Incident Type 2 Diabetes Research Articles

Retinol and Retinol Binding Protein 4 Levels and Cardiometabolic Disease Risk.

Background:Despite mechanistic studies linking retinol and RBP4 (retinol binding protein 4) to the pathogenesis of cardiovascular diseases (CVD) and type 2 diabetes (T2D), epidemiological evidence is still conflicting. We investigated whether conflicting results of previous studies may be explained by differences in the association of retinol and RBP4 with cardiometabolic risk across subgroups with distinct sex, hypertension state, liver, or kidney function.Methods:We used case-cohorts nested in the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Potsdam cohort (N=27 548) comprising a random sample of participants (n=2500) and all physician-verified cases of incident CVD (n=508, median follow-up time 8.2 years) and T2D (n=820, median follow-up time 6.3 years). We estimated nonlinear and linear multivariable-adjusted associations between the biomarkers and cardiometabolic diseases by restricted cubic splines and Cox regression, respectively, testing potential interactions with hypertension, liver, and kidney function. Additionally, we performed 2-sample Mendelian Randomization analyses in publicly available data.Results:The association of retinol with cardiometabolic risk was modified by hypertension state (P interaction CVD<0.001; P interaction T2D<0.001). Retinol was associated with lower cardiometabolic risk in participants with treated hypertension (hazard ratioper SD [95% CI]: CVD, 0.71 [0.56–0.90]; T2D, 0.81 [0.70–0.94]) but with higher cardiometabolic risk in normotensive participants (CVD, 1.32 [1.06–1.64]; T2D, 1.15 [0.98–1.36]). Our analyses also indicated a significant interaction between RBP4 and hypertension on CVD risk (P interaction=0.04). Regarding T2D risk, we observed a u-shaped association with RBP4 in women (P nonlinearity=0.01, P effect=0.02) and no statistically significant association in men. The biomarkers’ interactions with liver or kidney function were not statistically significant. Hypertension state-specific associations for retinol concentrations with cardiovascular mortality risk were replicated in National Health and Nutrition Examination Survey III.Conclusions:Our findings suggest a hypertension-dependent relationship between plasma retinol and cardiometabolic risk and complex interactions of RBP4 with sex and hypertension on cardiometabolic risk.

Metabolic and Genetic Markers Improve Prediction of Incident Type 2 Diabetes: A Nested Case-Control Study in Chinese.

It is essential to improve the current predictive ability for type 2 diabetes (T2D) risk. We aimed to identify novel metabolic markers for future T2D in Chinese individuals of Han ethnicity and to determine whether the combined effect of metabolic and genetic markers improves the accuracy of prediction models containing clinical factors. A nested case-control study containing 220 incident T2D patients and 220 age- and sex- matched controls from normoglycemic Chinese individuals of Han ethnicity was conducted within the Wuxi Non-Communicable Disease cohort with a 12-year follow-up. Metabolic profiling detection was performed by high-performance liquid chromatography‒mass spectrometry (HPLC-MS) by an untargeted strategy and 20 single nucleotide polymorphisms (SNPs) associated with T2D were genotyped using the Iplex Sequenom MassARRAY platform. Machine learning methods were used to identify metabolites associated with future T2D risk. We found that abnormal levels of 5 metabolites were associated with increased risk of future T2D: riboflavin, cnidioside A, 2-methoxy-5-(1H-1, 2, 4-triazol-5-yl)- 4-(trifluoromethyl) pyridine, 7-methylxanthine, and mestranol. The genetic risk score (GRS) based on 20 SNPs was significantly associated with T2D risk (OR = 1.35; 95% CI, 1.08-1.70 per SD). The area under the receiver operating characteristic curve (AUC) was greater for the model containing metabolites, GRS, and clinical traits than for the model containing clinical traits only (0.960 vs 0.798, P = 7.91 × 10-16). In individuals with normal fasting glucose levels, abnormal levels of 5 metabolites were associated with future T2D. The combination of newly discovered metabolic markers and genetic markers could improve the prediction of incident T2D.

NAFLD improves risk prediction of type 2 diabetes: with effect modification by sex and menopausal status.

