association of ADI with type 2 diabetes (T2D), a major CVD risk factor, is incompletely described. This knowledge may guide primary CVD prevention. Method: Rochester Epidemiology Project is a medical record linkage system of persons in southeast Minnesota and southwest Wisconsin. We identified 253,890 persons (aged 4–98 yrs on July 1, 2015) in 9 counties with &gt;90% population coverage. ADI scores, from 2015 home addresses, were grouped into quartiles of low (Q1) to high (Q4) deprivation. We excluded persons with type 1 diabetes (T1D) or history of T2D and identified new T2D cases (2015-2020) using ICD codes, HbA1c and medications. We examined the association between ADI quartile and risk of incident T2D using Cox regression with persons right censored at death, T2D, T1D or last visit. Models were adjusted for age and gender, and reported adjusted hazard ratios (aHR [95% confidence interval]). Results: Age, gender, and race statistically differed across ADI quartiles (Table). Age × ADI interaction was significant ( P &lt;.001). T2D incidence ranged from 6.3 (Q1) to 9.0 (Q4) per 1000 person-years ( P &lt;.001). Women vs. men/non-binary persons (combined due to limited non-binary persons) had 30% lower risk of incident T2D (aHR 0.70 [0.67–0.72]). Risk of incident T2D was higher in persons from higher ADI areas. At median age of 48.6 yrs, the risk was 30% higher in Q2 (aHR 1.3 [1.22–1.38]), 38% higher in Q3 (aHR 1.38 [1.30–1.47]) and 53% higher in Q4 (aHR 1.53 [1.43–1.62]) vs. Q1. Higher ADI was associated with higher incident T2D in younger persons, with risk attenuation with increasing age (Figure). Conclusion: In this population cohort, persons, particularly of younger age, living in more deprived areas had a higher risk of incident T2D. ADI may help identify areas for targeted T2D screening, with implications for CVD screening and prevention.

Associations of sugary beverage intake with type 2 diabetes and the role of physical activity: a prospective cohort study

BackgroundHigher consumption of sugary beverages (SB) has been associated with type 2 diabetes (T2D), but whether these associations are modified by physical activity remains unclear. This study aimed to examine the associations of SB intake, including sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), and natural juices (NJ) with the risk of incident T2D, and the potential role of physical activity.MethodsWe included 153,862 diabetes-free participants in the UK Biobank who completed both the International Physical Activity Questionnaire at recruitment (2006–2010) and at least one 24-h dietary recall questionnaire in 2009–2012. We assessed the associations of each SB with the risk of incident T2D using Cox proportional hazard models, and explored the interactions between each SB and physical activity.ResultsDuring a median follow-up of 11.8 years, 6631 participants developed incident T2D. Participants consuming more SSB and ASB (comparing > 2 to 0 unit/d) had a higher hazard of T2D (hazard ratio [HR]: 1.17, 95% confidence interval [CI]: 1.05–1.31 for SSB; 1.54, 1.37–1.74 for ASB), while medium intake of NJ showed an inverse association (HR> 0–1 vs. 0 unit/d: 0.87, 95% CI: 0.82–0.92; HR> 1–2 vs. 0 unit/d: 0.88, 95% CI: 0.81–0.97) with incident T2D. No significant interactions between physical activity and SSB/ASB were found (P-interaction=0.204 for SSB, 0.926 for ASB), but the protective association of medium NJ intake with T2D was stronger among participants with higher level of physical activity (P-interaction = 0.043).ConclusionsHigher intake of SSB and ASB was related to higher risks of T2D. Medium NJ intake was associated with a lower risk of T2D, particularly among individuals with higher physical activity level. These findings emphasized the importance of healthy beverage intake and adequate physical activity in diabetes prevention.

