Background: The American Heart Association’s (AHA) Life’s Essential 8 (LE8) identifies essential metrics for cardiovascular disease prevention and includes blood glucose, blood lipids, blood pressure, nicotine exposure, physical activity, diet, sleep duration, and body mass index (BMI). While the LE8 has been linked to cardiovascular outcomes, associations with type 2 diabetes (T2D) remain less established, particularly in diverse populations. Objective: To examine the association between LE8 and incident T2D among postmenopausal women and to evaluate subgroups by race, ethnicity, and age. Methods: We included 19,403 postmenopausal women in the Women’s Health Initiative without T2D at baseline. The overall LE8 score (0–100) was calculated using AHA definitions and categorized as high (80–100), moderate (60–79), and low (0–59), with higher scores indicating a healthier lifestyle. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between LE8 and incident T2D, adjusted for potential confounders. Results: During a mean of 16.3 years of follow-up, 3921 cases of T2D were identified. Women in the highest LE8 category had a 57% lower risk of T2D compared with those in the lowest category (HR, 0.43, 95% CI [0.38, 0.49]). A 20-point higher LE8 score was associated with a 43% lower risk (0.57 [0.54, 0.60]). Among the individual LE8 metrics, per 20-point increase in blood glucose (0.61 [0.59, 0.63]) and BMI (0.88 [0.87, 0.90]) were most strongly associated with T2D, followed by smoking (0.96 [0.94–0.98]), blood lipids (0.95 [0.93–0.97]), and blood pressure (0.95 [0.93–0.96]). Diet, physical activity, and sleep were not significantly associated with T2D in this population. Subgroup analyses showed stronger associations among Hispanic/Latina women (0.58 [0.55, 0.62]) compared with non-Hispanic women (0.46 [0.41, 0.53]), per 20-point increase. Associations were also stronger among younger women, but did not vary by race. Conclusions: Higher LE8 scores were associated with reduced risk of T2D in postmenopausal women, with blood glucose and BMI having the strongest associations with T2D. LE8 may serve as a practical framework for risk assessment to reduce T2D incidence in aging women.

The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors-particularly physical activity, obesity and diet-explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood (n = 6454) and lung (n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank-derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Background: While B-vitamins have long been hypothesized to hold promise for primary stroke prevention, there is a lack of systematic and comprehensive assessment of the impact of the full range of folate intake and status, as well as other B-vitamins. Methods: We examined roles of B-vitamins (dietary intake and supplements) in the Women's Health Initiative (WHI, 154,718 postmenopausal women) and circulating biomarkers in the United States (US) All of Us Research Program (AoU, 99,667 adults) for incident stroke, adjusting for known risk factors using multivariable Cox models. Mendelian randomization (MR), B-vitamin interactions, homocysteine mediation, and subgroup analyses by risk factors were evaluated. Results: In WHI (7,577 incident strokes over median 19.2-year follow-up), higher baseline intakes of thiamin (highest vs. lowest quintile medians: 4.6 vs. 0.9 mg/d), riboflavin (5.9 vs. 1.3 mg/d), niacin (54.6 vs. 11.8 mg/d), pyridoxine (6.2 vs. 1.1 mg/d), and folate (913.6 vs. 253.9 mcg/d) were associated with lower stroke risk (HRs for highest vs. lowest quintile: 0.85-0.90). In AoU (5,163 incident strokes over median 5.7-year follow-up), higher plasma folate (24 vs. 7 nmol/L) and pyridoxine (234 vs. 18 nmol/L) linked to lower overall stroke risk (HRs: 0.82 and 0.60). Inverse relations for intakes and levels persisted for ischemic stroke, except plasma pyridoxine with hemorrhagic stroke. Significant interactions seen for thiamin-folate, riboflavin-niacin, and niacin-folate pairs. Inverse associations for thiamin, pyridoxine, and folate intakes were stronger in younger participants; thiamin, niacin, pyridoxine, folate, and cobalamin in lipid-lowering drug users. Higher plasma folate strongly associated with reduced risk in college-educated or smokers. Homocysteine mediated 12% of plasma folate-stroke link. MR supported pyridoxine and folate effects on small vessel stroke (OR per standard deviation: 0.96 and 0.52). Conclusions: Higher folate and pyridoxine exposures consistently linked to lower stroke risk, largely independent of homocysteine. Higher thiamin, riboflavin, and niacin intakes also associated with lower risk, varying by participant characteristics. Findings support considering these vitamins in stroke prevention guidelines for subgroups like younger adults, smokers, and lipid-lowering drug users.

