Higher Risk Of Type 2 Diabetes Research Articles

Remnant Cholesterol Is an Independent Predictor of Type 2 Diabetes: A Nationwide Population-Based Cohort Study.

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.

Prediction of clinical events by liver stiffness and chronic kidney disease by NAFLD in patients with type-2 diabetes

Background & AimsNon-alcoholic fatty liver disease (NAFLD) is associated with poorer glycemic control and a higher risk of type-2 diabetes (T2D) complications, extrahepatic and cardiovascular disease (CVD). Our study aim was to evaluate the association between NAFLD, T2D complications, and the development of overall clinical events (OCE) (CV, liver-related, and mortality) in patients with T2D. MethodsProspective single-center study comprising T2D subjects with no history of CVD and non-T2D matched controls. Patients were selected from the Outpatient Diabetes Clinic of Vall d’Hebron Hospital and related primary care centers. Results186 diabetics and 57 controls were included. Amongst T2D, 124/186 subjects had NAFLD (66.6%). T2D-NAFLD subjects showed a heavier metabolic burden and higher median liver stiffness (5.6kPa [4.5–7.3] vs 4.8 [4.2–5.8]; p=0.004) compared to non-NAFLD diabetics. During a median follow-up of 5.6 years, 33 (17.7%) T2D patients developed OCE vs 4 (7.0%) controls (p=0.049). No differences were found for OCE between NAFLD and non-NAFLD diabetics (16.9% vs 19.4%; p=0.68). CV was the most reported outcome and only one liver event occurred. NAFLD diabetics showed more often chronic kidney disease (CKD), whereas T2D complications and subclinical CVD rates were similar. A higher liver stiffness, older age, and male gender were independently associated with OCE amongst the entire T2D population and NAFLD diabetics. ConclusionsNAFLD and liver stiffness were associated with CKD and clinical outcomes in diabetics, respectively. A hepatic evaluation is recommended to identify high-risk T2D patients that would benefit from early referral to specialized care.

Evaluating the role of non-alcoholic fatty liver disease in cardiovascular diseases and type 2 diabetes: a Mendelian randomization study in Europeans and East Asians.

Whether non-alcoholic fatty liver disease (NAFLD) causes cardiovascular disease (CVD) and type 2 diabetes (T2D) is unclear and possible differences between ethnicities have not been thoroughly explored. We used Mendelian randomization (MR) to assess the role of NAFLD in CVD and T2D risk in Europeans and East Asians. We conducted a MR study using genetic predictors of alanine aminotransferase (ALT), liability to NAFLD, aspartate transaminase (AST), liver magnetic resonance imaging corrected T1 and proton density fat fraction and combined them with genome-wide association studies (GWAS) summary statistics of CVD, T2D and glycaemic traits (sample size ranging from 14 400 to 977 320). Inverse-variance weighted analysis was used to assess the effect of NAFLD in these outcomes, with sensitivity analyses and replication in FinnGen. We conducted analyses in East Asians using ethnicity-specific genetic predictors of ALT and AST, and the respective outcome GWAS summary statistics. In Europeans, higher ALT was associated with higher T2D risk (odds ratio: 1.77 per standard deviation, 95% CI 1.5 to 2.08), with similar results for other exposures, across sensitivity analyses and in FinnGen. Although NAFLD proxies were related to higher coronary artery disease (CAD) and stroke risk, sensitivity analyses suggested possible bias by horizontal pleiotropy. In East Asians, higher ALT was possibly associated with higher T2D risk, and ALT and AST were inversely associated with CAD. NAFLD likely increases the risk of T2D in Europeans and East Asians. Potential differential effects on CAD between Europeans and East Asians require further investigation.