EPA and DHA inhibit LDL-induced upregulation of human adipose tissue NLRP3 inflammasome/IL-1β pathway and its association with diabetes risk factors

Elevated numbers of atherogenic lipoproteins (apoB) predict the incidence of type 2 diabetes (T2D). We reported that this may be mediated via the activation of the NLRP3 inflammasome, as low-density lipoproteins (LDL) induce interleukin-1 beta (IL-1β) secretion from human white adipose tissue (WAT) and macrophages. However, mitigating nutritional approaches remained unknown. We tested whether omega-3 eicosapentaenoic and docosahexaenoic acids (EPA and DHA) treat LDL-induced upregulation of WAT IL-1β-secretion and its relation to T2D risk factors. Twelve-week intervention with EPA and DHA (2.7 g/day, Webber Naturals) abolished baseline group-differences in WAT IL-1β-secretion between subjects with high-apoB (N = 17) and low-apoB (N = 16) separated around median plasma apoB. Post-intervention LDL failed to trigger IL-1β-secretion and inhibited it in lipopolysaccharide-stimulated WAT. Omega-3 supplementation also improved β-cell function and postprandial fat metabolism in association with higher blood EPA and mostly DHA. It also blunted the association of WAT NLRP3 and IL1B expression and IL-1β-secretion with multiple cardiometabolic risk factors including adiposity. Ex vivo, EPA and DHA inhibited WAT IL-1β-secretion in a dose-dependent manner. In conclusion, EPA and DHA treat LDL-induced upregulation of WAT NLRP3 inflammasome/IL-1β pathway and related T2D risk factors. This may aid in the prevention of T2D and related morbidities in subjects with high-apoB.Clinical Trail Registration ClinicalTrials.gov (NCT04496154): Omega-3 to Reduce Diabetes Risk in Subjects with High Number of Particles That Carry “Bad Cholesterol” in the Blood – Full Text View - ClinicalTrials.gov.

Evaluating the causal effects between Grave’s disease and diabetes mellitus: a bidirectional Mendelian randomization study

BackgroundGraves’ disease (GD) is an autoimmune disease associated with an increased incidence of other autoimmune diseases. To investigate the causality between GD and Diabetes mellitus (DM), we designed bidirectional two-sample Mendelian randomization (MR) and multivariable MR (MVMR) studies.MethodsSingle-nucleotide polymorphisms (SNPs) associated with GD, thyroid peroxidase (TPO), thyroglobulin (Tg), thyroid-stimulating hormone (TSH), type 1 diabetes (T1D), and type 2 diabetes (T2D) were obtained from the IEU Open GWAS and FinnGen biobank databases. For the forward MR study, we used GD (sample size = 458,620) as the exposure and T1D (sample size = 520,580) and T2D (sample size = 211,766) as the outcomes. Next, high risk of T1D and T2D were used as exposure variables, and GD was used as the outcome variable for the reverse MR analysis. Finally, MVMR analysis was conducted to investigate the probable relationship between DM and indicators for thyroid function like TPO, Tg, and TSH. The inverse variance weighting (IVW) was used as the main method. Finally, the heterogeneity and sensitivity were assessed.ResultsThere were 27, 88, and 55 SNPs associated with GD, T1D, and T2D, respectively. A significant causal connection between higher genetic liability of GD and the risk of T2D (OR [95% CI] = 1.059 [1.025–1.095], P = 5.53e-04) was found in the forward MR analysis. Comparatively, the significant causal relationship between higher genetic liability of GD and the risk of T1D was not demonstrated (OR [95% CI] = 0.998[0.927,1.074], P=0.949). However, reverse MR suggested that there was a genetic susceptibility to T1D that increased the likelihood of developing GD (OR [95% CI] = 1.173[1.117,1.231], P = 1.913e-10), while T2D did not (OR [95% CI] = 0.963 [0.870–1.066], P = 0.468). Furthermore, there was inadequate evidence to suggest that abnormal TSH, TPO, and Tg levels increase the risk of incident T1D or T2D in individuals with GD. MVMR revealed no causal relationship among Tg, TSH, TPO, T1D, or T2D.ConclusionThere was no increased risk of T1D with an increase in genetic susceptibility to GD, although higher genetic susceptibility to T1D has been shown to be associated with increased risk of developing GD. A unidirectional causal relationship between the genetic liability for GD and increased risk of T2D was observed using MR analyses. MVMR analysis showed no statistically relevant causality between the genetic liability for TSH, TPO, or Tg and the risk of either T1D or T2D.