The effects of sex and menopausal status on the association between NAFLD and incident type 2 diabetes (T2D) remain unclear. We investigated the effect modification by sex and menopause in the association between NAFLD and T2D; also, the added predictive ability of NAFLD for the risk of T2D was assessed. This cohort study comprised 245,054 adults without diabetes (109,810 premenopausal women; 4958 postmenopausal women; 130,286 men). Cox proportional hazard models were used to estimate hazard ratios (HRs; 95% confidence intervals [CIs]) for incident T2D according to NAFLD status. The incremental predictive role of NAFLD for incident T2D was assessed using the area under the receiver operating characteristic curve, net reclassification improvement, and integrated discrimination improvement. A total of 8381 participants developed T2D (crude incidence rate/103 person-years: 2.9 premenopausal women; 12.2 postmenopausal women; 9.3 men) during median follow-up of 5.3 years. NAFLD was positively associated with incident T2D in all groups. After adjustment for potential confounders, the multivariable-adjusted HRs (95% CIs) for incident T2D comparing NAFLD to no NAFLD were 4.63 (4.17-5.14), 2.65 (2.02-3.48), and 2.16 (2.04-2.29) in premenopausal women, postmenopausal women, and men, respectively. The risks of T2D increased with NAFLD severity as assessed by serum fibrosis markers, and the highest relative excess risks were observed in premenopausal women. The addition of NAFLD to conventional risk factors improved risk prediction for incident T2D in both sexes, with a greater improvement in women than men. NAFLD, including more severe NAFLD, is a stronger risk factor for incident T2D in premenopausal women than in postmenopausal women or men; protection against T2D is lost in premenopausal women with NAFLD.

DNA methylation trajectories and accelerated epigenetic aging in incident type 2 diabetes.

DNA methylation (DNAm) patterns across the genome changes during aging and development of complex diseases including type 2 diabetes (T2D). Our study aimed to estimate DNAm trajectories of CpG sites associated with T2D, epigenetic age (DNAmAge), and age acceleration based on four epigenetic clocks (GrimAge, Hannum, Horvath, phenoAge) in the period 10years prior to and up to T2D onset. In this nested case-control study within Doetinchem Cohort Study, we included 132 incident T2D cases and 132 age- and sex-matched controls. DNAm was measured in blood using the Illumina Infinium Methylation EPIC array. From 107 CpG sites associated with T2D, 10 CpG sites (9%) showed different slopes of DNAm trajectories over time (p < 0.05) and an additional 8 CpG sites (8%) showed significant differences in DNAm levels (at least 1%, p-value per time point < 0.05) at all three time points with nearly parallel trajectories between incident T2D cases and controls. In controls, age acceleration levels were negative (slower epigenetic aging), while in incident T2D cases, levels were positive, suggesting accelerated aging in the case group. We showed that DNAm levels at specific CpG sites, up to 10years before T2D onset, are different between incident T2D cases and healthy controls and distinct patterns of clinical traits over time may have an impact on those DNAm profiles. Up to 10years before T2D diagnosis, cases manifested accelerated epigenetic aging. Markers of biological aging including age acceleration estimates based on Horvath need further investigation to assess their utility for predicting age-related diseases including T2D.

Ambient air pollution, lifestyle, and genetic predisposition associated with type 2 diabetes: findings from a national prospective cohort study

BackgroundThe combined effects of ambient air pollution, lifestyle, and genetic predisposition on incident Type 2 Diabetes (T2D) have not been well documented. MethodsA total of 263,733 participants without T2D at baseline were identified from the UK Biobank. Annual concentrations of five air pollutants were estimated using Land Use Regression, while a healthy lifestyle score (HLS) was constructed using 7 major lifestyle factors, and polygenic risk score (PRS) was generated using 73 genetic variants. Cox regression was used to determine the association between air pollution and incident T2D for different HLS/PRS categories. Potential HLS/PRS interactions and population attributable fraction (PAF) were also examined. ResultsDuring a median follow-up of 11.94 years, 7827 (2.97 %) incident T2D cases were identified. Association between air pollution and incident T2D was stronger among those with higher HLS/PRS in a dose-response fashion. In addition, synergistic interactions between lifestyles and air pollution were observed. Lifestyle was the leading risk factor of T2D with a weighted PAF of 25.54 % (95 % CI: 19.22 %, 27.77 %) for intermediate HLS and 24.24 % (18.24 %, 26.36 %) due to unhealthy HLS. Overall, we estimated that about 25 % of T2D cases could be attributable to air pollution and associated interactions. ConclusionsAssociations between air pollution and T2D were stronger among individuals with unhealthier lifestyle on an additive interaction scale. Public health interventions that address both reduction of exposure to high levels of air pollution in addition to lifestyle changes may have more benefit on reducing T2D risk than focusing on lifestyle changes alone.