OBJECTIVES:Cognitive impairment is a major public health concern among older adults. This study examined the associations of purpose in life (PIL), personal growth (PG), and life satisfaction (LS) with cognitive impairment risk, as well as potential underlying pathways. METHODS:The study population comprised 1,179 U.S. women (aged 77-93 years) from the Women's Health Initiative Memory Study - Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) cohort who completed psychological well-being assessments in 2012 and were followed until 2021. Cognitive status was evaluated annually using standardized assessments and central adjudication. RESULTS:Over an average of 5.4 years of follow-up, 355 participants were classified with MCI (175) or dementia (180). The association between PIL and cognitive impairment was largely mediated by lower perceived stress and higher physical activity (61%), rendering the direct effect non-significant. Women in the highest PG quartile had a 33% lower risk of impairment (HR = 0.67, 95% CI: 0.46-0.96). Mediation analyses showed both direct and indirect effects of PG. No association was found for LS. CONCLUSIONS:PG and PIL were linked to lower cognitive impairment risk, primarily via stress reduction and physical activity. Targeting these factors may promote cognitive health among aging populations.

Objective. This study aimed to characterize plasma metabolomic signatures reflecting the metabolic pathways of plant and animal protein intake, and examine their association with the risk of type 2 diabetes (T2D). Methods. In three cohorts, plasma metabolites were profiled from 11,742 participants from the Nurses' Health Study (NHS; mean age 56.8 y), NHSII (mean age 44.6 y), and Health Professional's Follow-Up Study (mean age 63.3 y) using liquid chromatography mass spectrometry. Protein intakes (% kcal) were derived from two repeated food frequency questionnaires closest to the blood draw. Elastic net regressions identified metabolomic signatures of plant and animal protein intake and their ratio. Metabolomic signatures were replicated in the Women's Health Initiative (WHI; n = 2,092) cohort. Multivariable-adjusted Cox regression models evaluated associations between signatures and T2D. Results. Signatures for plant protein, animal protein, and their ratio comprised 63, 50, 40 metabolites. Seventeen metabolites overlapped between the three signatures, including creatine, C34:5 phosphatidylcholine plasmalogens, C18:0 sphingomyelin, and N-acetylornithine. Higher plant protein signature scores were associated with lower T2D risk [HR per 1SD = 0.91 (0.83, 1.00); p = 0.049], while higher animal protein signature scores were associated with higher risk [HR per 1SD = 1.13 (1.03, 1.23); p = 0.008], with consistent replication. Conclusions. Plant and animal protein intake have distinct plasma metabolomic signatures. The biological footprint of plant protein exposure is favorably associated with T2D, whereas that of animal protein is adverse. Findings from these prospective cohort studies support that increased plant protein intake may provide benefits for T2D prevention.