Association Between Circulating Vitamin K Levels, Gut Microbiome, and Type 1 Diabetes: A Mendelian Randomization Study

Background/Objectives: Nutritional deficiencies have been proposed as possible etiological causes for autoimmune diseases, among which type 1 diabetes (T1D). Vitamin K (VK) has potentially positive effects on type 2 diabetes, but its role on T1D in humans remains largely unknown. We aimed to examine the presence of a causal association between VK and T1D using a Mendelian randomization (MR) approach. Methods: Genetic variants from a genome-wide association study (GWAS) for VK (N= 2138 Europeans) were used as instruments in our two-sample MR study to investigate whether circulating VK levels are causally associated with the risk of T1D in a large European T1D GWAS cohort (18,942 cases/520,580 controls). Through a multivariable MR (MVMR), the effects of both VK and specific gut microbiota on T1D were investigated given that the gut microbiome synthesizes VK. Results: We found that changes in levels of circulating VK did not affect T1D risk in our univariate two-sample MR, but this study had limited power to detect small effects of VK (OR for T1D of less than 0.8). However, our MVMR indicated a suggestive association of VK with the risk of T1D adjusting for two different gut microbiome populations. Conclusions In conclusion, VK levels are unlikely to significantly affect the risk of T1D, but small effects cannot be excluded, and the role of gut microbiome in this association should be further investigated.

Codesigning a Digital Type 2 Diabetes Risk Communication Tool in Singapore: Qualitative Participatory Action Research Approach.

Diabetes is a serious public health concern worldwide. Despite public health efforts encouraging early screening and improving knowledge of effective interventions for those at increased risk of type 2 diabetes (T2D), the incorporation of preventative behaviors into an individual's daily life remains suboptimal. Successfully and accurately increasing risk perception has been demonstrated to increase behavioral intention. The study aims to codesign a T2D risk communication tool by engaging public participants to (1) identify key characteristics that contribute to an effective risk communication tool and (2) test and iterate to develop a culturally sensitive and meaningful risk communication tool that can motivate T2D preventative behaviors. We adopted a novel methodology, "Patient and Public Involvement (PPI) Hawkers," where we approached patrons at hawker centers and public eateries frequented by all local residents to evaluate and test 3 prototypes for the tool. The three prototypes were (1) "Diabetes Onset"-estimated age of diabetes onset of T2D based on one's risk factors, (2) "Relative Risk"-the relative risk of T2D is presented in a 1-10 scale indicating where one's risk score lie in relation to others, and (3) "Metabolic Age"-the median age of the risk category based on one's risk factors, presented to be compared against their chronological age. We gathered reactions and feedback through rapid testing and iteration to understand which risk result presentation would be received the best. All the collected data were revisited and analyzed using an inductive thematic analysis to identify the key characteristics contributing to an effective risk communication tool. We engaged with 112 participants (female: n=59, 56%) across 6 hawker centers. The key characteristics that were important to participants emerged in four main themes: (1) appeal and user experience, in terms of format and readability; (2) trust and validity of the institution providing the tool and the accuracy of the risk result; (3) threat appraisal: salience of risk information, which influenced their risk perception; and (4) coping appraisal: facilitators for behavior change, which impacted their intention for implementing T2D preventative behaviors. The predictive nature of the prototype entitled "Diabetes Onset" was poorly received and removed after the first iteration. The Relative Risk prototype was valued for being straightforward but feared to be boring. The Metabolic Age prototype was anticipated to be more motivating for behavior change, but there were some concerns that the terminology may not be understood by everyone. Participants were divided on which of the 2 prototypes, "Metabolic Age" or "Relative Risk," they would favor adopting. Further testing is now required to determine which prototype will be more effective in motivating behavior change. This study's insights on the design process and valued characteristics of a risk communication tool will inform future development of such interventions.

Diet-Wide Association Study for the Incidence of Type 2 Diabetes in Three Population-Based Cohorts