Percentage of Age-Predicted Cardiorespiratory Fitness May Be a Stronger Risk Indicator for Incident Type 2 Diabetes Than Absolute Levels of Cardiorespiratory Fitness.

There are inverse and independent associations between cardiorespiratory fitness (CRF) and several adverse cardiometabolic outcomes. The percentage of age-predicted CRF (%age-predicted CRF) is comparable to absolute CRF as a risk indicator for some of these outcomes, but the association between %age-predicted CRF and risk of type 2 diabetes (T2D) has not been previously investigated. We aimed to assess the association between %age-predicted CRF and T2D in a prospective cohort study. Cardiorespiratory fitness, as measured directly by peak oxygen uptake, was assessed in 1901 men aged 42-60 yr who underwent cardiopulmonary exercise testing. The age-predicted CRF estimated from a regression equation for age was converted to %age-predicted CRF using (achieved CRF/age-predicted CRF) × 100. Hazard ratios (95% CI) were estimated for T2D. During a median follow-up of 26.8 yr, 227 T2D cases were recorded. The risk of T2D decreased continuously with increasing %age-predicted CRF ( P value for nonlinearity = .30). A 1-SD increase in %age-predicted CRF was associated with a decreased risk of T2D in analysis adjusted for established risk factors (HR = 0.68: 95% CI, 0.59-0.79). The corresponding adjusted risk was (HR = 0.51: 95% CI, 0.35-0.75) comparing extreme tertiles of %age-predicted CRF. The respective estimates for the association between absolute CRF and T2D were-HR (95% CI)-0.71 (0.60-0.83) and 0.64 (0.44-0.95). Percentage of age-predicted CRF is linearly, inversely, and independently associated with the risk of incident T2D and may be a stronger risk indicator for T2D compared to absolute CRF in a general population of middle-aged and older men.

Association between lipid peroxidation and risk of type 2 diabetes in women

In-vitro and animal studies demonstrate that lipid peroxidation plays an important role in the pathogenesis of type 2 diabetes (T2D). However, human data from prospective studies are limited and contradictory. We used data originally collected in two nested case-control studies of cancer to prospectively evaluate whether systemic levels of lipid peroxidation were associated with incidence of T2D in 1917 women who were 40–70 years old and diabetes-free at baseline. Lipid peroxidation was measured by urinary F2-isoprostanes (F2-IsoPs) and its major metabolite 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M) with GC/NICI-MS assays. The Cox regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident T2D. After a median follow-up of 10.1 years, 187 women were diagnosed with T2D. Urinary concentrations of both F2-IsoPs and F2-IsoP-M were significantly higher in T2D cases than in non-cases. Both biomarkers were positively associated with subsequent risk of T2D in multivariable-adjusted Cox models. When further adjusted for body mass index (BMI), the positive association with F2-IsoP-M was attenuated and no longer statistically significant, whereas the association with F2-IsoPs remained (P for overall significance < 0.001). HR for T2D was 1.68 (95% CI: 1.13, 2.51) for the highest vs the lowest quartile of F2-IsoPs. Moreover, this association appeared more pronounced among women with higher BMI. In summary, our study suggests that F2-IsoPs could be of significance in T2D risk prediction among middle-aged and elderly women.

Longitudinal Branched-Chain Amino Acids, Lifestyle Intervention, and Type 2 Diabetes in the Finnish Diabetes Prevention Study.

