Plasma Metabolomic Signatures of Sugar-Sweetened Beverage Consumption and Risk of Type 2 Diabetes Among US Adults

Abstract Objectives Sugar-sweetened beverage (SSB) consumption is associated with a higher risk of type 2 diabetes (T2D), but the metabolic changes linking SSB consumption to T2D are not fully understood. Thus, we aimed to identify a plasma metabolomic signature of SSB consumption and evaluate its association with incident T2D. Methods We used liquid chromatography–mass spectrometry to measure plasma metabolites (>200) among 3,434 participants from three US cohorts: Nurses’ Health Study (NHS), NHS II, and Health Professionals Follow-up Study (HPFS). SSB consumption (servings/day; sodas, fruit punches, and other sugary drinks) was estimated from food frequency questionnaires. We used elastic net regression with 10-fold-cross-validation to identify metabolites associated with higher SSB consumption among a training set of participants (n = 2068) and replicated the association in a testing set (n = 1366). A metabolomic signature score was calculated as the weighted sum of SSB-associated metabolites. Pearson correlation (r) coefficients and 95% confidence intervals (CI) between the metabolomic signature and self-reported SSB consumption were calculated. We used multivariable Cox regression models to estimate hazard ratios (HR) and CI of the identified metabolomic signature with incident T2D among all participants. Results We identified an SSB plasma metabolomic signature of 71 metabolites, primarily lipids and amino acids. Pearson correlation (r) coefficients between self-reported SSBs and the plasma metabolomic signature were 0.18 (95% CI: 0.14, 0.22; P < 0.0001) and 0.19 (95% CI: 0.14, 0.24; P < 0.0001) in the training and testing sets, respectively. After a median follow-up of 22 years, the metabolomic signature was significantly associated with higher T2D risk [HR for quartile (Q) 1 versus 4 (95% CI): 1.45 (1.02, 2.05); P = 0.04] in models adjusting for factors related to demographics, lifestyle, diet, and body mass index. The association persisted when further adjusting for self-reported SSB consumption [HR for Q1 versus Q4 (95% CI): 1.42 (1.00, 2.02); P = 0.05]. Conclusions We identified a novel metabolomic signature of SSB consumption in US adults that associated with elevated incident T2D risk. This signature may reflect both SSB consumption and metabolic changes related to T2D risk, although residual confounding cannot be ruled out. Funding Sources NIH.

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Clinical and metabolic predictors of regression to normoglycemia in a population at intermediate cardiometabolic risk

10.21203/rs.3.rs-109666/v1 ◽

2020 ◽

Author(s):

Magdalena del Rocio Sevilla-Gonzalez ◽

Jordi Merino ◽

Hortensia Moreno ◽

Rosalba Rojas-Martinez ◽

Donaji Gomez-Velasco ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cox Regression ◽

Fasting Glucose ◽

Plasma Metabolites ◽

Good Prediction ◽

Adjusted Relative Risk ◽

Clinical Factors ◽

Conversion Rates

Abstract Background: Impaired fasting glucose (IFG) is a prevalent and potentially reversible intermediate stage leading to type 2 diabetes that increases risk for cardiometabolic complications. The identification of clinical and molecular factors associated with the reversal, or regression, from IFG to a normoglycemia state would enable more efficient cardiovascular risk reduction strategies. The aim of this study was to identify clinical and biological predictors of regression to normoglycemia in a non-European population that is characterized by increased type 2 diabetes conversion rates.Methods: We conducted a prospective, population-based study among 9,637 Mexican individuals using clinical features and plasma metabolites. Among them, 491 subjects were classified as IFG, defined as fasting glucose between 100 and 125 mg/dL. Regression to normoglycemia was defined by fasting glucose less than 100 mg/dL in the follow-up visit. Plasma metabolites were profiled by Nuclear Magnetic Resonance. Multivariable Cox regression models were used to examine the associations of clinical and metabolomic factors with regression to normoglycemia. We assessed the predictive capabilities to regress to normoglycemia of models that included clinical factors alone and models that included clinical factors and prioritized metabolites. Results: During a median follow-up period of 2.5 years, 22.6% of participants (n=111) regressed to normoglycemia, and 29.5% progressed to type 2 diabetes (n=145). The multivariate adjusted relative risk of regression to normoglycemia was 1.10 (95% confidence interval [CI], 1.25 to 1.32) per 10 years of age increase, 0.94 (95% CI, 0.91-0.98) per 1 SD increase in BMI, and 0.91 (95% CI, 0.88 – 0.95) per 1 SD increase in fasting glucose. A model including information from age, fasting glucose, and BMI showed a good prediction of regression to normoglycemia (AUC = 0.73 (95% CI, 0.66 - 0.78). Adding information from prioritized metabolites (TG in large HDL, albumin, and citrate) marginally improved the predictive capability beyond clinical factors (AUC = 0.74 (95% CI 0.68 - 0.80), p value = 0.485)Conclusion: In individuals with IFG, information from three clinical variables easily obtained in the clinical setting showed a good prediction of regression to normoglycemia beyond metabolomic features. Our findings can serve to inform and design future cardiovascular prevention strategies.