Background: Dietary factors are well-known modifiable risk factors for type 2 diabetes (T2D), but many studies overlook the interrelationships between these factors, even though foods are often consumed together and contain a variety of nutrients. Objectives: In this study, we employed a diet-wide association study approach to investigate the links between various dietary factors and T2D onset, taking into account complex dietary patterns. Methods: We analyzed 16,666 participants without T2D from three Korean population-based cohorts: the Multi-Rural Communities Cohort (n = 8302), the Atherosclerosis Risk of a Rural Area Korean General Population cohort (n = 4990), and the Kanghwa cohort (n = 3374). A two-step approach was employed. In the first step, robust Poisson regression analysis was used for the initial screening (false discovery rate-adjusted p-values &lt; 0.05). In the second step, a hierarchical cluster analysis was conducted of all dietary factors, followed by mutual adjustment of the screened factors within each cluster to account for interrelationships. Results: The 11 food clusters screened were cooked rice with beans, rice cakes, breads/spreads, bread products, cheese and pizza/hamburger, grain powder, snack/confections, nuts and roasted beans, soy milk, traditional beverages, and non-native fruit. These factors were similarly distributed across three of the seven clusters in each cohort. After mutual adjustment, cooked rice with beans (p-value ≤ 2.00 × 10−7 in all three cohorts) and non-native fruits (p-value ≤ 5.91 × 10−3 in two cohorts) remained significantly associated with lower T2D risk in more than one cohort. Conclusions: The inverse association of cooked rice with beans, not observed with other types of cooked rice, and that of non-native fruits, suggest that incorporating beans into rice and eating various fruits may be an effective strategy for preventing diabetes.

Biomarkers of glucose-insulin homeostasis and incident type 2 diabetes and cardiovascular disease: results from the Vitamin D and Omega-3 trial

BackgroundDysglycemia and insulin resistance increase type 2 diabetes (T2D) and cardiovascular disease (CVD) risk, yet associations with specific glucose-insulin homeostatic biomarkers have been inconsistent. Vitamin D and marine omega-3 fatty acids (n-3 FA) may improve insulin resistance. We sought to examine the association between baseline levels of insulin, C-peptide, HbA1c, and a novel insulin resistance score (IRS) with incident cardiometabolic diseases, and whether randomized vitamin D or n-3 FA modify these associations.MethodsVITamin D and OmegA-3 TriaL (NCT01169259) was a randomized clinical trial testing vitamin D and n-3 FA for the prevention of CVD and cancer over a median of 5.3 years. Incident cases of T2D and CVD (including cardiovascular death, myocardial infarction, stroke, and coronary revascularization) were matched 1:1 on age, sex, and fasting status to controls. Conditional logistic regressions adjusted for demographic, clinical, and adiposity-related factors were used to assess the adjusted odds ratio (aOR) per-standard deviation (SD) and 95%CI of baseline insulin, C-peptide, HbA1c, and IRS (Insulin×0.0295 + C-peptide×0.00372) with risk of T2D, CVD, and coronary heart disease (CHD).ResultsWe identified 218 T2D case-control pairs and 715 CVD case-control pairs including 423 with incident CHD. Each of the four biomarkers at baseline was separately associated with incident T2D, aOR (95%CI) per SD increment: insulin 1.46 (1.03, 2.06), C-peptide 2.04 (1.35, 3.09), IRS 1.72 (1.28, 2.31) and HbA1c 7.00 (3.76, 13.02), though only HbA1c remained statistically significant with mutual adjustments. For cardiovascular diseases, we only observed significant associations of HbA1c with CVD (1.19 [1.02, 1.39]), and IRS with CHD (1.25 [1.04, 1.50]), which persisted after mutual adjustment. Randomization to vitamin D and/or n-3 FA did not modify the association of these biomarkers with the endpoints.ConclusionsEach of insulin, C-peptide, IRS, and HbA1c were associated with incident T2D with the strongest association noted for HbA1c. While HbA1c was significantly associated with CVD risk, a novel IRS appears to be associated with CHD risk. Neither vitamin D nor n-3 FA modified the associations between these biomarkers and cardiometabolic outcomes.

Gestational Diabetes Mellitus and Subsequent Risks of Diabetes and Cardiovascular Diseases: the Life Course Perspective and Implications of Racial Disparities.

