Circulating Trimethylamine N-Oxide Is Associated with Increased Risk of Cardiovascular Mortality in Type-2 Diabetes: Results from a Dutch Diabetes Cohort (ZODIAC-59)

Trimethylamine N-oxide (TMAO), a novel cardiovascular (CV) disease and mortality risk marker, is a gut microbiota-derived metabolite as well. Recently, plasma concentrations of branched-chain amino acids (BCAA) have been reported to be affected by microbiota. The association of plasma TMAO with CV mortality in Type 2 Diabetes (T2D) and its determinants are still incompletely described. We evaluated the association between plasma BCAA and TMAO, and the association of TMAO with CV mortality in T2D individuals. We used data of 595 participants (mean age 69.5 years) from the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort were analyzed. Plasma TMAO and BCAA were measured with nuclear magnetic resonance spectroscopy. CV mortality risk was estimated using multivariable-adjusted Cox regression models. Cross-sectionally, TMAO was independently associated with BCAA standardized (Std) β = 0.18 (95% Confidence Interval (CI) 0.09; 0.27), p <0.001. During a median follow-up of 10 years, 113 CV deaths were recorded. In Cox regression analyses, adjusted for multiple clinical and laboratory variables including BCAA, TMAO was independently associated with CV mortality: adjusted hazard ratio (adjHR) 1.93 (95% CI 1.11; 3.34), p = 0.02 (for the highest vs. the lowest tertile of the TMAO distribution). The same was true for analyses with TMAO as continuous variable: adjHR 1.32 (95% CI 1.07; 1.63), p = 0.01 (per 1 SD increase). In contrast, BCAAs were not associated with increased CV mortality. In conclusion, higher plasma TMAO but not BCAA concentrations are associated with an increased risk of CV mortality in individuals with T2D, independent of clinical and biochemical risk markers.

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Plasma Branched-Chain Amino Acids and Risk of Incident Type 2 Diabetes: Results from the PREVEND Prospective Cohort Study

Journal of Clinical Medicine ◽

10.3390/jcm7120513 ◽

2018 ◽

Vol 7 (12) ◽

pp. 513 ◽

Cited By ~ 20

Author(s):

Jose Flores-Guerrero ◽

Maryse Osté ◽

Lyanne Kieneker ◽

Eke Gruppen ◽

Justyna Wolak-Dinsmore ◽

...

Keyword(s):

Type 2 Diabetes ◽

Amino Acids ◽

Cell Function ◽

Cox Regression ◽

Branched Chain Amino Acids ◽

Resonance Spectroscopy ◽

Net Reclassification Improvement ◽

Increased Risk ◽

Branched Chain

Plasma branched-chain amino acids (BCAAs) are linked to metabolic disease, but their relevance for prediction of type 2 diabetes development is unclear. We determined the association of plasma BCAAs with type 2 diabetes risk in the prevention of renal and vascular end-stage disease (PREVEND) cohort. The BCAAs were measured by means of nuclear magnetic resonance spectroscopy. We evaluated the prospective associations of BCAAs with type 2 diabetes in 6244 subjects. The BCAAs were positively associated with HOMA-IR after multivariable adjustment (p < 0.0001). During median follow-up for 7.5 years, 301 cases of type 2 diabetes were ascertained. The Kaplan-Meier plot demonstrated that patients in the highest BCAA quartile presented a higher risk (p log-rank < 0.001). Cox regression analyses revealed a positive association between BCAA and type 2 diabetes; the hazard ratio (HR) for the highest quartile was 6.15 (95% CI: 4.08, 9.24, p < 0.0001). After adjustment for multiple clinical and laboratory variables, the association remained (HR 2.80 (95% CI: 1.72, 4.53), p < 0.0001). C-statistics, Net reclassification improvement, and −2 log likelihood were better after adding BCAAs to the traditional risk model (p = 0.01 to <0.001). In conclusions, high concentrations of BCAAs associate with insulin resistance and with increased risk of type 2 diabetes. This association is independent of multiple risk factors, HOMA-IR and β cell function.

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Association of Plasma Leucine-Rich α-2 Glycoprotein 1, a Modulator of Transforming Growth Factor-β Signaling Pathway, With Incident Heart Failure in Individuals With Type 2 Diabetes

10.2337/figshare.13222055 ◽

2020 ◽

Author(s):

Jian-Jun Liu ◽

Sharon LT Pek ◽

Jiexun Wang ◽

Sylvia Liu ◽

Keven Ang ◽

...