Abstract 13226: Low-Carbohydrate Diets and Risk of Type 2 Diabetes in U.S. Men and Women

Introduction: Evidence regarding associations between overall low-carbohydrate diets (LCDs) and the risk of developing type 2 diabetes (T2D) remains to be mixed. In the current analysis, we aimed to prospectively assess associations of various LCDs that emphasize different quality of protein, fat, and carbohydrate with T2D risk in U.S. men and women. Methods: A prospective cohort study was conducted in 203,541 men and women participating in the Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-Up Study who were free of T2D, cardiovascular disease, and cancer at baseline and were followed for up to >30 years. Five LCD scores based on sources of protein, fat, and carbohydrate differentiated by their qualities were derived every four years based on dietary assessments by a validated food frequency questionnaire. Results: During 5,095,048 person-years of follow-up, 19,675 T2D cases were documented. In the multivariable model, a higher overall LCD score was associated with higher T2D risk in a dose-response manner: the hazard ratio (HR) comparing highest vs. lowest quintile was 1.28 (95% confidence interval: 1.22-1.34; P -trend <0.001). A vegetable-based LCD score that emphasizes vegetable protein and fat intake was associated with 6% lower T2D risk (0.94 [0.90-0.98; P -trend =0.003]), and a healthy LCD score that further de-emphasizes refined carbohydrate intake was associated with 15% lower T2D risk (0.85 [0.81-0.89; P -trend <0.001]). In contrast, LCD scores emphasizing high animal protein and fat intake were associated with higher T2D risk. The HRs (95% CIs) comparing extreme quintiles were 1.35 (1.29-1.42; P -trend <0.001) for an overall animal-based LCD score and 1.39 (1.32-1.46; P -trend <0.001) when such a score that further de-emphasizes whole grain intake. Conclusions: LCDs were not beneficial for the primary prevention of T2D unless they emphasize the quality of the macronutrient compositions.

Abstract 12593: Type 2 Diabetes Mellitus Polygenic Score Predicts New Onset Diabetes in Patients With Established Atherosclerotic Cardiovascular Disease: A FOURIER Sub-Study

Introduction: Polygenic scores (PS) have been created to predict the risk of developing type 2 diabetes (T2D). We tested whether a contemporary T2D PS predicts new-onset T2D in individuals with established atherosclerotic cardiovascular disease (ACSVD) and across a range of HbA1c and BMI levels. Methods: We analyzed individuals without T2D at baseline with available genotyping data from the FOURIER trial. Genetic risk was characterized using a PS for T2D based on 554 previously identified genome-wide significant single nucleotide polymorphisms. PS was analyzed continuously and categorized as high (top 20%) vs. low (bottom 80%). New-onset T2D was pre-specified and adjudicated centrally according to the American Diabetes Association definitions. HRs were calculated and adjusted for baseline age, sex, BMI, HbA1c, SBP, DBP, HDL-C, and triglycerides. Results: The 9115 participants in this study had mean age of 63±9 yrs and 22.5% were women. Mean HbA1c and BMI were 5.6±0.4% and 28.7±5 kg/m 2 , respectively. A total of 641 new-onset diabetes cases occurred over a median of 2.3 years of follow up. T2D PS significantly predicted new-onset T2D (adjusted HR per 1-SD increase 1.13 95% CI 1.04-1.23, P=0.006). The rates of new-onset T2D in the high and low genetic risk categories were 10.8% vs. 6.6 %, respectively (adjusted HR 1.41 95% CI 1.18-1.69, P<0.001, Panel A). The predictive strength of high genetic risk for T2D appeared strongest in those without key clinical risk factors, namely, those without pre-diabetes [HR 2.01 (1.03-3.89); Panel B] and those with normal weight [HR 2.77 (1.65-4.66); Panel C]. There was no treatment interaction with evolocumab for new-onset T2D. Conclusions: Within a relatively short follow up, we found that a contemporary T2D PS strongly predicted new-onset T2D in patients with established ASCVD. This genetic risk appeared more discriminatory in those lacking traditional clinical risk factors.