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications worldwide and the prevalence is continuously rising globally. Importantly, GDM is not an isolated complication of pregnancy. Growing evidence suggests that individuals with GDM, compared to those without GDM, have an increased risk of subsequent type 2 diabetes (T2D) and cardiovascular diseases (CVD). Substantial racial and ethnic disparities exist in the risk of GDM. However, the role of race and ethnicity in the progression from GDM to T2D and CVD remains unclear. The purpose of the current review is to summarize recent research about GDM and its life-course impacts on cardiometabolic health, including 1) the peak time of developing T2D and CVD risks after GDM, 2) the racial and ethnic disparities in the risk cardiometabolic diseases after GDM, 3) the biological plausibility and underlying mechanisms, and 4) recommendations for screening and prevention of cardiometabolic diseases among individuals with GDM, collectively to provide an updated review to guide future research. Growing evidence has indicated that individuals with GDM had greater risks of T2D (7.4 to 9.6 times), hypertension (78% higher), and CDV events (74% higher) after GDM than their non-GDM counterparts. More recently, a few studies also suggested that GDM could slightly increase the risk of mortality. Available evidence suggests that key CVD risk factors such as blood pressure, plasma glucose, and lipids levels are all elevated as early as < 1year postpartum in individuals with GDM. The risk of T2D and hypertension is likely to reach a peak between 3-6years after the index pregnancy with GDM compared to normal glycemia pregnancy. Cumulative evidence also suggests that the risk of cardiometabolic diseases including T2D, hypertension, and CVD events after GDM varies by race and ethnicity. However, whether the risk is higher in certain racial and ethnic groups and whether the pattern may vary by the postpartum cardiometabolic outcome of interest remain unclear. The underlying mechanisms linking GDM and subsequent T2D and CVD are complex, often involving multiple pathways and their interactions, with the specific mechanisms varying by individuals of different racial and ethnic backgrounds. Diabetes and CVD risk screening among individuals with GDM should be initiated early during postpartum and continue, if possible, frequently. Unfortunately, adherence to postpartum glucose testing with either obstetrician or primary care providers remained poor among individuals with GDM. A life-course perspective may provide critical information to address clinical and public health gaps in postpartum screening and interventions for preventing T2D and CVD risks in individuals with GDM. Future research investigating the racial- and ethnic-specific risk of progression from GDM to cardiometabolic diseases and the role of multi-domain factors including lifestyle, biological, and socio-contextual factors are warranted to inform tailored and culture-appropriate interventions for high-risk subpopulations. Further, examining the barriers to postpartum glucose testing among individuals with GDM is crucial for the effective prevention of cardiometabolic diseases and for enhancing life-long health.

Understanding Community-Specific Health Behaviors to Prevent Type 2 Diabetes and Depression in Rural Adolescents: A Qualitative Study.

Type 2 diabetes (T2D) and depression co-occur, and rates are on the rise in adolescents, disproportionately affecting teenagers in rural communities and those who identify as members of historically disadvantaged racial/ethnic groups. Addressing the promotion of health behaviors is important for prevention of these comorbid health concerns; however, disparities in their prevalence highlight that a healthy lifestyle is not equally accessible for all individuals. Thus, holistic and multi-level approaches that address structural inequities, leverage cultural and family assets, and are effectively integrated into the community are critically needed. This project is an initial phase of a broader community-academic collaboration that aims to address preventable chronic diseases and mental health in adolescents living in the rural Mountain West by tailoring an evidence-based health behavior and lifestyle intervention for these communities. Interviewers conducted semi-structured interviews with N = 19 individuals (n = 11 adolescents, 11-17years, n = 8 mothers) who lived in neighboring counties in the rural Mountain Western USA and had a family history of T2D. Interview schedules were developed by an interdisciplinary team, with community input, and covered topics such as food and staying active, stress, T2D risk, and community and culture. Using thematic analysis, data were reduced through coding, categorization, and development of themes. Data revealed three major themes: "Families Face Systemic Barriers to Health," "Family Routines Support Health," and "Connection is Crucial to Holistic Health." Findings reveal opportunities for addressing health inequities and developing effective, integrated T2D and depression prevention strategies within this specific community. They also potentially contain insights that may be applicable to others interested in adapting interventions for diverse groups.