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Transforming Growth Factor ◽

Cox Regression ◽

Transforming Growth Factor Β ◽

Continuous Variable ◽

Clinical Variable ◽

Adjusted Risk ◽

Increased Risk

Objective: Leucine-rich alpha-2 glycoprotein 1 (LRG1) is a circulating protein which potentially involves in several pathways related with pathogenesis of heart failure (HF). We aim to study whether plasma LRG1 is associated with risk of incident HF and hospitalization attributable to HF (HHF) in individuals with type 2 diabetes. Design and Methods: 1978 individuals with type 2 diabetes were followed for a median of 7.1 (IQR 6.1-7.6) years. Association of LRG1 with HF was studied by cause-specific Cox regression models. Results: 191 incident HF and 119 HHF events were identified in follow-up. As compared to quartile 1, participants with LRG1 in quartile 3 and 4 had 3.60 (95% CI 1.63- 7.99) and 5.99 (95% CI 2.21-16.20) folds increased risk for incident HF, and 5.88 (95% CI 1.83-18.85) and 10.44 (95% CI 2.37- 45.98) folds increased risk for HHF after adjustment for multiple known cardio-renal risk factors. As a continuous variable, 1- SD increment in natural log-transformed LRG1 was associated with 1.78 (95% CI 1.33-2.38) folds adjusted risk for incident HF and 1.92 (95% CI 1.27- 2.92) folds adjusted risk for HHF. Adding LRG1 onto clinical variable- based model improved risk discrimination for incident HF (AUC 0.79 to 0.81, P=0.02) and HHF (AUC 0.81 to 0.84, P=0.02). Conclusion: Plasma LRG1 is associated with risk of incident HF and HHF, suggesting that it may potentially involve in pathogenesis of HF in individuals with type 2 diabetes. Further studies are warranted to determine whether LRG1 may be a novel biomarker for HF risk-stratification.

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Association of Plasma Leucine-Rich α-2 Glycoprotein 1, a Modulator of Transforming Growth Factor-β Signaling Pathway, With Incident Heart Failure in Individuals With Type 2 Diabetes

10.2337/figshare.13222055.v1 ◽

2020 ◽

Author(s):

Jian-Jun Liu ◽

Sharon LT Pek ◽

Jiexun Wang ◽

Sylvia Liu ◽

Keven Ang ◽

...

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Transforming Growth Factor ◽

Cox Regression ◽

Transforming Growth Factor Β ◽

Continuous Variable ◽

Clinical Variable ◽

Adjusted Risk ◽

Increased Risk

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Myopia and Early Onset Type 2 Diabetes: A Nationwide Cohort Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab669 ◽

2021 ◽

Author(s):

Alon Peled ◽

Itamar Raz ◽

Inbar Zucker ◽

Estela Derazne ◽

Jacob Megreli ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Cohort Study ◽

Young Adulthood ◽

Military Service ◽

High Myopia ◽

Continuous Variable ◽

Dependent Manner ◽

Increased Risk

Abstract Objective A correlation between myopia and insulin-resistance has been suggested. We investigated the association between myopia in adolescence and type 2 diabetes (T2D) incidence in young adulthood. Design Population-based, retrospective, cohort study. Methods 1,329,705 adolescents (579,543 women, 43.6%) aged 16-19 years, medically examined before mandatory military service during 1993-2012; and whose data were linked to the Israel National Diabetes Registry. Myopia was defined based on right eye refractive data. Cox proportional models were applied, separately for women and men, to estimate hazard ratios (HRs) for T2D incidence per person-years of follow-up. Results There was an interaction between myopia and sex with T2D (P<0.001). For women, T2D incidence rates (per 100,000 person-years) were 16.6, 19.2, and 25.1 for those without myopia, and with mild-to-moderate and high myopia, respectively. These corresponded to HRs of 1.29 (95%CI 1.14-1.45) and 1.63 (1.21-2.18) for women with mild-to-moderate and high myopia, respectively, compared to those without myopia, after adjustment for age at study entry, birth year, adolescent BMI, cognitive performance, socioeconomic status, and immigration status. Results persisted in extensive sensitivity and subgroup analyses. When managed as a continuous variable, every 1 diopter lower spherical equivalent yielded a 6.5% higher adjusted HR for T2D incidence (P= 0.003). There was no significant association among men. Conclusions For women, myopia in adolescence was associated with a significantly increased risk for incident T2D in young adulthood, in a severity-dependent manner. This finding may support the role of insulin resistance in myopia pathogenesis.

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Abstract MP037: Plasma Organochlorine Concentration and Risk of Diabetes: the Nurses' Health Study

Circulation ◽

10.1161/circ.125.suppl_10.amp037 ◽

2012 ◽

Vol 125 (suppl_10) ◽

Author(s):

Hongyu Wu ◽

Kimberly A Bertrand ◽

Anna L Choi ◽

Frank B Hu ◽

Francine Laden ◽

...

Keyword(s):