Abstract 12926: Senescent CD8 T Cells are Enriched in Atherosclerotic Plaques From Patients With Type 2 Diabetes and Their Circulating Levels Are Normalized by Intensive Lipid Lowering

Introduction: Senescence is a key driver of age-related chronic inflammatory diseases including type 2 diabetes (T2D). Senescent T cells lose their ability to control tissue homeostasis and present aberrant cytokine and cytotoxic responses that ultimately cause tissue damage. Atherosclerotic plaques from T2D present more severe pathology than patients with no diabetes (ND) and circulating senescent CD8 T cells are increased in T2D and associated with myocardial infarction. However, whether senescent CD8 T cells accumulate in atherosclerotic plaques of T2D patients is unknown. Hypothesis: Senescent T cells infiltrate atherosclerotic plaques and contribute to the aggravated cardiovascular risk in T2D. Methods: We performed unbiased scRNA-seq analysis (75,049 total cells) of plaques from T2D (n=12) and ND patients (n=10) enrolled in the Athero-In Study. Circulating immune cells from T2D (n=16) and ND (n=6) patients enrolled in the CHORD study were analyzed using mass cytometry (CyTOF) before and after lipid lowering treatment. Results: We found a cluster of CD8 T cells expressing a senescence gene signature ( B3GAT1, KLRG1, KLRF1), as well as proinflammatory ( IFNG, TNF, CCL4, CCL5 ) and cytotoxic ( GZMB, PRF1, GNLY ) genes. Plaque senescent CD8 T cells showed a terminally differentiated effector memory phenotype (TEMRA) with high expression of CX3CR1 and low expression of lymphoid-homing genes ( SELL, CCR7) . CyTOF analysis revealed that circulating senescent CD8+ CD28- CD57+ T cells were increased in T2D compared to ND patients. Treatment with PCSK9 inhibitor plus statin/ezetimibe, which reduced LDL levels by >70% at 4 weeks, normalized senescent CD8 T cell frequency in T2D patients to the levels of ND subjects at baseline. No changes were observed in cells from cholesterol-reduced ND patients. Conclusions: Our results show that senescent CD8+ T cells are enriched in atherosclerotic plaques and blood of T2D patients. The observation that acute lipid lowering normalized circulating senescent CD8 T cells in T2D patients indicates that T cell senescence can be improved by more aggressive lipid control in high risk T2D subjects. Further analyses are needed to understand how T cell senescence contributes to atherosclerosis and impaired regression in T2D.

The role of ultra-processed food consumption and depression on type 2 diabetes incidence: a prospective community study in Quebec, Canada.

The goal of the present study was to evaluate the association between depression and ultra-processed food (UPF) consumption as risk factors for developing type 2 diabetes (T2D). A prospective community study. Baseline data (2009-2010) from CARTaGENE community health study from Quebec, Canada, were used. Food and drink consumption was assessed using the Canadian-Diet History Questionnaire II and grouped according to their degree of processing by the NOVA classification, and participants were categorised into tertiles of UPF (g/d). Depression was defined using either a validated cut-off score on the Patient Health Questionnaire-9 or antidepressant use. The outcome was the incidence of T2D, examined in 3880 participants by linking survey data with administrative health insurance data. Cox regression models estimated the associations between UPF, depression and incident T2D. 40-69-year-old individuals at baseline. In total, 263 (6·8 %) individuals developed T2D. Participants with high depressive symptoms and high UPF consumption showed the highest risk for T2D (adjusted hazard ratios (aHR) = 1·58, 95 % CI (0·98, 2·68)), compared to those with low depressive symptoms and low UPF consumption. The risk for T2D was similar when high depressive symptoms and antidepressant use were combined with high UPF (aHR 1·62, 95 % CI (1·02, 2·57)). This study shows that co-occurring depression and high UPF consumption were associated with a higher risk for T2D. Early management and monitoring of both risk factors might be essential for diabetes prevention.

Proteomic signatures for identification of impaired glucose tolerance.