Type 2 diabetes risk is associated with poorer general health and mental health in women and men

Abstract Background Increasing evidence points to a relation between cardiometabolic and mental health, but population-based data are scarce. We investigated the association of type 2 diabetes (T2D) risk to general and mental health with a focus on potential differences between women and men. Methods The study population comprised 5,192 adults (18+ years) without known diabetes based on data of the German Health Update (GEDA) 2022. T2D risk was assessed by the German Diabetes Risk Score (GDRS), that estimates the 5-year probability of developing T2D and was categorized into low, still low, elevated, and high risk. Sex-specific Poisson regression analyses were conducted including self-rated health (SRH), self-rated mental health (SRMH), depressive symptoms (PHQ-2) and anxiety symptoms (GAD-2) as dichotomous dependent variables and age, educational level, living alone, region of residence, and social support as covariables. Results Women had a higher prevalence of low T2D risk (66.1%) and a lower prevalence of high T2D risk (9.4 %) than men (55.3% vs. 16.3%). Compared to those with low T2D risk, women and men with a high T2D risk were less likely to report very good/good SRH (women: prevalence ratio: 0.63; 95% confidence interval: 0.51-0.79; men: 0.69; 0.57-0.84) or excellent/very good SRMH (women: 0.53, 0.39-0.73; men: 0.85, 0.63-1.15). Further, those with a high T2D risk had a higher risk of depressive symptoms (women: 1.71, 1.05-2.81; men: 2.23, 1.22-4.05) and anxiety symptoms (women: 1.84, 1.03-3.29; men: 2.73, 1.09-6.81). No statistically significant interactions between sex and T2D risk were observed regarding the included health outcomes. Conclusions A high T2D risk is associated with a lower probability of a favourable SRH and SRMH and a higher risk of depressive and anxiety symptoms in men and women. The underlying mechanisms need further identification, in order to design synergistically beneficial health promotion for cardiometabolic and mental health. Key messages • No sex-specific differences in general and mental health were found in people at high T2D risk. • Further research is needed to identify the underlying mechanism to improve general and mental health.

Exposure to food additive mixtures and type 2 diabetes risk in the NutriNet-Santé cohort

Abstract Background So far, the safety evaluation of food additives has been performed substance by substance, while in real life, millions of individuals are exposed to mixtures of food additives daily. According to preliminary experimental data, some of these chemicals, alone and/or in synergy are suspected to impact metabolic health. The objective of this study was to investigate for the first time the associations between exposure to mixtures of food additives and type 2 diabetes (T2D) risk in a large prospective cohort of French adults. Methods Participants (n = 108,783, 79.2% women, mean age=42.4 years, SD = 14.6) from the NutriNet-Santé cohort (2009-2024) completed repeated 24h-dietary records, detailing industrial product brands. Additive exposure was assessed using composition databases and laboratory assays. Five mixtures of additives were identified through non-negative matrix factorisation (NMF). Associations between these mixtures and the risk of T2D were characterised using multivariable proportional hazards Cox models adjusted for known risk factors. Findings 1115 participants were identified with T2D during follow-up. Two additive mixtures were associated with increased T2D risk. The first mixture included higher exposure to modified starches E14xx, pectins E440, guar gum E412, carrageenan E407, and polyphosphates E452 (HRper 1SD increment=1.11 [1.05-1.18]), p &amp;lt; 0.0001). The second mixture comprised citric acid E330, sodium citrates E331, phosphoric acid E338, sulphite ammonia caramel E150d, acesulfame-K E950, aspartame E951, sucralose E955 and arabic gum E414 (HR1SD=1.13 [1.08-1.18]), p &amp;lt; 0.0001). Interpretation This large prospective cohort study revealed direct associations between T2D risk and exposure to two food additive mixtures. Molecular epidemiology and experimental studies will be necessary to depict underlying mechanisms and potential cocktail effects. Key messages • Consumed together, widely used food additives may contribute to T2D aetiology, shedding light on the detrimental impact of highly processed foods on metabolic health. • This study highlights positives associations between T2D risk and exposure to two food additive mixtures.

Food additive preservatives and antioxidants and risk of type 2 diabetes - NutriNet-Santé cohort

