Association between long-term fine particulate matter exposure and incident type 2 diabetes in a low-exposure Danish cohort: An AIRCARD analysis.

Lifestyle intervention prevents or delays type 2 diabetes (T2D) in subjects at a high risk of T2D. However, it is not known whether genetic variants modify the effect on incident T2D during lifestyle intervention. To investigate whether a low or high genetic risk has effects on incident T2D in a group-based lifestyle intervention study. The T2D-GENE trial involved 973 men from the Metabolic Syndrome in Men (METSIM) cohort, aged 50-75 years, body mass index ≥25 kg/m2, fasting plasma glucose 5.6-6.9 mmol/L, hemoglobin A1c < 48 mmol/mol, and either a low or high genetic risk score for T2D. There were 2 intervention groups, a low (n = 315) and high genetic risk for T2D (n = 313). They were provided with a 3-year group-based intervention with access to a web portal focused on healthy diet and physical activity. There were also corresponding population-based control groups at low (n = 196) and high (n = 149) genetic risk for T2D who had two laboratory visits (0 and 3 years) and general health advice as a part of their METSIM cohort protocol. The primary outcome was incident T2D, and a secondary outcome was glycemia. The intervention significantly lowered the risk of T2D among the participants with a high genetic risk for T2D [hazards ratio (HR) 0.30, 95% confidence interval (CI) 0.16-0.56, P < .001) whereas in the low genetic risk group the effect was not significant (HR 0.69, 95% CI 0.36-1.32, P = .262). The intervention effect was not significantly different between the high and low genetic risk groups (P = .135). The intervention significantly ameliorated the worsening of glycemia and decreased weight both in the low and high genetic risk groups. Our results showed that individuals with a high genetic risk for T2D benefitted from a low-cost group-based intervention focusing on healthy diet and physical activity. Therefore, all individuals at risk of T2D should be encouraged to make lifestyle changes regardless of genetic risk.

Objective: Smoking is an establish risk factor for type 2 diabetes (T2D); however, little is known about how the timing patterns of smoking is related to T2D risk. We prospectively assessed the association of smoking timing with risk of T2D and examined whether smoking amount or genetic susceptibility might modify the relationship. Methods: This study analyzed 294815 participants from the UK Biobank who were free of diabetes at baseline and with complete data on the time from waking to the first cigarette. Cox proportional hazards models were used to evaluate the association between smoking timing and risk of incident T2D. Results: During a median follow-up time of 12 years, a total of 9937 incident cases of T2D were documented among the 294815 participants. Compared to non-smokers, shorter time from waking to the first cigarette was significantly associated with a higher risk of incident T2D ( P for trend &lt;0.0001). The adjusted hazard ratio (aHR) associated with smoking timing was 1.46 (95% confidence interval [CI] 1.17-1.81) for &gt;2 hours, 1.51 (1.21-1.87) for 1-2 hours, 1.58 (1.34-1.85) for 30-60 minutes, 1.86 (1.57-2.21) for 5-15 minutes, and 2.01 (1.60-2.54) for &lt;5 minutes, respectively. We found that even among light smokers, those with the shortest time from waking to the first cigarette had a 105% higher risk of T2D (HR 2.05, 95% CI 1.52-2.76), which was comparable to heavy smokers. The genetic risk score for T2D did not modify this association ( P -interaction =0.51). Conclusions: Our findings indicate that shorter time from waking to the first cigarette is significantly associated with a higher risk of incident T2D, independent of the amount of cigarettes smoked.

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 &lt;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&lt;0.001). Also, we observed that the associations between proteomic BMI signature and incident T2D were stronger in women than men ( P for interaction &lt; 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.