The implementation of recommendations for type 2 diabetes (T2D) screening and diagnosis focuses on the measurement of glycated hemoglobin (HbA1c) and fasting glucose. This approach leaves a large number of individuals with isolated impaired glucose tolerance (iIGT), who are only detectable through oral glucose tolerance tests (OGTTs), at risk of diabetes and its severe complications. We applied machine learning to the proteomic profiles of a single fasted sample from 11,546 participants of the Fenland study to test discrimination of iIGT defined using the gold-standard OGTTs. We observed significantly improved discriminative performance by adding only three proteins (RTN4R, CBPM and GHR) to the best clinical model (AUROC = 0.80 (95% confidence interval: 0.79-0.86), P = 0.004), which we validated in an external cohort. Increased plasma levels of these candidate proteins were associated with an increased risk for future T2D in an independent cohort and were also increased in individuals genetically susceptible to impaired glucose homeostasis and T2D. Assessment of a limited number of proteins can identify individuals likely to be missed by current diagnostic strategies and at high risk of T2D and its complications.

Cumulative Consumption of Sulfur Amino Acids and Risk of Diabetes: A Prospective Cohort Study

Cross-sectional studies have suggested that consumption of sulfur amino acids (SAAs), including methionine and cysteine, is associated with a higher risk of type 2 diabetes (T2D) in humans and with T2D-related biomarkers in animals. But whether higher long-term SAA intake increases the risk of T2D in humans remains unknown. We aimed to investigate the association between long-term dietary SAA intake and risk of T2D. We analyzed data collected from 2 different cohorts of the Framingham Heart Study, a long-term, prospective, and ongoing study. The Offspring cohort (1991-2014) included participants from fifth through ninth examinations, and the Third-Generation cohort (2002-2011) included participants from first and second examinations. After excluding participants with a clinical history of diabetes, missing dietary data, or implausible total energy intake, 3222 participants in the Offspring cohort and 3205 participants in the Third-Generation cohort were included. Dietary intake was assessed using a validated FFQ. The relations between energy-adjusted total SAA (methionine and cysteine) intake or individual SAA intake (in quintiles) and risk of incident T2D were estimated via Cox proportional hazards models after adjusting for dietary and nondietary risk factors. Associations across the 2 cohorts were determined by direct combination and meta-analysis. During the 23 y of follow-up, 472 participants reported a new diagnosis of T2D in the 2 cohorts. In the meta-analysis, the HRs of T2D comparing the highest with the lowest intake of total SAAs, methionine, and cysteine were 1.8 (95% CI: 1.3, 2.5), 1.7 (95% CI: 1.2, 2.3), and 1.4 (95% CI: 1.0, 2.1), respectively. The association of SAA intake with T2D was attenuated after adjusting animal protein intake in sensitivity analyses. Our findings show that excess intake of SAAs is associated with higher risk of T2D. Dietary patterns that are low in SAAs could help in preventing T2D.

Nitrites and nitrates dietary exposure from natural sources and additives and type-2 diabetes risk

Abstract Nitrates and nitrites occur naturally in water and soil and are commonly ingested from drinking water and dietary sources. They are also used as food additives. The epidemiological evidence linking exposure to nitrites/nitrates with type-2 diabetes (T2D) risk is scarce. We aimed to study these associations in a large population based prospective cohort study. Overall, 104,168 adults from the French NutriNet-Santé cohort study (median follow-up time 6.7 years) were included. Associations between intakes of nitrites and nitrates (evaluated using repeated 24h dietary records, linked to a comprehensive food composition database and accounting for details of commercial names/brands of industrial products) and risk of T2D were assessed using cause-specific multivariable Cox proportional hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). During follow-up, 969 incident T2D cases were ascertained. Total nitrites and nitrites from natural sources were both positively associated with higher T2D risk (HRtertile 3 vs.1=1.29 (95% CI 1.06-1.56), Ptrend=0.004, and 1.27 (95% CI 1.05-1.54), Ptrend=0.01, respectively). Participants with higher exposure to nitrites from food additives (i.e. above the sex-specific median), and specifically those having higher exposure to sodium nitrite (e250) had a higher T2D risk compared with those who were not exposed to food additive nitrites (HRtertile 3 vs.1=1.58 (95% CI 1.28-1.94), Ptrend<0.001, and 1.59 (95% CI 1.30-1.96), Ptrend<0.001), respectively). There was no evidence for an association between nitrates of any source and T2D risk (all Ptrend>0.4). In this large prospective cohort, a higher dietary exposure to nitrites (from both natural sources and food additives) was associated with higher T2D risk. These results provide additional evidence in the context of current discussions about updating regulations on the use of nitrites as food additives. Key messages • A high exposure to dietary nitrites (from both natural and food additive sources) is associated with an increased risk of type-2 diabetes. • These findings support further regulations concerning the use of nitrites as food additives in processed meats.