Metabolomic indices summarizing diet-related metabolic responses are instrumental for examining and replicating diet–disease associations. Here we aim to identify metabolomic signatures characterizing the amounts and types of dietary carbohydrate and assess their associations with type 2 diabetes (T2D) risk. Nutritional metabolomics indices were developed using data from 1,196 healthy participants in the Lifestyle Validation Study with 7-day diet records (7DDRs). Elastic net regression within cross-validation was used to derive metabolomic indices of total carbohydrates and primary food sources. Replication was conducted using feeding menu data among 153 women from the Nutrition and Physical Activity Assessment Study. Associations with incident T2D were examined using multivariable Cox regression in 11,454 participants from the Nurses’ Health Study, Nurses’ Health Study II and Health Professionals Follow-up Study. Metabolites positively associated with total carbohydrates and added sugars mainly included glycerolipids (diacylglycerols and triglycerides), whereas glycerophospholipids (phosphatidylethanolamines and phosphatidylcholines) were inversely associated. Whole grains were linked to betaine, 3-indolepropionic acid (IPA) and hippuric acid; vegetables and legumes to IPA, N-acetylornithine and pipecolic acid; and fruits to proline-betaine and IPA. Identified metabolomic signatures showed significant correlations with a 7-day diet record-assessed diet in the Lifestyle Validation Study (Pearson r 0.33–0.65). In the Nutrition and Physical Activity Assessment Study, the metabolomic index of total carbohydrates was also significantly correlated with intake (r = 0.40). Signatures for total carbohydrates, added sugars, refined grains and potatoes were associated with higher T2D risk (HR per s.d. (95

BACKGROUND:Multivitamin-multimineral (MVM) supplements have been associated with lower blood pressure (BP) in several small trials. We investigated the effects of a MVM on incident hypertension and BP in a secondary analysis of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). METHODS:COSMOS is a 2×2 factorial, double-blinded RCT testing effects of cocoa extract and MVM supplementation among women aged ≥65 years and men aged ≥60 years. Among 8905 COSMOS participants free from hypertension, effects of MVM supplementation on incident hypertension were investigated. Hypertension diagnosis was ascertained through self-reports. Additionally, in two substudies with BP measurements (N = 529 at clinic by research staff and 994 at home by technician), we evaluated the effects on 2-year BP changes. RESULTS:Incident hypertension was observed in N = 1034 (22.9%) in MVM arm and N = 1039 (23.6%) in placebo arm over a median of 3.4 years (IQR: 3.0, 3.9) of follow-up, with hazard ratio (HR) 0.98 [95% CI: 0.90, 1.06]. Effects differed according to baseline diet quality, with HRs of incident hypertension 0.81 [0.70, 0.95] and 1.14 [1.01, 1.28] among participants with lower and higher Alternate Mediterranean Diet score, respectively (P-interaction = .001). There was no effect of MVM on 2-year changes in systolic BP (4.4 mmHg in MVM; 4.5 mmHg in placebo), while pronounced effects were observed for baseline normal BP (P-interaction = .004). CONCLUSIONS:MVM supplementation versus placebo did not reduce hypertension incidence or lower BP overall. Exploratory analyses showed greater reduction in hypertension risk and BP changes among those with lower dietary quality and normal BP at baseline, respectively. CLINICAL TRIAL REGISTRATION:NCT02422745.

BACKGROUND:Weight changes after menopause contribute to cardiometabolic risk, yet hormonal determinants of long-term weight trajectories remain incompletely understood. Asprosin, a fasting-induced adipokine involved in hepatic gluconeogenesis and appetite regulation, has been associated with metabolic disease, although its prospective role in affecting weight change remains unknown. OBJECTIVES:This study aimed to examine whether plasma asprosin concentrations are directly and prospectively associated with changes in body weight and body composition among postmenopausal women. METHODS:In a case-control study of 4020 postmenopausal women (1987 newly developed/incident diabetes cases and 2033 matched controls) nested within the Women's Health Initiative, we prospectively evaluated participants' baseline plasma concentrations of asprosin in relation to 3-y changes in weight, measures of central obesity, and the risk of major weight gain or loss (≥7% of baseline weight). Associations were examined overall and stratified by baseline body mass index (BMI) or whether the participant developed diabetes during follow-up. Dual-energy X-ray absorptiometry-derived fat and lean mass were available for a subset of participants (n = 178). RESULTS:In the full cohort (n = 4020), baseline asprosin was not associated with 3-y weight change or changes in central adiposity. However, among matched controls with BMI <30 kg/m2, participants in the highest asprosin quartile gained 1.61 kg less than those in the lowest quartile [adjusted β: -1.61; 95% confidence interval (CI): -2.69, -0.52; P-trend < 0.01] and had lower odds of major weight gain (adjusted OR: 0.57; 95% CI: 0.37, 0.88; P-trend < 0.01) and higher odds of major weight loss (adjusted odds ratio: 1.83; 95% CI: 1.10, 3.05; P-trend = 0.02). CONCLUSIONS:In this prospective study of postmenopausal women followed for 3 y, baseline asprosin concentrations were associated with weight change in apparently healthy women without diabetes or obesity.