&lt;p&gt; &lt;/p&gt; &lt;p&gt;&lt;strong&gt;OBJECTIVE&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;To examine the relationship between intakes of a) vegetables/potatoes and incident type 2 diabetes (T2D), and b) explore whether the relationship between vegetable intake and incident T2D is mediated by baseline BMI.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;RESEARCH DESIGN AND METHODS&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;Cross-sectional associations between exposures (baseline intakes of total vegetables, vegetable subgroups, and potatoes), and baseline BMI were assessed by multivariable-adjusted linear regression models. Associations between exposures and incident T2D were examined by multivariable-adjusted Cox proportional hazards models. Mediation by BMI was quantified through exploring natural direct and indirect effects.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;RESULTS&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;Among 54,793 participants of the Danish Diet, Cancer and Health cohort, 7,695 T2D cases were recorded during a median follow-up of 16.3 years. Participants in the highest total vegetable intake quintile (median: 319 g/d) had a 0.35 kg/m2 (95%CI:-0.46, -0.24) lower BMI and a 21% (95%CI: 16, 26%) lower risk of incident T2D after multivariable adjustments, compared to those in the lowest quintile (median: 67 g/d). Baseline BMI mediated ~21% of the association between vegetable intakes and incident T2D. Participants in the highest compared to the lowest (median: 256 vs 52 g/d) potato intake quintile had a 9% (95%CI: 2, 16%) higher risk of T2D after multivariable adjustments with no association found after accounting for underlying dietary patterns. Of the vegetable subclasses, higher intakes of green leafy and cruciferous vegetables were associated with a statistically significantly lower risk of T2D. &lt;/p&gt; &lt;p&gt;&lt;strong&gt;CONCLUSIONS&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;The findings provide evidence that a higher vegetable, but not potato, intake might help to mitigate T2D risk, partly by reducing BMI.&lt;/p&gt;

&lt;p&gt; &lt;/p&gt; &lt;p&gt;&lt;strong&gt;OBJECTIVE&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;To examine the relationship between intakes of a) vegetables/potatoes and incident type 2 diabetes (T2D), and b) explore whether the relationship between vegetable intake and incident T2D is mediated by baseline BMI.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;RESEARCH DESIGN AND METHODS&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;Cross-sectional associations between exposures (baseline intakes of total vegetables, vegetable subgroups, and potatoes), and baseline BMI were assessed by multivariable-adjusted linear regression models. Associations between exposures and incident T2D were examined by multivariable-adjusted Cox proportional hazards models. Mediation by BMI was quantified through exploring natural direct and indirect effects.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;RESULTS&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;Among 54,793 participants of the Danish Diet, Cancer and Health cohort, 7,695 T2D cases were recorded during a median follow-up of 16.3 years. Participants in the highest total vegetable intake quintile (median: 319 g/d) had a 0.35 kg/m2 (95%CI:-0.46, -0.24) lower BMI and a 21% (95%CI: 16, 26%) lower risk of incident T2D after multivariable adjustments, compared to those in the lowest quintile (median: 67 g/d). Baseline BMI mediated ~21% of the association between vegetable intakes and incident T2D. Participants in the highest compared to the lowest (median: 256 vs 52 g/d) potato intake quintile had a 9% (95%CI: 2, 16%) higher risk of T2D after multivariable adjustments with no association found after accounting for underlying dietary patterns. Of the vegetable subclasses, higher intakes of green leafy and cruciferous vegetables were associated with a statistically significantly lower risk of T2D. &lt;/p&gt; &lt;p&gt;&lt;strong&gt;CONCLUSIONS&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;The findings provide evidence that a higher vegetable, but not potato, intake might help to mitigate T2D risk, partly by reducing BMI.&lt;/p&gt;