Circadian nutritional behaviours and risk of type 2 diabetes in NutriNet-Santé

Abstract Skipping breakfast and late-night-eating have been associated with risk factors for type 2 diabetes (T2D). However, less is known about the link between daily timing and frequency of food intake and risk of developing T2D. The objective of the present study is to investigate the associations between circadian nutritional behaviours, defined by meal timings and frequency, and risk of T2D. 103,312 adults (79% females, mean age at baseline=42.7) from the French NutriNet-Santé cohort were included. Participants’ circadian nutritional behaviours were assessed using repeated 24 h dietary records. Associations of time of first and last meal of the day, meal frequency and of nighttime fasting duration with risk of T2D were assessed by multivariable Cox proportional hazard models adjusted for known risk factors. During a median follow-up of 7.3 years, 963 new cases of T2D were ascertained. Compared with subjects reporting on average a first meal before 8AM, those having a first meal after 9AM had a higher risk of developing T2D, HR = 1.59 (1.30 to 1.94). A late time of last meal (after 9PM) was associated with a higher risk of T2D, HR = 1.28 (1.06 to 1.54), but this association was no longer significant after adjusting for time of first meal. Each additional eating episode was associated with a reduction of the risk of T2D, HR = 0.95 (0.90 to 0.99), p-value=0.01. Overall, nighttime fasting duration was not associated with risk of T2D, except in participants having breakfast before 8AM after a nighttime fasting duration of more than 13 hours (HR = 0.47, 0.27 to 0.82). In this large prospective study, circadian nutritional behaviours were associated with risk of T2D. Daytime nutritional behaviours and specifically an early first meal was associated with a lower risk of type 2 diabetes. If confirmed in other largescale studies, an early breakfast should be considered in preventive strategies for type 2 diabetes. Key messages • If confirmed in other largescale studies, an early breakfast could be considered in preventive strategies for type 2 diabetes. • Beyond nutritional quality of meals, meal timing could also be a risk factor for type-2 diabetes.

The urban exposome and type 2 diabetes: A deep learning approach

BACKGROUND AND AIM: Type 2 diabetes (T2D) is a chronic disease with high individual and societal burden. Risk of T2D is partly influenced by urban characteristics, such as air pollution, or indirectly through their relation with lifestyle behaviours (e.g. walkability, food environment). Environmental characteristics are generally studied individually in their association with T2D, but occur simultaneously in real life, and may associate with T2D in nonlinear and non-additive ways. We aimed to identify which factors of the urban exposome are associated with T2D by applying artificial neural networks (ANN). In addition, we compared results of ANN model with penalized regression LASSO, as a more conventional method. METHODS: We analyzed baseline data from 14,829 participants of the Occupational and Environmental Health Cohort study living across the Netherlands. Self-reported questionnaire data were used to identify participants diagnosed with T2D (n=676(4.6%)). Exposome variables (n=86) were linked to individual home addresses, including air pollution, traffic noise, green-space, chemicals in drinking water, built environmental and neighborhood socio-demographic characteristics. Models were adjusted for individual socio-demographic variables. Nested cross-validation was used to determine the optimal model parameters of both approaches (ANN and LASSO), and the cross-validated predictive accuracies were compared. RESULTS: One exposure was selected by each approach. Living in neighborhoods with a higher share of non-Western immigrants (selected by ANN) was associated with a higher risk of T2D. Higher average home value in residential neighborhood (selected by LASSO) was associated with a lower risk of T2D. Cross-validated prediction error logLoss (sd) was 0.177 (0.0060) for ANN and 0.167 (0.0022) for LASSO. CONCLUSIONS: Neighborhood socio-demographic characteristics are associated with the risk of T2D. Accuracy of the ANN model was lower than LASSO, which might be due to the low prevalence of diabetes and relatively weak signal in the data. KEYWORDS: Multiple exposures, Machine learning, Neighborhood socio-demographic characteristics