Abstract Background Experimental studies suggested potential detrimental effects of some food additive preservatives and antioxidants (PA) on metabolic health, but epidemiological data is lacking. This study aimed to investigate for the first time the associations between exposures to a wide range of PA and type 2 diabetes (T2D) risk in a large population-based cohort. Methods Participants (n = 108,723, 79.2% women, mean age=42.5y, SD = 14.6) from the French NutriNet-Santé prospective cohort (2009-2023) completed repeated 24h-dietary records including specific brands of industrial products. PA exposure was assessed using composition databases and laboratory assays. We characterised associations between time-dependent exposures to PA and risk of T2D using multivariable Cox models adjusted for known confounders. Results 1131 T2D cases were identified during follow-up. Exposures to the following PA were associated with a higher risk of T2D: potassium sorbate E202 (HR per a 25 mg/d increment=1.12, 1.08-1.17, p &amp;lt; 0.001), sodium nitrite E250 (HR 0.25 mg/d = 1.06, 1.00-1.12, p = 0.04), calcium propionate E282 (HR 25 mg/d =1.07, 1.02-1.12, p = 0.008), lecithins E322 (HR 100 mg/d =1.02, 1.01-1.04, p = 0.008), citric acid E330 (HR 500 mg/d=1.08, 1.04-1.12, p &amp;lt; 0.001), and phosphoric acid E338 (HR 50 mg/d=1.11, 1.05-1.18, p &amp;lt; 0.001). Conclusions This large prospective cohort revealed positive associations between T2D risk and exposures to several PA widely used in industrial foods. Key messages • This large prospective cohort revealed positive associations between T2D risk and exposures to several PA widely used in industrial foods. • If these results are confirmed, regulations governing PA’s use by the food industry could be re-evaluated for better short- and long-term consumer protection.

Mediating pathways between attention deficit hyperactivity disorder and type 2 diabetes mellitus: evidence from a two-step and multivariable Mendelian randomization study.

Type 2 diabetes (T2D) is a global health burden, more prevalent among individuals with attention deficit hyperactivity disorder (ADHD) compared to the general population. To extend the knowledge base on how ADHD links to T2D, this study aimed to estimate causal effects of ADHD on T2D and to explore mediating pathways. We applied a two-step, two-sample Mendelian randomization (MR) design, using single nucleotide polymorphisms to genetically predict ADHD and a range of potential mediators. First, a wide range of univariable MR methods was used to investigate associations between genetically predicted ADHD and T2D, and between ADHD and the purported mediators: body mass index (BMI), childhood obesity, childhood BMI, sedentary behaviour (daily hours of TV watching), blood pressure (systolic blood pressure, diastolic blood pressure), C-reactive protein and educational attainment (EA). A mixture-of-experts method was then applied to select the MR method most likely to return a reliable estimate. We used estimates derived from multivariable MR to estimate indirect effects of ADHD on T2D through mediators. Genetically predicted ADHD liability associated with 10% higher odds of T2D (OR: 1.10; 95% CI: 1.02, 1.18). From nine purported mediators studied, three showed significant individual mediation effects: EA (39.44% mediation; 95% CI: 29.00%, 49.73%), BMI (44.23% mediation; 95% CI: 34.34%, 52.03%) and TV watching (44.10% mediation; 95% CI: 30.76%, 57.80%). The combination of BMI and EA explained the largest mediating effect (53.31%, 95% CI: -1.99%, 110.38%) of the ADHD-T2D association. These findings suggest a potentially causal, positive relationship between ADHD liability and T2D, with mediation through higher BMI, more TV watching and lower EA. Intervention on these factors may thus have beneficial effects on T2D risk in individuals with ADHD.

Transcriptome-wide Mendelian randomization during CD4+ T cell activation reveals immune-related drug targets for cardiometabolic diseases

Immunity has shown potentials in informing drug development for cardiometabolic diseases, such as type 2 diabetes (T2D) and coronary artery disease (CAD). Here, we performed a transcriptome-wide Mendelian randomization (MR) study to estimate the putative causal effects of 11,021 gene expression profiles during CD4+ T cells activation on the development of T2D and CAD. Robust MR and colocalization evidence was observed for 162 genes altering T2D risk and 80 genes altering CAD risk, with 12% and 16% respectively demonstrating CD4+ T cell specificity. We observed temporal causal patterns during T cell activation in 69 gene-T2D pairs and 34 gene-CAD pairs. These genes were eight times more likely to show robust genetic evidence. We further identified 25 genes that were targets for drugs under clinical investigation, including LIPA and GCK. This study provides evidence to support immune-to-metabolic disease connections, and prioritises immune-mediated drug targets for cardiometabolic diseases.