ContextCirculating branched-chain amino acids (BCAAs) are associated with the risk of type 2 diabetes (T2D).ObjectiveWe examined to what extent lifestyle intervention aiming to prevent T2D interacts with this association and how BCAA concentrations change during the intervention.MethodsWe computed trajectory clusters by k-means clustering of serum fasting BCAAs analyzed annually by mass spectrometry during a 4-year intervention. We investigated whether baseline BCAAs, BCAA trajectories, and BCAA change trajectories predicted T2D and whether BCAAs predicted T2D differently in the intervention (n = 198) and control group (n = 196).ResultsElevated baseline BCAAs predicted the incidence of T2D in the control group (hazard ratio [HR] 1.05 per 10 μmol/L, P = 0.01), but not in the intervention group. BCAA concentration decreased during the first year in the whole cohort (mean −14.9 μmol/L, P < 0.001), with no significant difference between the groups. We identified 5 BCAA trajectory clusters and 5 trajectory clusters for the change in BCAAs. Trajectories with high mean BCAA levels were associated with an increased HR for T2D compared with the trajectory with low BCAA levels (trajectory with highest vs lowest BCAA, HR 4.0; P = 0.01). A trajectory with increasing BCAA levels had a higher HR for T2D compared with decreasing trajectory in the intervention group only (HR 25.4, P < 0.001).ConclusionLifestyle intervention modified the association of the baseline BCAA concentration and BCAA trajectories with the incidence of T2D. Our study adds to the accumulating evidence on the mechanisms behind the effect of lifestyle changes on the risk of T2D.

Development and validation of a metabolite score for red meat intake: an observational cohort study and randomized controlled dietary intervention

ABSTRACTBackgroundSelf-reported meat consumption is associated with disease risk but objective assessment of different dimensions of this heterogeneous dietary exposure in observational and interventional studies remains challenging.ObjectivesWe aimed to derive and validate scores based on plasma metabolites for types of meat consumption. For the most predictive score, we aimed to test whether the included metabolites varied with change in meat consumption, and whether the score was associated with incidence of type 2 diabetes (T2D) and other noncommunicable diseases.MethodsWe derived scores based on 781 plasma metabolites for red meat, processed meat, and poultry consumption assessed with 7-d food records among 11,432 participants in the EPIC-Norfolk (European Prospective Investigation into Cancer and Nutrition-Norfolk) cohort. The scores were then tested for internal validity in an independent subset (n = 853) of the same cohort. In focused analysis on the red meat metabolite score, we examined whether the metabolites constituting the score were also associated with meat intake in a randomized crossover dietary intervention trial of meat (n = 12, Lyon, France). In the EPIC-Norfolk study, we assessed the association of the red meat metabolite score with T2D incidence (n = 1478) and other health endpoints.ResultsThe best-performing score was for red meat, comprising 139 metabolites which accounted for 17% of the explained variance of red meat consumption in the validation set. In the intervention, 11 top-ranked metabolites in the red meat metabolite score increased significantly after red meat consumption. In the EPIC-Norfolk study, the red meat metabolite score was associated with T2D incidence (adjusted HR per SD: 1.17; 95% CI: 1.10, 1.24).ConclusionsThe red meat metabolite score derived and validated in this study contains metabolites directly derived from meat consumption and is associated with T2D risk. These findings suggest the potential for objective assessment of dietary components and their application for understanding diet–disease associations.The trial in Lyon, France, was registered at clinicaltrials.gov as NCT03354130.

Hepatocyte Rap1a contributes to obesity- and statin-associated hyperglycemia.

SUMMARYExcessive hepatic glucose production contributes to the development of hyperglycemia and is a key feature of type 2 diabetes. Here, we report that activation of hepatocyte Rap1a suppresses gluconeogenic gene expression and glucose production, whereas Rap1a silencing stimulates them. Rap1a activation is suppressed in obese mouse liver, and restoring its activity improves glucose intolerance. As Rap1a′s membrane localization and activation depends on its geranylgeranylation, which is inhibited by statins, we show that statin-treated hepatocytes and the human liver have lower active-Rap1a levels. Similar to Rap1a inhibition, statins stimulate hepatic gluconeogenesis and increase fasting blood glucose in obese mice. Geranylgeraniol treatment, which acts as the precursor for geranylgeranyl isoprenoids, restores Rap1a activity and improves statin-mediated glucose intolerance. Mechanistically, Rap1a activation induces actin polymerization, which suppresses gluconeogenesis by Akt-mediated FoxO1 inhibition. Thus, Rap1a regulates hepatic glucose homeostasis, and blocking its activity, via lowering geranylgeranyl isoprenoids, contributes to statin-induced glucose intolerance.