Economic evaluation of using polygenic risk score to guide risk screening and interventions for the prevention of type 2 diabetes in individuals with high overall baseline risk.

Type 2 diabetes (T2D) with increasing prevalence is a significant global public health challenge. Obesity, unhealthy diet, and low physical activity are one of the major determinants of the rise in T2D prevalence. In addition, family history and genetic risk of diabetes also play a role in the process of developing T2D. Therefore, solutions for the early identification of individuals at high risk for T2D for early targeted detection of T2D, prevention, and intervention are highly preferred. Recently, novel genomic-based polygenic risk scores (PRSs) have been suggested to improve the accuracy of risk prediction supporting the targeting of preventive interventions to those at highest risk for T2D. Therefore, the aim of the present study was to assess the cost-utility of an additional PRS testing information (as a part of overall risk assessment) followed by a lifestyle intervention and an additional medical therapy when estimated 10-year overall risk for T2D exceeded 20% among Finnish individuals screened as at the high-risk category (i.e., 10%–20% 10-year overall risk of T2D) based on traditional risk factors only. For a cost-utility analysis, an individual-level state-transition model with probabilistic sensitivity analysis was constructed. A 1-year cycle length and a lifetime time horizon were applied in the base-case. A 3% discount rate was used for costs and QALYs. Cost-effectiveness acceptability curve (CEAC) and estimates for the expected value of perfect information (EVPI) were calculated to assist decision makers. The use of the targeted PRS strategy reclassified 12.4 percentage points of individuals to be very high-risk individuals who would have been originally classified as high risk using the usual strategy only. Over a lifetime horizon, the targeted PRS was a dominant strategy (i.e., less costly, more effective). One-way and scenario sensitivity analyses showed that results remained dominant in almost all simulations. However, there is uncertainty, since the probability (EVPI) of cost-effectiveness at a WTP of 0€/QALY was 63.0% (243€) indicating the probability that the PRS strategy is a dominant option. In conclusion, the results demonstrated that the PRS provides moderate additional value in Finnish population in risk screening leading to potential cost savings and better quality of life when compared with the current screening methods for T2D risk.

Immunoglobulin G N-glycan, inflammation and type 2 diabetes in East Asian and European populations: a Mendelian randomization study

BackgroundImmunoglobulin G (IgG) N-glycans have been shown to be associated with the risk of type 2 diabetes (T2D) and its risk factors. However, whether these associations reflect causal effects remain unclear. Furthermore, the associations of IgG N-glycans and inflammation are not fully understood.MethodsWe examined the causal associations of IgG N-glycans with inflammation (C-reactive protein (CRP) and fibrinogen) and T2D using two-sample Mendelian randomization (MR) analysis in East Asian and European populations. Genetic variants from IgG N-glycan quantitative trait loci (QTL) data were used as instrumental variables. Two-sample MR was conducted for IgG N-glycans with inflammation (75,391 and 18,348 participants of CRP and fibrinogen in the East Asian population, 204,402 participants of CRP in the European population) and T2D risk (77,418 cases and 356,122 controls of East Asian ancestry, 81,412 cases and 370,832 controls of European ancestry).ResultsAfter correcting for multiple testing, in the East Asian population, genetically determined IgG N-glycans were associated with a higher risk of T2D, the odds ratios (ORs) were 1.009 for T2D per 1- standard deviation (SD) higher GP5, 95% CI = 1.003–1.015; P = 0.0019; and 1.013 for T2D per 1-SD higher GP13, 95% CI = 1.006–1.021; P = 0.0005. In the European population, genetically determined decreased GP9 was associated with T2D (OR = 0.899 per 1-SD lower GP9, 95% CI: 0.845–0.957). In addition, there was suggestive evidence that genetically determined IgG N-glycans were associated with CRP in both East Asian and European populations after correcting for multiple testing, but no associations were found between IgG N-glycans and fibrinogen. There was limited evidence of heterogeneity and pleiotropy bias.ConclusionsOur results provided novel genetic evidence that IgG N-glycans are causally associated with T2D.