Impact of lifestyle intervention on vitamin D, Adiponectin, Insulin-like growth factor 1 and Proneurotensin in overweight individuals from the Middle East

BackgroundImmigrants from the Middle East (ME) have a higher prevalence of type 2 diabetes (T2D) compared to the native-born Swedish population. In individuals free from T2D, ME immigrants are more insulin resistant and have lower levels of adjusted insulin secretion (Disposition index, DIo) compared to Swedish-born individuals. The ethnic differences are not fully explained by traditional risk factors. This has raised the question as to whether hormonal factors other than insulin are involved, contributing to higher T2D risk in ME immigrants. AimsIn ME immigrants at high risk of developing T2D, we aimed to study the effect of a randomized culturally adapted lifestyle intervention on the levels of Vitamin D (25(OH)D), insulin-like growth factor 1 (IGF-1), Pro-neurotensin (Pro-NT) and Adiponectin. Furthermore, we aimed to study if the effect of the intervention was associated to these hormones, or if a direct effect of the intervention remained after accounting for these. MethodsIn this culturally adapted randomized controlled trial of four months duration, eligible ME immigrants at high risk of developing T2D identified in the MEDIM cohort were invited to participate. The intervention group (N= 35) received a culturally adapted lifestyle intervention program consisting of seven group sessions and cooking classes. The control group (N= 32) were given treatment as usual with oral and written information to improve their lifestyle habits. Using mixed models’ linear regression analysis, the changes in the levels of 25(OH)D, IGF-1, Adiponectin and Pro-NT were assessed by comparing the groups and we further studied the effects of the changes on insulin action and secretion. ResultsThe adjusted levels of 25(OH)D significantly increased in the intervention group compared to the control group (β for the effect of the intervention on 25(OH)D: 0.061, 95% CI 0.009-0.113, P = 0.023). The increase in insulin sensitivity index (ISI) observed in the intervention compared to the control group was altered after adjusting for 25(OH)D: 0.129, 95% CI -0.016-0.274, P = 0.078). IGF-1, Adiponectin and Pro-NT did not significantly influence the change over time concerning insulin secretion. ConclusionLifestyle intervention increases the adjusted levels of 25(OH)D. Moreover, the effect of the lifestyle intervention on insulin action and secretion was altered when adjusting for 25(OH)D.

Risk of type-2-diabetes after breast cancer treatment: a population-based cohort study in Denmark.

Data on type 2 diabetes (T2D) risk after breast cancer (BC) could guide preventive strategies. Yet, studies had limitations regarding sample size, follow-up, and contemporary treatments. We evaluated the risk of T2D after BC overall, by cancer treatment, and compared with a matched cohort of cancer-free women. We assembled a population-based cohort of early-stage BC patients aged ≥30 years diagnosed during 1996-2021 in Denmark. We created a comparison cohort of five cancer- and T2D-free women for each BC case, matched six months after BC diagnosis date on age and region. We followed both cohorts until T2D diagnosis, emigration, death, or December 31, 2022. We computed 5-year cumulative incidences and used Cox models to calculate time-varying adjusted hazard ratios (aHR) of T2D. Among 74,526 BC survivors and 372,630 matched cancer-free women, 5-year cumulative incidences of T2D were 3.8% (95%CI = 3.7-3.9) and 3.3% (95%CI = 3.3-3.4), respectively. The aHR of T2D was elevated but attenuated over follow-up (aHR5-years=1.20, 95%CI = 1.15-1.25, and aHR15-years=1.09, 95%CI = 1.05-1.12). Adjuvant endocrine therapy (aHR = 1.14; 95%CI = 1.10-1.19), aromatase inhibitors (aHR = 1.25; 95%CI = 1.18-1.32), and less so tamoxifen (aHR = 1.05; 95%CI = 0.99-1.11), were associated with elevated risk of T2D in women with BC vs cancer-free women. Among BC patients, chemotherapy (aHR = 1.10, 95%CI = 1.03-1.17) and radiation therapy (right-sided aHR = 1.18, 95%CI = 1.09-1.27 and left-sided aHR = 1.24, 95%CI = 1.15-1.33) were associated with increased T2D risk. BC was associated with excess risk of T2D, though of lower magnitude than previously reported. The excess risk was temporary and related to BC treatment but could also be influenced by obesity and heightened T2D diagnostic activity.