INTRODUCTION:Understanding the risk factors that associate with early cognitive decline in Alzheimer's disease (AD) is important to identify high-risk individuals and initiate early intervention. Existing studies show that APOEε4, systemic inflammation, and diabetes may play roles in cognitive decline, but the extent to which these factors interact with each other remains unclear. Our objective was to examine the main effects and higher-order interactions between APOEε4, high sensitivity-C-reactive protein (hs-CRP) as a measure of systemic inflammation, and diabetes on domain-specific measures of cognitive function in two ancillary studies of post-menopausal women from the Women's Health Initiative (WHI). METHOD:We identified 2979 cognitively unimpaired women from the WHI Epidemiology of Cognitive Health Outcomes and the WHI Memory Study of Younger Women with cognitive follow-up of up to 13 years. Linear mixed-effects models examined the main and interactive effects of APOEε4, hs-CRP, and diabetes on longitudinal changes in the personal communication for Cognitive Status-modified Test (TICS-m), East Boston Memory Test (immediate and delayed; EBMT), Oral Trail Making Test (OTMT), Verbal Fluency Test (VF-A), Digit Span Test Backwards (DST-backward), and the California Verbal Learning Test (CVLT). All models were adjusted for baseline age, education, body mass index, the WHI randomization arm, and the cohort. RESULTS:APOEε4 carriers had steeper cognitive decline in TICS-m, EBMT (immediate and delayed), VF-A, and CVLT scores relative to non-carriers. Higher levels of hs-CRP were associated with steeper cognitive decline in the DST-backwards scores. There was no association of diabetes or any evidence of interactive effects on cognitive decline in our study. CONCLUSIONS:In this large longitudinal study of post-menopausal women, our findings support the hypothesis that genetic risk and systemic inflammation independently influence cognitive decline, but there was no evidence of synergistic effects in postmenopausal women. Further research is needed to elucidate the mechanistic pathways underlying these associations with cognitive decline.

BACKGROUND:Defining the minimum carbohydrate requirement is crucial for health and disease prevention. However, the estimated average requirement (EAR) for carbohydrates in adults was based on limited data that might not reflect physiological adaptations or individual differences. OBJECTIVES:We aimed to assess 1) the minimum dietary carbohydrate requirement in apparently healthy Chinese adults by identifying the highest carbohydrate intake that avoids nutritional ketosis, 2) the effect modification by sex and age, and 3) validate a novel ex vivo method to monitor the 24-h dynamics of β-hydroxybutyrate (BHB). METHODS:In this controlled feeding trial, 22 healthy adults first completed a 3-d very low-carbohydrate diet (20 g/d) to induce nutritional ketosis (fasting venous BHB ≥0.5 mmol/L). Carbohydrate intake was then progressively increased (40, 50, 70, 90, and 110 g/d) while maintaining constant protein and fat intakes. We measured circulating BHB levels via the reference-standard venous blood biochemistry and a novel ex vivo method for continuous ketone monitoring (CKM). Linear mixed-effects models were used to estimate the carbohydrate intake threshold corresponding to a BHB concentration of 0.5 mmol/L. RESULTS:During the study period, participants' resting metabolic rate remained unchanged, although a shift from carbohydrate to fat oxidation was confirmed during ketosis. A significant negative nonlinear relationship was observed between carbohydrate intake and BHB levels. The minimum carbohydrate requirements were ∼105 g/d for males and 93 g/d for females, as indicated by venous blood measures, and 88 g/d for males and 78 g/d for females via CKM. There was a strong agreement between the CKM and venous measurements (intraclass correlation coefficient = 0.93). CONCLUSIONS:Findings from this controlled feeding study established the minimum carbohydrate requirement to avoid significant fat mobilization in healthy Chinese adults, revealing a marked sex difference, and validated the clinical utility of a novel ex vivo method for dynamic metabolic monitoring. This trial was registered at clinicaltrials.gov as ChiCTR2500102659. (https://www.chictr.org.cn/showproj.html?proj=272503).