The iHealth-T2D study: a cluster randomised trial for the prevention of type 2 diabetes amongst South Asians with central obesity and prediabetes—a statistical analysis plan

BackgroundSouth Asians are at high risk of type 2 diabetes (T2D). Lifestyle modification is effective at preventing T2D amongst South Asians, but the approaches to screening and intervention are limited by high costs, poor scalability and thus low impact on T2D burden. An intensive family-based lifestyle modification programme for the prevention of T2D was developed. The aim of the iHealth-T2D trial is to compare the effectiveness of this programme with usual care.MethodsThe iHealth-T2D trial is designed as a cluster randomised controlled trial (RCT) conducted at 120 sites across India, Pakistan, Sri Lanka and the UK. A total of 3682 South Asian men and women with age between 40 and 70 years without T2D but at elevated risk for T2D [defined by central obesity (waist circumference ≥ 95 cm in Sri Lanka or ≥ 100 cm in India, Pakistan and the UK) and/or prediabetes (HbA1c ≥ 6.0%)] were included in the trial. Here, we describe in detail the statistical analysis plan (SAP), which was finalised before outcomes were available to the investigators. The primary outcome will be evaluated after 3 years of follow-up after enrolment to the study and is defined as T2D incidence in the intervention arm compared to usual care. Secondary outcomes are evaluated both after 1 and 3 years of follow-up and include biochemical measurements, anthropometric measurements, behavioural components and treatment compliance.DiscussionThe iHealth-T2D trial will provide evidence of whether an intensive family-based lifestyle modification programme for South Asians who are at high risk for T2D is effective in the prevention of T2D. The data from the trial will be analysed according to this pre-specified SAP.Ethics and disseminationThe trial was approved by the international review board of each participating study site. Study findings will be disseminated through peer-reviewed publications and in conference presentations.Trial registrationEudraCT 2016–001,350-18. Registered on 14 April 2016. ClinicalTrials.gov NCT02949739. Registered on 31 October 2016.

White rice, brown rice and the risk of type 2 diabetes: a systematic review and meta-analysis

ObjectiveIntake of white rice has been associated with elevated risk for type 2 diabetes (T2D), while studies on brown rice are conflicting. To inform dietary guidance, we synthesised the evidence...

Associations of Physical Activity, Kidney Function, Diet, and Inflammatory Markers in High-Risk Type-2 Diabetes With Early-Stage Chronic Kidney Disease (CKD)