Although the atherogenic effect of remnant cholesterol (remnant-C) has been widely recognized, the relationship between remnant-C and glucose metabolism remains unclear. This retrospective, longitudinal study investigated the relationship between remnant-C and incident type 2 diabetes (T2D) in a nationwide cohort of Korean adults. A total of 8,485,539 Korean adults without diabetes participated in the national health screening in 2009 and were followed up until 2019. The relationship between remnant-C quartiles and incident T2D was examined by Cox regression models. The risk of incident T2D over the continuum of remnant-C was examined with cubic spline analysis. During the median follow-up period of 9.28 years, 584,649 individuals (6.8%) developed T2D. In multivariable-adjusted analyses, participants in the upper quartile of remnant-C had a higher risk of T2D, with hazard ratios of 1.25 (95% CI 1.24-1.27) in the second quartile, 1.51 (95% CI 1.50-1.53) in the third quartile, and 1.95 (95% CI 1.93-1.97) in the fourth quartile, compared with the lowest quartile. The increase in the risk of T2D owing to high remnant-C concentration was more profound in individuals with fewer traditional T2D risks, such as women, and absence of metabolic abnormalities, including impaired fasting glucose, hypertension, and atherogenic dyslipidemia. Moreover, the magnitude of the increased risk for incident T2D in individuals with higher remnant-C quartiles was higher in younger participants than older participants. These findings indicate that remnant-C profiles provide additional information in predicting future progression of T2D, independent of the conventional lipid parameters.

&lt;p&gt; &lt;/p&gt; &lt;p&gt;&lt;strong&gt;OBJECTIVE: &lt;/strong&gt;Although the atherogenic effect of remnant cholesterol (remnant-C) has been widely recognized, the relationship between remnant-C and glucose metabolism remains unclear. This retrospective longitudinal study investigated the relationship between remnant-C and incident type 2 diabetes (T2D) in a nationwide cohort of Korean adults.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;RESEARCH DESIGN AND METHODS:&lt;/strong&gt; A total of 8,485,539 Korean adults without diabetes participated in the national health screening in 2009 and were followed up until 2019. The relationship between remnant-C quartiles and incident T2D was examined by Cox regression models. The risk of incident T2D over the continuum of remnant-C was examined with cubic spline analysis.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;RESULTS:&lt;/strong&gt; During the median follow-up period of 9.28 years, 584,649 (6.8%) individuals developed T2D. In multivariable-adjusted analyses, participants in the upper quartile of remnant-C had a higher risk of T2D, with hazard ratios of 1.25 (95% CI, 1.24–1.27) in the second quartile and 1.51 (95% CI, 1.50–1.53) in the third quartile, 1.95 (1.93–1.97) in the fourth quartile, compared to the lowest quartile. The increase in the risk of T2D owing to high remnant-C concentration was more profound in individuals with fewer traditional T2D risks such as women, and absence of metabolic abnormalities including impaired fasting glucose, hypertension, and atherogenic dyslipidemia. Moreover, the magnitude of the increased risk for incident T2D in individuals with higher remnant-C quartiles was higher in younger than older participants.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;CONCLUSIONS:&lt;/strong&gt; These findings indicate that remnant-C profiles provide additional information in predicting future progression of T2D, independent of the conventional lipid parameters.&lt;/p&gt;

&lt;p&gt; &lt;/p&gt; &lt;p&gt;&lt;strong&gt;OBJECTIVE: &lt;/strong&gt;Although the atherogenic effect of remnant cholesterol (remnant-C) has been widely recognized, the relationship between remnant-C and glucose metabolism remains unclear. This retrospective longitudinal study investigated the relationship between remnant-C and incident type 2 diabetes (T2D) in a nationwide cohort of Korean adults.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;RESEARCH DESIGN AND METHODS:&lt;/strong&gt; A total of 8,485,539 Korean adults without diabetes participated in the national health screening in 2009 and were followed up until 2019. The relationship between remnant-C quartiles and incident T2D was examined by Cox regression models. The risk of incident T2D over the continuum of remnant-C was examined with cubic spline analysis.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;RESULTS:&lt;/strong&gt; During the median follow-up period of 9.28 years, 584,649 (6.8%) individuals developed T2D. In multivariable-adjusted analyses, participants in the upper quartile of remnant-C had a higher risk of T2D, with hazard ratios of 1.25 (95% CI, 1.24–1.27) in the second quartile and 1.51 (95% CI, 1.50–1.53) in the third quartile, 1.95 (1.93–1.97) in the fourth quartile, compared to the lowest quartile. The increase in the risk of T2D owing to high remnant-C concentration was more profound in individuals with fewer traditional T2D risks such as women, and absence of metabolic abnormalities including impaired fasting glucose, hypertension, and atherogenic dyslipidemia. Moreover, the magnitude of the increased risk for incident T2D in individuals with higher remnant-C quartiles was higher in younger than older participants.&lt;/p&gt; &lt;p&gt;&lt;strong&gt;CONCLUSIONS:&lt;/strong&gt; These findings indicate that remnant-C profiles provide additional information in predicting future progression of T2D, independent of the conventional lipid parameters.&lt;/p&gt;