Nonlinear association between changes in fasting plasma glucose and the incidence of diabetes in a nondiabetic Chinese cohort

BackgroundLimited data show that changes in fasting plasma glucose (FPG changes) are related to the incidence of type 2 diabetes (T2D). We aimed to correlate FPG changes with incident diabetes and evaluate FPG changes as a marker to screen participants at high risk of T2D in China.MethodsA total of 116,816 individuals were followed during a median follow-up of 3.10 years by secondary analysis in a nondiabetic Chinese cohort. The turning points were derived from a receiver operating characteristic curve. Hazard ratios (HRs) were evaluated by Cox proportional hazards models.ResultsA total of 2669 cases of T2D were identified (788 women and 1881 men). The age-standardized incidence of diabetes was 12.87 per 1000 person-years (women: 11.04; men: 14.69). A nonlinear relationship between FPG changes and incident diabetes is shown by the fitting curves. The curves were categorized into three stages by two turning points (-0.04 and 1.25 mmol/L) and conformed to the hook-like pattern: an initial decrease (stage-1), then a transient sharp elevation (stage-2), followed by a slow increase (stage-3). HRs per SD of FPG changes on incident diabetes varied with stage: stage-1: 0.16 (0.12, 0.23), stage-2: 0.20 (0.15, 0.28) and stage-3: 0.22 (0.16, 0.31). Compared with stage-1, the HR in stage-3 was significantly higher at 28.05 (23.99, 32.79), while the increase in stage-2 was slight at 2.16 (1.79, 2.61), and the HR in stage-3 rose to 30.09 (25.02, 36.19).ConclusionsFPG changes had a strong correlation with the incidence of T2D and was a steady indicator that was used to distinguish the participants at high risk of diabetes.

Healthful Plant-Based Diet and Incidence of Type 2 Diabetes in Asian Population.

Plant-based diets have been suggested to be beneficial for type 2 diabetes (T2D). However, studies investigating the association between the healthiness of a plant-based diet and T2D risk are limited. This study explored the prospective association between scores from three different plant-based diet indices and risk of T2D and investigated whether associations differ by demographic and lifestyle factors in the Korean population. Data were derived from the Korean Genome and Epidemiology Study (KoGES), a prospective cohort study initiated between 2001 and 2002. Dietary intakes were assessed using a validated food frequency questionnaire. Scores for three plant-based diet indices (overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI)) were measured. A total of 7363 Korean adults aged 40–69 years without T2D and related chronic diseases at baseline were included. Incident T2D was defined as elevated plasma glucose (≥126 mg/dL), self-report of a doctor’s diagnosis of T2D, or use of oral hypoglycemic drug. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs for T2D risk. During a follow-up period of 14 years, 977 participants developed T2D. A 10-point higher score in hPDI was associated with a 14% lower risk of T2D (HR: 0.86, 95% CI, 0.77–0.95), adjusting for potential confounders. In subgroup analysis, inverse associations between hPDI and T2D risk were stronger in participants with a family history of T2D (HR: 0.58, 95% CI, 0.44 0.76) or history of hypertension (HR: 0.73, 95% CI, 0.60 0.89) than those without a family history of T2D (p interaction = 0.01) or history of hypertension (p interaction = 0.04). Considering the quality of the plant foods may be important for the prevention of T2D in the Korean population, which habitually consumes diets rich in plant foods.

Relation of Change or Substitution of Low- and No-Calorie Sweetened Beverages With Cardiometabolic Outcomes: A Systematic Review and Meta-analysis of Prospective Cohort Studies.