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Clinical and metabolomic predictors of regression to normoglycemia in a population at intermediate cardiometabolic risk

Cardiovascular Diabetology ◽

10.1186/s12933-021-01246-1 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Magdalena del Rocío Sevilla-González ◽

Jordi Merino ◽

Hortensia Moreno-Macias ◽

Rosalba Rojas-Martínez ◽

Donají Verónica Gómez-Velasco ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cox Regression ◽

Fasting Glucose ◽

Plasma Metabolites ◽

P Value ◽

Good Prediction ◽

Adjusted Relative Risk ◽

Clinical Factors

Abstract Background Impaired fasting glucose (IFG) is a prevalent and potentially reversible intermediate stage leading to type 2 diabetes that increases risk for cardiometabolic complications. The identification of clinical and molecular factors associated with the reversal, or regression, from IFG to a normoglycemia state would enable more efficient cardiovascular risk reduction strategies. The aim of this study was to identify clinical and biological predictors of regression to normoglycemia in a non-European population characterized by high rates of type 2 diabetes. Methods We conducted a prospective, population-based study among 9637 Mexican individuals using clinical features and plasma metabolites. Among them, 491 subjects were classified as IFG, defined as fasting glucose between 100 and 125 mg/dL at baseline. Regression to normoglycemia was defined by fasting glucose less than 100 mg/dL in the follow-up visit. Plasma metabolites were profiled by Nuclear Magnetic Resonance. Multivariable cox regression models were used to examine the associations of clinical and metabolomic factors with regression to normoglycemia. We assessed the predictive capability of models that included clinical factors alone and models that included clinical factors and prioritized metabolites. Results During a median follow-up period of 2.5 years, 22.6% of participants (n = 111) regressed to normoglycemia, and 29.5% progressed to type 2 diabetes (n = 145). The multivariate adjusted relative risk of regression to normoglycemia was 1.10 (95% confidence interval [CI] 1.25 to 1.32) per 10 years of age increase, 0.94 (95% CI 0.91–0.98) per 1 SD increase in BMI, and 0.91 (95% CI 0.88–0.95) per 1 SD increase in fasting glucose. A model including information from age, fasting glucose, and BMI showed a good prediction of regression to normoglycemia (AUC = 0.73 (95% CI 0.66–0.78). The improvement after adding information from prioritized metabolites (TG in large HDL, albumin, and citrate) was non-significant (AUC = 0.74 (95% CI 0.68–0.80), p value = 0.485). Conclusion In individuals with IFG, information from three clinical variables easily obtained in the clinical setting showed a good prediction of regression to normoglycemia beyond metabolomic features. Our findings can serve to inform and design future cardiovascular prevention strategies.

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Shortened Relative Leukocyte Telomere Length is Associated with Prevalent and Incident Cardiovascular Complications in Type 2 Diabetes- Analysis from the Hong Kong Diabetes Register

10.2337/figshare.12498335 ◽

2020 ◽

Author(s):