Background: Experimental evidence suggests de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated (SFA) and monounsaturated fatty acids (MUFA), and also through altered activity of the key regulatory enzyme, Stearoyl-CoA desaturase-1 (SCD-1). Only limited studies have utilized biomarkers of SFA, MUFA and estimated SCD-1 activity to assess their prospective association with risk of type 2 diabetes (T2D). Objective: To investigate the association of 3 major circulating SFA (palmitic acid,16:0, stearic acid,18:0) and MUFA (oleic acid,18:1n-9) in the DNL pathway with metabolic risk factors and incident T2D in a community based cohort of US adults (aged≥65y). In secondary analyses, we assessed relations of other fatty acid biomarkers in the DNL pathway (14:0, 16:1n-7, 16:1n-9, 18:1n-7, and SCD-1 activity estimated by 16:1n-7/16:0 and 18:1n-9/18:0), as well as dietary intake of individual SFA and MUFA with incident T2D. Methods: Among 3060 participants free of T2D and with plasma phospholipid fatty acid measures in 1992 (study baseline), incident T2D cases were identified by medication use assessed annually and repeated blood glucose measures. Usual dietary habits were assessed by repeated FFQs. Associations of fatty acids with metabolic risk factors and incident diabetes were evaluated by multivariate linear regression and Cox proportional models, respectively. Results: During 30,763 person-years of follow-up, 353 incident cases were identified. Higher circulating 16:0 and 18:0 were associated with adverse metabolic profiles including greater BMI, inflammation biomarkers and HOMA-IR (P-trend&lt;0.01 for each), whereas higher 18:1n-9 showed generally beneficial associations (P-trend&lt;0.001 for each). After adjustment for demographic and lifestyle factors, a higher risk of T2D was seen for 16:0 (quintile 5 vs. 1 HR 2.39, 95% CI 1.65-3.46, P-trend&lt;0.001) and 18:0 (HR 1.48, 95% CI 1.04-2.11, P-trend=0.009), but not for 18:1n-9 (HR 0.87, 95% CI 0.59-1.27, P-trend=0.77). In secondary analyses, 16:1n-7 (HR 1.50, 95% CI 1.03-2.20, P-trend=0.03) was positively associated while 18:1n-7 (HR 0.50, 95% CI 0.35-0.72, P-trend&lt;0.001) was inversely associated with risk of T2D. Other fatty acid biomarkers, estimated SCD-1 activity and dietary intake of individual fatty acids, as isocaloric replacement for carbohydrate, were not significantly associated with incident T2D. Conclusion: Circulating levels of 16:0, 18:0 and 16:1n-7 were associated with an increased risk of incident T2D in older adults, whereas 18:1n-7 was associated with lower risk. These results highlight the need for further investigation of biological mechanisms that link specific fatty acids in the DNL pathway to pathogenesis of T2D.