BACKGROUNDAdverse associations of low- and no-calorie sweetened beverages (LNCSB) with cardiometabolic outcomes in observational studies may be explained by reverse causality and residual confounding.PURPOSETo address these limitations we used change analyses of repeated measures of intake and substitution analyses to synthesize the association of LNCSB with cardiometabolic outcomes.DATA SOURCESMEDLINE, Embase, and the Cochrane Library were searched up to 10 June 2021 for prospective cohort studies with ≥1 year of follow-up duration in adults.STUDY SELECTIONOutcomes included changes in clinical measures of adiposity, risk of overweight/obesity, metabolic syndrome, type 2 diabetes (T2D), cardiovascular disease, and total mortality.DATA EXTRACTIONTwo independent reviewers extracted data, assessed study quality, and assessed certainty of evidence using GRADE. Data were pooled with a random-effects model and expressed as mean difference (MD) or risk ratio (RR) and 95% CI.DATA SYNTHESISA total of 14 cohorts (416,830 participants) met the eligibility criteria. Increase in LNCSB intake was associated with lower weight (5 cohorts, 130,020 participants; MD −0.008 kg/year [95% CI −0.014, −0.002]). Substitution of LNCSB for sugar-sweetened beverages (SSB) was associated with lower weight (three cohorts, 165,579 participants; MD, −0.12 [−0.14, −0.10,] kg/y) and lower incidence of obesity (OB) (one cohort, 15,765 participants; RR 0.88 [95% CI 0.88, 0.89]), coronary heart disease (six cohorts, 233,676 participants; 0.89 [0.81, 0.98]), cardiovascular disease mortality (one cohort, 118,363 participants; 0.95 [0.90, 0.99]), and total mortality (one cohort, 118,363 participants; 0.96 [0.94, 0.98]) with no adverse associations across other outcomes. Substitution of water for SSB showed lower weight (three cohorts, 165,579 participants; MD −0.10 kg/year [−0.13, −0.06]), lower waist circumference (one cohort, 173 participants; −2.71 cm/year [−4.27, −1.15]) and percent body fat (one cohort, 173 participants; −1.51% per year [−2.61, −0.42]), and lower incidence of OB (one cohort, 15,765 participants; RR 0.85 [0.75, 0.97]) and T2D (three cohorts, 281,855 participants; 0.96 [0.94, 0.98]). Substitution of LNCSB for water showed no adverse associations.LIMITATIONSThe evidence was low to very low certainty owing to downgrades for imprecision, indirectness, and/or inconsistency.CONCLUSIONSLNCSB were not associated with cardiometabolic harm in analyses that model the exposure as change or substitutions. The available evidence provides some indication that LNCSB in their intended substitution for SSB may be associated with cardiometabolic benefit, comparable with the standard of care, water.

Fasting Proinsulin Independently Predicts Incident Type 2 Diabetes in the General Population.

Fasting proinsulin levels may serve as a marker of β-cell dysfunction and predict type 2 diabetes (T2D) development. Kidneys have been found to be a major site for the degradation of proinsulin. We aimed to evaluate the predictive value of proinsulin for the risk of incident T2D added to a base model of clinical predictors and examined potential effect modification by variables related to kidney function. Proinsulin was measured in plasma with U-PLEX platform using ELISA immunoassay. We included 5001 participants without T2D at baseline and during a median follow up of 7.2 years; 271 participants developed T2D. Higher levels of proinsulin were associated with increased risk of T2D independent of glucose, insulin, C-peptide, and other clinical factors (hazard ratio (HR): 1.28; per 1 SD increase 95% confidence interval (CI): 1.08–1.52). Harrell’s C-index for the Framingham offspring risk score was improved with the addition of proinsulin (p = 0.019). Furthermore, we found effect modification by hypertension (p = 0.019), eGFR (p = 0.020) and urinary albumin excretion (p = 0.034), consistent with an association only present in participants with hypertension or kidney dysfunction. Higher fasting proinsulin level is an independent predictor of incident T2D in the general population, particularly in participants with hypertension or kidney dysfunction.

Meat Food Group Intakes and the Risk of Type 2 Diabetes Incidence.

AimThis study aimed to evaluate the association of meats and their substitute food group intakes, including nuts, eggs, and legumes, with type 2 diabetes (T2D).MethodsFor this secondary analysis, we selected eligible adults (n = 6,112) from the Tehran Lipid and Glucose Study participants with a median follow-up of 6.63 years. Expert nutritionists assessed dietary intakes using a valid and reliable semiquantitative food frequency questionnaire. Biochemical and anthropometric variables were assessed at baseline and follow-up examinations. We used multivariable Cox proportional hazard regression models to estimate the new onset of T2D concerning meats and their substitute food groups.ResultsWe performed this study on 2,749 men and 3,363 women, aged 41.4 ± 14.2 and 39.1 ± 13.1 years, respectively. The number of participants with incident T2D was 549. After adjusting for confounders, legume [HR: 1, 0.74 (0.58–0.94), 0.69 (0.54–0.90), 0.65 (0.50–0.84), P-trend = 0.01)] was inversely associated with incident T2D. Fish intake [HR: 1, 1.0 (0.79–1.27), 1.17 (0.91–1.50), 1.14 (0.89–1.45), P-trend = 0.01)] was positively associated with incident T2D. In subjects who reported poultry consumption of 36.4–72.8 g/day, a positive association [HR: 1.33 (1.03–1.71)] between poultry intake and T2D risk was observed.ConclusionOur findings revealed that a diet rich in legumes significantly reduced the risk of T2D incidence, while a diet high in poultry increased the risk of T2D incidence, probably due to high-temperature cooking methods and environmental contaminants.