Feifei Cheng ◽

Andrea O Luk ◽

Claudia HT Tam ◽

Baoqi Fan ◽

Hongjiang Wu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Hong Kong ◽

Telomere Length ◽

Cox Regression ◽

Quantitative Polymerase Chain Reaction ◽

Hazard Ratio ◽

Chinese Patients ◽

Diabetes Register

Objective: Several studies support potential links between leukocyte relative telomere length (rLTL), a biomarker of biological aging and type 2 diabetes. This study investigates relationships between rLTL and subsequent cardiovascular disease (CVD) in patients with type 2 diabetes. Research design and methods: Consecutive Chinese patients with type 2 diabetes (N=5349) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using quantitative polymerase chain reaction. CVD was diagnosed based on ICD-9 code. Results: Mean (SD) follow-up was 13.4(5.5) years. rLTL was correlated inversely with age, diabetes duration, blood pressure, HbA1c, urine ACR and positively with eGFR (all P<0.001). Subjects with versus without CVD at baseline had shorter rLTL (4.3±1.2 vs. 4.6±1.2, P<0.001). Of the 4541 CVD-free subjects at baseline, the 1140 who developed CVD during follow-up had shorter rLTL than those remaining CVD-free after adjusting for age, sex, smoking and albuminuria status (4.3±1.2 vs. 4.7±1.2, P<0.001). In Cox regression models, shorter rLTL was associated with higher risk of incident CVD (hazard ratio (95% CI) for each unit decrease: 1.252 (1.195-1.311), P<0.001), which remained significant after adjusting for age, sex, BMI, SBP, LDL-C, HbA1c, eGFR and ACR (hazard ratio (95% CI): 1.141 (1.084-1.200), P<0.001). Conclusions: rLTL is significantly shorter in type 2 diabetes patients with CVD, is associated with cardiometabolic risk factors, and is independently associated with incident CVD. Telomere length may be a useful biomarker for CVD risk in type 2 diabetes.

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Abstract MP05: Leisure-Time Running and Incident Type 2 Diabetes

Circulation ◽

10.1161/circ.131.suppl_1.mp05 ◽

2015 ◽

Vol 131 (suppl_1) ◽

Author(s):

Duck-chul Lee ◽

Carl J. Lavie ◽

Timothy S. Church ◽

Xuemei Sui ◽

Steven N. Blair

Keyword(s):

Type 2 Diabetes ◽

Lower Risk ◽

Leisure Time ◽

Cox Regression ◽

Smoking Status ◽

Physical Activities ◽

Incident Type ◽

Incident Type 2 Diabetes

Introduction: There is still little evidence on the dose-response relation between leisure-time running and incident type 2 diabetes (T2D). Hypothesis: We examined the hypothesis that running reduces the risk of developing T2D. Methods: Participants were 19,347 adults aged 18 to 100 years (mean age, 44) who received an extensive preventive medical examination during 1974-2006 in the Aerobics Center Longitudinal Study. Participants were free of cardiovascular disease, cancer, and T2D at baseline. Running and other physical activities were assessed on the medical history questionnaire by self-reported leisure-time activities during the past 3 months. We defined T2D as fasting glucose ≥126 mg/dl, insulin use, or physician-diagnosis during follow-up medical examinations. Cox regression was used to quantify the association between running and T2D after adjusting for baseline age, sex, examination year, body mass index, smoking status, heavy alcohol drinking, abnormal electrocardiogram, hypertension, hypercholesterolemia, and levels of other physical activities. Results: During an average follow-up of 6.5 years, 1,015 adults developed T2D. Approximately 30% of adults participated in leisure-time running. Runners had a 29% lower risk of developing T2D compared with non-runners. The hazard ratios (95% confidence intervals) of T2D were 0.97 (0.74-1.27), 0.66 (0.49-0.89), 0.62 (0.45-0.85), 0.78 (0.58-1.03), and 0.57 (0.42-0.79) across quintiles (Q) of running time (minutes/week); 0.99 (0.76-1.30), 0.60 (0.44-0.82), 0.72 (0.55-0.94), 0.65 (0.47-0.90), and 0.63 (0.47-0.86) across Q of running distance (miles/week); 1.08 (0.83-1.40), 0.67 (0.50-0.90), 0.70 (0.53-0.93), 0.61 (0.45-0.83), and 0.53 (0.36-0.76) across Q of running frequency (times/week); 0.95 (0.73-1.24), 0.70 (0.52-0.94), 0.62 (0.45-0.84), 0.73 (0.55-0.97), and 0.58 (0.42-0.80) across Q of total amount of running (MET-minutes/week); and 0.95 (0.71-1.28), 0.76 (0.59-0.99), 0.59 (0.42-0.83), 0.66 (0.51-0.85), and 0.62 (0.43-0.90) across Q of running speed (mph), respectively, compared with no running after adjusting for confounders including levels of other physical activities. Conclusions: Participating in leisure-time running is associated with markedly lower risk of developing T2D in adults. Except for those in the very lowest Q for running doses, even relatively low running doses (starting with Q 2) were associated with marked reductions in T2D risk over time, supporting the prescription of running to reduce T2D.