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in elevated risks for coronary heart disease (CHD) and death, but its association with incident type 2 diabetes (T2D) is unknown. Hypothesis: We hypothesized that CHIP is associated with elevated risk of incident T2D. Methods: CHIP was derived from whole genome sequencing of blood DNA in NHLBI Trans-omics for Precision Medicine (TOPMed) cohorts. We analyzed 17,637 participants without prior T2D, cardiovascular disease, or cancer at blood draw, with prospective follow-up for incident T2D. We evaluated baseline prevalence of CHIP vs. no CHIP with incident T2D risk using Cox regression. We also investigated CHIP variants previously related to CHD: DNMT3A , TET2 , ASXL1 , JAK2 , and TP53 . We estimated multivariable-adjusted hazard ratios and 95% confidence intervals (HR [CI]) adjusted for age, sex, body mass index, smoking, alcohol, and education. We combined cohort estimates via fixed effects meta-analysis. Results: On average, participants were age 63.4 years (SD=11.5) and 76% female. Prevalence of CHIP was 6.0% (1,055) at baseline. There were 2,467 incident T2D cases over mean=9.8 years follow-up. Compared to those without a mutation, having CHIP was associated with a 23% higher T2D risk, both overall (combined HR=1.23; 95% CI=1.04, 1.45), and among those with CHD-related CHIP mutations (87% of total CHIP): HR=1.23 (1.03, 1.46). Although those with CHIP mutations of TET2 (HR=1.48; 1.05, 2.08) and ASXL1 (HR=1.76; 1.03, 2.99) had larger elevations in T2D risk, and DNMT3A was suggestive of increased T2D risk (HR=1.15; 0.93, 1.43), statistical power was limited for JAK2 and TP53 mutation analyses. Conclusions: CHIP was associated with higher incidence of T2D. CHIP mutations located on loci previously implicated in aging and CHD were also related to T2D, suggesting shared pathology of atherosclerosis and T2D.

Background: Type 2 diabetes (T2D) is a complex disease driven by lifestyle and genetic factors. The extent to which dietary fat quality may modify T2D genetic burden on the incidence of T2D is unknown. Methods: We used Cox proportional-hazards models to calculate adjusted hazard ratios (HRs) for T2D among 103,2participants of European descent from 15 prospective cohort studies. T2D genetic risk profile was characterized by a 68-variant genetic risk score (GRS) weighted by published effect sizes. Diet was recorded using validated cohort-specific dietary assessment tools. Findings: During a median follow-up of 12 years, 20,451 participants developed T2D. The relative risk of T2D per increment of 10 risk alleles in the GRS was 1.68 (95% confidence interval [CI] 1.62-1.74). Increasing monounsaturated fat intake in place of carbohydrates was associated with a higher risk of T2D (HR per 5% of energy 1.08, 95% CI 1.02-1.15), while increasing polyunsaturated or total ω-3 fat intake in place of carbohydrates was associated with a lower risk of T2D (HR per 5% of energy 0.92, 95% CI 0.85-1.00; and HR per increment of 1g/d 0.95, 95% CI, 0.92-0.99, respectively). We did not observe evidence of significant interactions between dietary fat subtypes and GRS on the risk of T2D. Interpretation: In the present long-term prospective study including 103,2participants, our results support that genetic risk profile and monounsaturated fat intake were each associated with a higher risk of T2D, whereas polyunsaturated fat intake was associated with a lower risk of T2D. Findings from this study suggest that dietary fat recommendations do not need to be tailored to individual T2D genetic risk profile for the primary prevention of T2D, and that dietary fat subtypes associate with the risk of T2D across the spectrum of T2D genetic risk. Disclosure J. Merino: None. H.S. Dashti: None. M. Guasch: None. C. Ellervik: None. C. Smith: None. T.O. Kilpelainen: None. D. Chasman: None. J.C. Florez: Consultant; Self; Intarcia Therapeutics, Inc.. Consultant; Spouse/Partner; Santen.

BackgroundThis study aims to explore the association of childhood maltreatment with obesity and type 2 diabetes (T2D) in adulthood, and whether obesity is a mediator of the latter.MethodsIn a retrospective cohort study using UK Biobank data, participants recalled childhood maltreatment. Linear regression, logistic regression, and Cox proportional hazard models were used to investigate the associations with body mass index (BMI), obesity, and T2D, adjusted for sociodemographic factors. Decomposition analysis was used to examine the extent to which T2D excess risk was attributed to BMI.ResultsOf the 153,601 participants who completed the childhood maltreatment questions, one-third reported some form of maltreatment. Prevalence of adult obesity and incidence of T2D were higher with the number of reported childhood maltreatment types. People who reported ≥3 types of childhood maltreatment were at higher risk of obesity (OR 1.55, 95% CI 1.47–1.63) and incident T2D (HR 1.65, 95% CI 1.52–1.80). Excess T2D risk among those reporting maltreatment could be reduced by 39% if their BMI was comparable to participants who had not been maltreated, assuming causality.ConclusionsPeople who recalled maltreatment in childhood are at higher risk of T2D in adulthood, partly due to obesity.