Postmenopausal women tend to experience significant changes in body composition, particularly abdominal adipose tissue (AAT) deposition patterns, which are hypothesized to be critical factors influencing future chronic disease risk. The level of protein intake to maintain or achieve a more favorable body composition for health in postmenopausal women is a central, largely unanswered question relating to the appropriateness of current dietary guideline recommendations for sufficient protein intake (set at 0.8 g/kg/day). To estimate the hypothetical effect of a range of protein intake levels on 3-year mean changes in body composition measures in postmenopausal women. We analyzed data from 3789 postmenopausal women aged 50–79 enrolled in the Women’s Health Initiative (WHI) to emulate a 3-year target trial of adhering to increasing levels of protein intake: ≥0.8 g/kg/d, ≥1.0 g/kg/d, ≥1.2 g/kg/d, and ≥1.5 g/kg/d. All participants had repeated Dual X-Ray Absorptiometry (DXA) scans with derived abdominal visceral (VAT) and subcutaneous adipose tissue (SAT). The measured differences in average levels of VAT, SAT, and other body composition measures determined at end of follow-up were estimated with the parametric-g formula. Over 3 years, hypothetical interventions of increasing levels of dietary protein intake are estimated to have dose-dependent reductions in abdominal VAT, SAT, and overall body fat, and increases in lean soft tissue, with potential benefits observed at ≥1.2 g/kg/day and the greatest estimated benefit at ≥1.5 g/kg/day of dietary protein. Compared to no intervention, if all participants hypothetically adhered to a total daily protein intake of ≥1.5 g/kg/day over 3 years, they would be estimated to have lower levels of VAT (−13.1 cm2, 95% Confidence Interval [CI] −18.9, −7.3), SAT (−25.3 cm2, 95% CI −39.7, −11.0), total body fat % (−1.0%, 95% CI −1.7, −0.3), body weight (−2.5 kg, 95% CI −3.7, −1.2) and greater lean soft tissue % (0.9%, 95% CI 0.3, 1.6) over 3 years. This hypothetical emulated intervention suggests that postmenopausal women who maintain a hypothetical total protein intake of at least 1.2 g/kg/day could experience beneficial changes in abdominal VAT, SAT, and overall body composition over three years, with even greater estimated benefits observed at an intake of 1.5 g/kg/day. These findings suggest that protein intake higher than guideline recommendations may better support healthier body composition and lower chronic disease risk in postmenopausal women.

Background:Evidence linking different B vitamins to stroke risk remains sparse, particularly regarding long-term intake and dose-response thresholds in populations fortified with folic acids. Objective:To prospectively investigate the associations of long-term intake of B vitamins and their circulating levels with incident stroke. Methods:Using a validated food frequency questionnaire, we assessed intake of B vitamins among 121,565 participants in the Women's Health Initiative (WHI). We also examined circulating levels of B vitamins in relation to stroke risk among 99,660 All of Us Research Program (AoU) participants. Multivariable Cox models estimated hazard ratios (HRs) and their 95 % confidence intervals (CIs). Results:In WHI (6803 incident stroke cases; median follow-up: 18.4 years), higher long-term intakes of thiamin, riboflavin, niacin, pyridoxine, and folate were significantly associated with lower stroke risk, with HRs (95 % CI) of 0.84 (0.76, 0.92), 0.90 (0.81, 0.99), 0.80 (0.72, 0.88), 0.88 (0.80, 0.96), and 0.88 (0.80, 0.97) comparing the highest to the lowest quintiles, respectively. Most B vitamins exhibited reverse J-shaped associations, whereas folate showed a linear inverse relationship up to at least 2000 dietary folate equivalent (DFE)/day. In AoU (5163 incident stroke cases; median follow-up: 5.7 years), higher plasma folate and pyridoxine were associated with lower risk (HRs: 0.86 and 0.50, respectively). Conclusions:In two large prospective cohorts of US adults, higher intake of thiamin, riboflavin, niacin, pyridoxine, and folate, as well as higher circulating concentrations of pyridoxine and folate, were associated with a lower risk of stroke, even after folic acid fortification.