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Correlation between markers of renal function and sight-threatening diabetic retinopathy in type 2 diabetes: a longitudinal study in an Indian clinic population

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001325 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001325 ◽

Cited By ~ 1

Author(s):

Ramachandran Rajalakshmi ◽

Coimbatore Subramanian Shanthi Rani ◽

Ulagamathesan Venkatesan ◽

Ranjit Unnikrishnan ◽

Ranjit Mohan Anjana ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Serum Creatinine ◽

Cox Regression ◽

Tertiary Care ◽

Cox Regression Analysis ◽

Increased Risk ◽

New Onset

IntroductionPrevious epidemiological studies have reported on the prevalence of diabetic kidney disease (DKD) and diabetic retinopathy (DR) from India. The aim of this study is to evaluate the effect of DKD on the development of new-onset DR and sight-threatening diabetic retinopathy (STDR) in Asian Indians with type 2 diabetes (T2D).Research design and methodsThe study was done on anonymized electronic medical record data of people with T2D who had undergone screening for DR and renal work-up as part of routine follow-up at a tertiary care diabetes center in Chennai, South India. The baseline data retrieved included clinical and biochemical parameters including renal profiles (serum creatinine, estimated glomerular filtration rate (eGFR) and albuminuria). Grading of DR was performed using the modified Early Treatment Diabetic Retinopathy Study grading system. STDR was defined as the presence of proliferative diabetic retinopathy (PDR) and/or diabetic macular edema. DKD was defined by the presence of albuminuria (≥30 µg/mg) and/or reduction in eGFR (<60 mL/min/1.73 m2). Cox regression analysis was used to evaluate the hazard ratio (HR) for DR and STDR.ResultsData of 19 909 individuals with T2D (mean age 59.6±10.2 years, mean duration of diabetes 11.1±12.1 years, 66.1% male) were analyzed. At baseline, DR was present in 7818 individuals (39.3%), of whom 2249 (11.3%) had STDR. During the mean follow-up period of 3.9±1.9 years, 2140 (17.7%) developed new-onset DR and 980 individuals with non-proliferative DR (NPDR) at baseline progressed to STDR. Higher serum creatinine (HR 1.5, 95% CI 1.3 to 1.7; p<0.0001), eGFR <30 mL/min/1.73 m2 (HR 4.9, 95% CI 2.9 to 8.2; p<0.0001) and presence of macroalbuminuria >300 µg/mg (HR 3.0, 95% CI 2.4 to 3.8; p<0.0001) at baseline were associated with increased risk of progression to STDR.ConclusionsDKD at baseline is a risk factor for progression to STDR. Physicians should promptly refer their patients with DKD to ophthalmologists for timely detection and management of STDR.

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Risk of early mortality and cardiovascular disease in type 1 diabetes: a comparison with type 2 diabetes, a nationwide study

Cardiovascular Diabetology ◽

10.1186/s12933-019-0953-7 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 7

Author(s):

You-Bin Lee ◽

Kyungdo Han ◽

Bongsung Kim ◽

Seung-Eun Lee ◽

Ji Eun Jun ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Type 1 Diabetes ◽

Cox Regression ◽

Early Mortality ◽

Hazard Ratios ◽

Epidemiological Characteristics

Abstract Background Both type 1 and type 2 diabetes are well-established risk factors for cardiovascular disease and early mortality. However, few studies have directly compared the hazards of cardiovascular outcomes and premature death among people with type 1 diabetes to those among people with type 2 diabetes and subjects without diabetes. Furthermore, information about the hazard of cardiovascular disease and early mortality among Asians with type 1 diabetes is sparse, although the clinical and epidemiological characteristics of Asians with type 1 diabetes are unlike those of Europeans. We estimated the hazard of myocardial infarction (MI), hospitalization for heart failure (HF), atrial fibrillation (AF), and mortality during follow-up in Korean adults with type 1 diabetes compared with those without diabetes and those with type 2 diabetes. Methods We used Korean National Health Insurance Service datasets of preventive health check-ups from 2009 to 2016 in this retrospective longitudinal study. The hazard ratios of MI, HF, AF, and mortality during follow-up were analyzed using the Cox regression analyses according to the presence and type of diabetes in ≥ 20-year-old individuals without baseline cardiovascular disease (N = 20,423,051). The presence and type of diabetes was determined based on the presence of type 1 or type 2 diabetes at baseline. Results During more than 93,300,000 person-years of follow-up, there were 116,649 MIs, 135,532 AF cases, 125,997 hospitalizations for HF, and 344,516 deaths. The fully-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MI, hospitalized HF, AF, and all-cause death within the mean follow-up of 4.6 years were higher in the type 1 diabetes group than the type 2 diabetes [HR (95% CI) 1.679 (1.490–1.893) for MI; 2.105 (1.901–2.330) for HF; 1.608 (1.411–1.833) for AF; 1.884 (1.762–2.013) for death] and non-diabetes groups [HR (95% CI) 2.411 (2.138–2.718) for MI; 3.024 (2.730–3.350) for HF; 1.748 (1.534–1.993) for AF; 2.874 (2.689–3.073) for death]. Conclusions In Korea, the presence of diabetes was associated with a higher hazard of cardiovascular disease and all-cause death. Specifically, people with type 1 diabetes had a higher hazard of cardiovascular disease and all-cause mortality compared to people with type 2 diabetes.