Background: Previous studies have examined the association between dairy fat intake and incident Type 2 Diabetes (T2D) by conducting analyses of dairy products stratified by fat content, although data linking dairy fat intake and incident T2D and their substitution for other nutrients are sparse. Objective: The aim of this study is to evaluate the association between dairy fat intake and risk of T2D. We assessed the hypothesis that replacing calories from dairy fat for other animal fat or refined carbohydrates will result in modest increases in T2D risk. Methods: We followed up 41,670 men in the Health Professionals Follow-Up Study (1986-2010), 84, 685 women in the Nurses’ Health Study (NHS; 1980-2012), and 90,325 women in the NHSII (1991-2011). Diet was assessed every 4 years with the use of validated food-frequency questionnaires, and other health and lifestyle covariates were collected biennially. Dairy fat contents were determined for dairy products and food items that contain dairy. Dairy fat intake from all relevant food items was summed to calculate total intake, which was expressed as percent of total energy. Incident T2D cases were identified by self-reports during follow-up and confirmed by a validated supplementary questionnaire. A time-dependent Cox proportional hazards regression was used to estimate the hazard ratio for dairy fat intake and T2D risk. Results: During 4,661,518 years of follow-up, we documented 18,298 incident T2D cases. In multivariate models, a 5% increase in energy dairy fat was associated with a 2% risk increase in T2D (RR: 1.02; 95% CI: 1.00, 1.05). In isocaloric substitution models, the replacement of 5% of calories from dairy fat with the equivalent energy from other sources of animal fat or carbohydrate from refined grains was associated with an 7% [RR: 1.07; 95% CI: 1.04, 1.09], and a 7% [RR: 1.07; 95% CI: 1.04, 1.11] increased risk of T2D, respectively. Conversely, a 5% calorie substitution of carbohydrate from whole grains was associated with 7% lower risk of T2D [RR: 0.93; 95% CI: 0.89, 0.97]. Conclusions: In conclusion, dairy fat intake was modestly associated with a higher T2D risk. The replacement of dairy fat with carbohydrates from whole grains may decrease incident T2D risk. Further research is warranted to elucidate the role of other components in dairy products that may contribute to previously reported null associations with T2D.

Metabolites of the tryptophan-kynurenine pathway (i.e., tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxyanthranilic) may be associated with diabetes development. Using a case-cohort design nested in the Prevención con Dieta Mediterránea (PREDIMED) study, we studied the associations of baseline and 1-year changes of these metabolites with incident type 2 diabetes (T2D). Plasma metabolite concentrations were quantified via LC-MS for n = 641 in a randomly selected subcohort and 251 incident cases diagnosed during 3.8 years of median follow-up. Weighted Cox models adjusted for age, sex, body mass index, and other T2D risk factors were used. Baseline tryptophan was associated with higher risk of incident T2D (hazard ratio = 1.29; 95% CI, 1.04-1.61 per SD). Positive changes in quinolinic acid from baseline to 1 year were associated with a higher risk of T2D (hazard ratio = 1.39; 95% CI, 1.09-1.77 per SD). Baseline tryptophan and kynurenic acid were directly associated with changes in homeostatic model assessment for insulin resistance (HOMA-IR) from baseline to 1 year. Concurrent changes in kynurenine, quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine/tryptophan ratio were associated with baseline-to-1-year changes in HOMA-IR. Baseline tryptophan and 1-year increases in quinolinic acid were positively associated with incident T2D. Baseline and 1-year changes in tryptophan metabolites predicted changes in HOMA-IR. Tryptophan levels may initially increase and then deplete as diabetes progresses in severity.

Glycemic index, glycemic load, and risk of type 2 diabetes: results from 3 large US cohorts and an updated meta-analysis