Objective: To examine the association between Life Essential 8 (LE8) and incident T2D in the Women's Health Initiative (WHI), and to assess whether associations varied by race and ethnicity. Research Design and Methods: Prospective cohort study of 19,403 postmenopausal women enrolled in the WHI without T2D at baseline. Data were analyzed from 1993 through 2024. The LE8 score (range, 0-100), comprising blood glucose, blood lipids, blood pressure, smoking, physical activity, diet, sleep, and body mass index (BMI), categorized as high (80-100), moderate (50-79), and low (0-49) according to AHA definitions. Incident treated T2D was self-reported during follow-up. Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs for LE8 categories and continuous scores. Results: During a mean follow-up of 16.3 years, 3921 women developed T2D. Compared with the lowest category, women in the highest LE8 category had a 57% lower risk of T2D (HR, 0.43; 95% CI, 0.38-0.49). A 20-point increase in LE8 score was associated with a 43% lower risk (HR, 0.57; 95% CI, 0.54-0.60). Among individual domains, BMI and glucose were most strongly associated with T2D. Subgroup analyses by 20-point increase in LE8 showed greater risk reduction among Hispanic/Latina women (HR, 0.46; 95% CI, 0.41-0.53) compared with non-Hispanic women (HR, 0.58; 95% CI, 0.55-0.62), but no significant association with race was observed. Conclusions: Higher LE8 scores are associated with a reduced risk of T2D in postmenopausal women, supporting LE8 as a useful framework for lifestyle-based diabetes prevention strategies.

Large-scale multiancestry genome-wide association studies have identified hundreds of loci associated with type 2 diabetes (T2D) and glycemic traits, yet imputed genotyping arrays limit the detection of low-frequency and rare variants. Whole-genome sequencing (WGS) offers a more complete view of genetic variation, especially across diverse populations. We analyzed high-coverage (38×) WGS data from 21,913 T2D case subjects, 61,036 control subjects, and up to 50,011 individuals with no diabetes with fasting glucose, fasting insulin, and HbA1c from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine Program. We performed single-variant association testing, conditional analysis, fine-mapping, and Bayesian colocalization to identify genetic signals and assess regulatory relevance in diabetes-related tissues. We identified 76 distinct association signals across 34 loci, including novel variants at DUSP9 for T2D, and ROBO1, NDN, and MYT1 for HbA1c. Fine-mapping narrowed credible sets and improved causal variant resolution. Colocalization highlighted 80 expression signals in diabetes-related tissues, linking genetic associations to functional regulatory mechanisms. Our findings demonstrate the utility of WGS to uncover novel variants in diverse populations, enhance locus resolution, and link regulatory variation to disease-relevant tissues. This work refines the genetic architecture of T2D and glycemic traits and supports precision medicine efforts targeting diverse populations. ARTICLE HIGHLIGHTS:We aimed to improve understanding of the genetic architecture of type 2 diabetes and glycemic traits by leveraging whole-genome sequencing in diverse populations. Our goal was to identify novel variants, refine known loci, and link genetic signals to regulatory mechanisms through colocalization with expression quantitative trait loci. We discovered novel variants, significantly improved fine-mapping resolution, and identified 80 regulatory colocalization signals in diabetes-relevant tissues. These findings support precision medicine approaches by connecting genetic variation to functional biology in type 2 diabetes.