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Awaking Blood Pressure Surge and Progression to Microalbuminuria in Type 2 Normotensive Diabetic Patients

Journal of Diabetes Research ◽

10.1155/2016/5876792 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Michelangela Barbieri ◽

Maria Rosaria Rizzo ◽

Ilaria Fava ◽

Celestino Sardu ◽

Nicola Angelico ◽

...

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Cox Regression ◽

Blood Pressure Monitoring ◽

Adult Patients ◽

Diabetic Patients ◽

Increased Risk ◽

Pressure Surge

Background. We investigated the predictive value of morning blood pressure surge (MBPS) on the development of microalbuminuria in normotensive adults with a recent diagnosis of type 2 diabetes.Methods. Prospective assessments of 24-hour ambulatory blood pressure monitoring and urinary albumin excretion were performed in 377 adult patients. Multivariate-adjusted Cox regression models were used to assess hazard ratios (HRs) between baseline and changes over follow-up in MBPS and the risk of microalbuminuria. The MBPS was calculated as follows: mean systolic BP during the 2 hours after awakening minus mean systolic BP during the 1 hour that included the lowest sleep BP.Results. After a mean follow-up of 6.5 years, microalbuminuria developed in 102 patients. An increase in MBPB during follow-up was associated with an increased risk of microalbuminuria. Compared to individuals in the lowest tertile (−0.67±1.10 mmHg), the HR and 95% CI for microalbuminuria in those in the highest tertile of change (24.86±6.92 mmHg) during follow-up were 17.41 (95% CI 6.26–48.42);pfor trend <0.001. Mean SD MBPS significantly increased in those who developed microalbuminuria from a mean [SD] of 10.6[1.4]to 36.8[7.1],p<0.001.Conclusion. An increase in MBPS is associated with the risk of microalbuminuria in normotensive adult patients with type 2 diabetes.

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P4992The ceramide-based Coronary Event Risk Test (CERT) predicts cardiovascular mortality in cardiovascular disease patients with type 2 diabetes mellitus as well as in those without diabetes

European Heart Journal ◽

10.1093/eurheartj/ehz746.0170 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

A Leiherer ◽

A Muendlein ◽

C H Saely ◽

R Laaksonen ◽

M Laaperi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Cardiovascular Mortality ◽

Cox Regression ◽

Hdl Cholesterol ◽

Coronary Event ◽

Event Risk ◽

Risk Predictor

Abstract Background The recently introduced Coronary Event Risk Test (CERT) is a validated cardiovascular risk predictor that uses circulating ceramide concentrations to allocate patients into one of four risk categories. Purpose The purpose of this study was to investigate the power of CERT to predict cardiovascular mortality in patients with established cardiovascular disease (CVD) including patients with type 2 diabetes (T2DM). Methods We investigated a total of 1087 patients with established CVD, including 360 patients with T2DM. At baseline, the prevalence of T2DM increased through CERT categories (29.1, 31.1, 37.4, and 53.4%, respectively, ptrend<0.001). Prospectively, cardiovascular deaths were recorded during a mean follow-up time of 8.1±3.2 years. Results A total of 130 cardiovascular deaths occurred. Overall, cardiovascular mortality increased with increasing CERT categories (figure) and was higher in T2DM patients than in those who did not have diabetes (17.7 vs. 9.4%; p<0.001). In Cox regression models, CERT categories predicted cardiovascular mortality in patients with T2DM (unadjusted HR 1.60 [1.28–2.01]; p<0.001; HR adjusted for age, gender, BMI, smoking, LDL cholesterol, HDL cholesterol, hypertension, and statin use 1.65 [1.27–2.15]; p<0.001) and in those without diabetes (unadjusted HR 1.43 [1.10–1.85]; p=0.008 and adjusted HR 1.41 [1.07–1.85]; p=0.015). Cardiovascular survival of CVD patients Conclusion We conclude that CERT predicts cardiovascular mortality in CVD patients with T2DM as well as in those without diabetes.

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