Incidence of Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease

Type 2 diabetes (T2D) is a growing problem in children. Children with NAFLD are at potentially high risk for developing T2D; however, the incidence of T2D in this population is unknown. This study aimed to determine the incidence of T2D in children with NAFLD and identify associated risk factors. Children with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network were followed longitudinally. Incidence of T2D was determined by using clinical history and fasting laboratory values. Cumulative incidence curves were developed for time to T2D. A Cox regression multivariable model was constructed using best subsets Akaike's Information Criteria selection. This study included 892 children with NAFLD and with a mean age of 12.8 years (2.7) followed for 3.8 years (2.3) with a total 3234 person-years at risk. The incidence rate of T2D was 3000 new cases per 100,000 person-years at risk. At baseline, 63 children had T2D, and during follow-up, an additional 97 children developed incident T2D, resulting in a period prevalence of 16.8%. Incident T2D was significantly higher in females versus males (hazard ratio [HR], 1.8 [1.0-2.8]), associated with BMI z-score (HR, 1.8 [1.0-3.0]), and more severe liver histology including steatosis grade (HR, 1.3 [1.0-1.7]), and fibrosis stage (HR, 1.3 [1.0-1.5]). Children with NAFLD are at high risk for existing and incident T2D. In addition to known risk factors for T2D (female and BMI z-score), severity of liver histology at the time of NAFLD diagnosis was independently associated with T2D development. Targeted strategies to prevent T2D in children with NAFLD are needed.

Fatigue, health-related quality-of-life and metabolic changes in men treated with enzalutamide or abiraterone acetate plus prednisone for metastatic castration-resistant prostate cancer: A randomised clinical trial (HEAT)

IntroductionEnzalutamide and abiraterone acetate plus prednisone (AAP) have similar efficacy in metastatic castration-resistant prostate cancer (mCRPC). Herein, we compare fatigue, health-related quality-of-life (HRQoL) and metabolic changes in men with mCRPC treated with enzalutamide and AAP. Materials and methodsIn this single-centre, open-labelled, phase IV trial, patients with metastatic prostate cancer progressing on androgen deprivation therapy were randomly assigned to enzalutamide (160 mg daily) or AAP (1000 mg abiraterone acetate and 10 mg prednisone daily) as first-line mCRPC treatment. The primary outcome was the difference in changed fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire). The secondary outcomes were differences in changed HRQoL (Functional Assessment of Cancer Therapy-Prostate questionnaire), body composition, weight, glucose homeostasis, lipid profile and blood pressure. All outcomes were assessed at baseline and at 12-week follow-up. Trial registration: clinicaltrialsregister.eu (2017-000099-27). Results170 patients were randomised (1:1) to enzalutamide or AAP. The primary outcome was positive with a clinically meaningful difference in fatigue, favouring AAP (3.4 points, 95% CI 1.2; 5.6, P = 0.003). The group difference in changed HRQoL did not reach clinical significance. The most important metabolic finding was a higher increase in glycated haemoglobin (HbA1c) for AAP than enzalutamide (3.4 mmol/mol, 95% CI 2.1; 4.8, P = 0.001). Eight patients developed type 2 diabetes (T2D) in the AAP group and none in the enzalutamide group. No treatment-related serious adverse event was observed. ConclusionsAAP resulted in less fatigue than enzalutamide in a randomised setting. This was at the expense of a higher HbA1c increase and incidence of T2D.

The Effect of Rye-Based Foods on Postprandial Plasma Insulin Concentration: The Rye Factor.