OBJECTIVES Quantitative information and associations of physical activity, kidney function, diet, and inflammation are dearth in high-risk diabetes. Yet could delay type-2 diabetes, late-stage chronic kidney disease (CKD) and could be useful in designing effective interventions. The study aims to quantify the associations of physical activity, kidney function, diet and inflammation in adults with high-risk type-2 diabetes (and early CKD) recruited to a lifestyle education programme.METHODS Baseline, 12-month dietary, accelerometery, and circulating inflammatory markers, Interleukin-6 (IL-6) and C-reactive protein (CRP) data were assessed from 159 (104 male) high-risk diabetes with stage 2 CKD (mean (SD) estimated glomerular filteration rate (eGFR); 77.5(7.6) ml/min/1.73m2, age; 66(6) years, BMI; 31.8(4.2) kg/m2) who were recruited to a lifestyle education programme. Linear regression examined the effects and associations of the outcome measures.RESULTS eGFR decreased by -2.0 (1.7) ml/min/1.73 m2 (P = 0.04) after 12-months, but mean daily steps, moderate to vigorous physical activity (MVPA) levels, intakes of fibre, total and unsaturated fat, and circulating IL-6 and CRP did not change. However, inter-individual responses were highly variable. eGFR correlated positively with baseline IL-6 (r = 0.17, P = 0.02). Unadjusted, there were no associations between change in eGFR (12_0) and change in any of the activity, inflammatory or dietary outcomes. However, the regression models of these outcomes for change in eGFR (12_0) became significant with multiple covariates.CONCLUSION A combination of healthy lifestyle behaviours should be encouraged for a positive effect on future kidney function.

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.

Susceptibility Loci for Type 2 Diabetes in the Ethnically Endogamous Indian Sindhi Population: A Pooled Blood Genome-Wide Association Study.

Type 2 diabetes (T2D) is a complex metabolic derangement that has a strong genetic basis. There is substantial population-specificity in the association of genetic variants with T2D. The Indian urban Sindhi population is at a high risk of T2D. The genetic basis of T2D in this population is unknown. We interrogated 28 pooled whole blood genomes of 1402 participants from the Diabetes In Sindhi Families In Nagpur (DISFIN) study using Illumina’s Global Screening Array. From a total of 608,550 biallelic variants, 140 were significantly associated with T2D after adjusting for comorbidities, batch effects, pooling error, kinship status and pooling variation in a random effects multivariable logistic regression framework. Of the 102 well-characterized genes that these variants mapped onto, 70 genes have been previously reported to be associated with T2D to varying degrees with known functional relevance. Excluding open reading frames, intergenic non-coding elements and pseudogenes, our study identified 22 novel candidate genes in the Sindhi population studied. Our study thus points to the potential, interesting candidate genes associated with T2D in an ethnically endogamous population. These candidate genes need to be fully investigated in future studies.

Polygenic risk for type 2 diabetes, lifestyle, metabolic health, and cardiovascular disease: a prospective UK Biobank study

BackgroundFew studies have examined associations between genetic risk for type 2 diabetes (T2D), lifestyle, clinical risk factors, and cardiovascular disease (CVD). We aimed to investigate the association of and potential interactions among genetic risk for T2D, lifestyle behavior, and metabolic risk factors with CVD.MethodsA total of 345,217 unrelated participants of white British descent were included in analyses. Genetic risk for T2D was estimated as a genome-wide polygenic risk score constructed from > 6 million genetic variants. A favorable lifestyle was defined in terms of four modifiable lifestyle components, and metabolic health status was determined according to the presence of metabolic syndrome components.ResultsDuring a median follow-up of 8.9 years, 21,865 CVD cases (6.3%) were identified. Compared with the low genetic risk group, participants at high genetic risk for T2D had higher rates of overall CVD events, CVD subtypes (coronary artery disease, peripheral artery disease, heart failure, and atrial fibrillation/flutter), and CVD mortality. Individuals at very high genetic risk for T2D had a 35% higher risk of CVD than those with low genetic risk (HR 1.35 [95% CI 1.19 to 1.53]). A significant gradient of increased CVD risk was observed across genetic risk, lifestyle, and metabolic health status (P for trend > 0.001). Those with favorable lifestyle and metabolically healthy status had significantly reduced risk of CVD events regardless of T2D genetic risk. This risk reduction was more apparent in young participants (≤ 50 years).ConclusionsGenetic risk for T2D was associated with increased risks of overall CVD, various CVD subtypes, and fatal CVD. Engaging in a healthy lifestyle and maintaining metabolic health may reduce subsequent risk of CVD regardless of genetic risk for T2D.