Consumption of whole grain has been associated with lower incidence of type-2 diabetes, cardiovascular disease and their risk factors including improved glycemic control. In comparison with other whole grain products, rye bread has been shown to induce lower insulin response in the postprandial phase, without affecting the glucose response. This phenomenon has been referred to as the “rye factor” and is being explored in this review where we summarize the findings from meal and extended meal studies including rye-based foods. Overall, results from intervention studies showed that rye-based foods vs. (wheat) control foods had positive effect on both insulin and glucose responses in the postprandial phase, rather than on insulin alone. Mechanistic studies have shown that the rye factor phenomenon might be due to slowing of the glucose uptake in the intestine. However, this has also been shown for wheat-based bread and is likely an effect of structural properties of the investigated foods rather than the rye per se. More carefully controlled studies where standardized structural properties of different cereals are linked to the postprandial response are needed to further elucidate the underlying mechanisms and determinants for the effect of specific cereals and product traits on postprandial glycemic control.

Prolactin and Maternal Metabolism in Women With a Recent GDM Pregnancy and Links to Future T2D: The SWIFT Study.

Prolactin is a multifaceted hormone known to regulate lactation. In women with gestational diabetes mellitus (GDM) history, intensive lactation has been associated with lower relative risk of future type 2 diabetes (T2D). However, the role of prolactin in T2D development and maternal metabolism in women with a recent GDM pregnancy has not been ascertained. We examined the relationships among prolactin, future T2D risk, and key clinical and metabolic parameters. We utilized a prospective GDM research cohort (the SWIFT study) and followed T2D onset by performing 2-hour 75-g research oral glucose tolerance test (OGTT) at study baseline (6-9 weeks postpartum) and again annually for 2 years, and also by retrieving clinical diagnoses of T2D from 2 years through 10 years of follow up from electronic medical records. Targeted metabolomics and lipidomics were applied on fasting plasma samples collected at study baseline from 2-hour 75-g research OGTTs in a nested case-control study (100 future incident T2D cases vs 100 no T2D controls). Decreasing prolactin quartiles were associated with increased future T2D risk (adjusted odds ratio 2.48; 95% CI, 0.81-7.58; P = 0.05). In women who maintained normoglycemia during the 10-year follow-up period, higher prolactin at baseline was associated with higher insulin sensitivity (P = 0.038) and HDL-cholesterol (P = 0.01), but lower BMI (P = 0.001) and leptin (P = 0.002). Remarkably, among women who developed future T2D, prolactin was not correlated with a favorable metabolic status (all P > 0.05). Metabolomics and lipidomics showed that lower circulating prolactin strongly correlated with a T2D-high risk lipid profile, with elevated circulating neutral lipids and lower concentrations of specific phospholipids/sphingolipids. In women with recent GDM pregnancy, low circulating prolactin is associated with specific clinical and metabolic parameters and lipid metabolites linked to a high risk of developing T2D.

Combined association of walking pace and grip strength with incident type 2 diabetes.

The current study aims to investigate the combined association of walking pace and grip strength with incident type 2 diabetes (T2D). A total of 205 738 participants (mean age 56.6 ± 8.1 years, 115 139 [56.0%] women) without diagnosed or unknown diabetes at baseline from the UK Biobank study were included in this prospective study. Walking pace was self‐reported as slow, average, or brisk. Grip strength was measured using a dynamometer and classified as weak, average, and strong. The combined association of walking pace and grip strength with incident T2D was investigated using Cox‐proportional hazards models with a 2‐year landmark analysis. The additive interaction was conducted by estimating relative excess risk due to interaction (RERI). After the median follow‐up period of 5.4 years (interquartile range: 4.8–6.5), 5082 (2.5%) participants were diagnosed with T2D. Compared to brisk‐strong individuals (reference group), people who were slow‐weak had a higher risk of T2D (hazard ratio: 1.64 [95% CI, 1.42–1.89]) after adjusting for all covariates. There were dose–response gradients across both walking pace and grip strength variables. There was a modest amount of negative additive interaction (RERI; −0.06 [95% CI, −0.16; −0.01]. To conclude, slower pace and weaker grip strength were associated with a higher risk of developing T2D, independent of sociodemographics, lifestyle, and adiposity. Combining walking pace and grip strength might be a practical approach to screening people who are at increased risk of developing T2D.