Type 2 Diabetes ◽

Polychlorinated Biphenyl ◽

Plasma Concentrations ◽

Diabetes Risk ◽

Health Study ◽

Blood Draw ◽

Incident Type ◽

Increased Risk ◽

Incident Type 2 Diabetes

Background: Animal experiments have suggested that exposure to persistent organic pollutants (POPs) may lead to increased risk of type 2 diabetes. Although recent human studies supported this hypothesis, evidence from prospective investigations is sparse. Objective: To examine the associations of plasma POP concentrations with risk of incident type 2 diabetes in a prospective setting among US women. Methods: Study population was comprised of participants from two independent nested case-control studies in the Nurses’ Health Study, in which major polychlorinated biphenyl (PCB 118, 138, 153, and 180), p-p'- dichlorodiphenyldichloroethylene (DDE), dichlorodiphenyltrichloroethane (DDT), and hexachlorobenzene (HCB) were measured. A non-parametric approach was used to derive standardized scores for plasma concentrations of lipid-adjusted POPs within each study to minimize between-study variation of the POP measurements. Risk of incident type 2 diabetes during the follow-up period (1990-2008) across the tertiles of the scores was examined. Results: Of 1,120 participants, we identified 48 incident type 2 diabetes cases. After adjusting for covariates assessed at blood draw in 1990, including smoking status, body mass index, and total fish intake, plasma HCB concentration was positively associated with type 2 diabetes risk: odds ratio (OR) (95% confidence interval [CI]) was 2.77 (1.17, 6.55, P for trend =0.022) comparing the highest vs. lowest tertile. Other POPs were not significantly associated with diabetes: the ORs (95% CI) were 1.10 (0.51, 2.34, P for trend =0.81) for p-p'-DDE, 0.93 (0.44, 1.95, P for trend =0.86) for DDT, and 0.88 (0.39, 1.97, P for trend =0.76) for sum of the 4 major PCBs, comparing the extreme tertiles. Conclusion: The significant association of plasma HCB concentration with diabetes risk supports a role of POP exposure in the etiology of type 2 diabetes. More prospective data are warranted to confirm these findings.

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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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MR-proANP and incident cardiovascular disease in patients with type 2 diabetes with and without heart failure with preserved ejection fraction

Cardiovascular Diabetology ◽

10.1186/s12933-020-01155-9 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Jesper Jensen ◽

Morten Schou ◽

Caroline Kistorp ◽

Jens Faber ◽

Tine W. Hansen ◽

...

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Ejection Fraction ◽

Natriuretic Peptides ◽

Continuous Variable ◽

Preserved Ejection Fraction ◽

Reduced Ejection Fraction ◽

Increased Risk ◽

Definition Of

Abstract Background Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a useful biomarker in outpatients with type 2 diabetes (T2D) to diagnose heart failure (HF). Elevated B-type natriuretic peptides are included in the definition of HF with preserved ejection fraction (HFpEF) but little is known about the prognostic value of including A-type natriuretic peptides (MR-proANP) in the evaluation of patients with T2D. Methods We prospectively evaluated the risk of incident cardiovascular (CV) events in outpatients with T2D (n = 806, mean ± standard deviation age 64 ± 10 years, 65% male, median [interquartile range] duration of diabetes 12 [6–17] years, 17.5% with symptomatic HFpEF) according to MR-proANP levels and stratified according to HF-status including further stratification according to a prespecified cut-off level of MR-proANP. Results A total of 126 CV events occurred (median follow-up 4.8 [4.1–5.3] years). An elevated MR-proANP, with a cut-off of 60 pmol/l or as a continuous variable, was associated with incident CV events (p < 0.001). Compared to patients without HF, patients with HFpEF and high MR-proANP (≥ 60 pmol/l; median 124 [89–202] pmol/l) and patients with HF and reduced ejection fraction (HFrEF) had a higher risk of CV events (multivariable model; hazard ratio (HR) 2.56 [95% CI 1.64–4.00] and 3.32 [1.64–6.74], respectively). Conversely, patients with HFpEF and low MR-proANP (< 60 pmol/l; median 46 [32–56] pmol/l) did not have an increased risk (HR 2.18 [0.78–6.14]). Conclusions Patients with T2D and HFpEF with high MR-proANP levels had an increased risk for CV events compared to patients with HFpEF without elevated MR-proANP and compared to patients without HF, supporting the use of MR-proANP in the definition of HFpEF from a prognostic point-of-view.

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The Risks of Cardiovascular Disease and Mortality Following Weight Change in Adults with Diabetes: Results from ADVANCE

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz045 ◽

2019 ◽

Vol 105 (1) ◽

pp. 152-162 ◽

Cited By ~ 1

Author(s):

Alexandra K Lee ◽

Mark Woodward ◽

Dan Wang ◽

Toshiaki Ohkuma ◽

Bethany Warren ◽

...

Keyword(s):

Type 2 Diabetes ◽

Weight Loss ◽

Weight Change ◽

Cox Regression ◽

Lifestyle Changes ◽

Baseline Body Mass Index ◽

Diabetes Medication ◽

Increased Risk ◽

All Cause Mortality

Abstract Context Weight loss is strongly recommended for overweight and obese adults with type 2 diabetes. Unintentional weight loss is associated with increased risk of all-cause mortality, but few studies have examined its association with cardiovascular outcomes in patients with diabetes. Objective To evaluate 2-year weight change and subsequent risk of cardiovascular events and mortality in established type 2 diabetes. Design and Setting The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation was an international, multisite 2×2 factorial trial of intensive glucose control and blood pressure control. We examined 5 categories of 2-year weight change: >10% loss, 4% to 10% loss, stable (±<4%), 4% to 10% gain, and >10% gain. We used Cox regression with follow-up time starting at 2 years, adjusting for intervention arm, demographics, cardiovascular risk factors, and diabetes medication use from the 2-year visit. Results Among 10 081 participants with valid weight measurements, average age was 66 years. By the 2-year examination, 4.3% had >10% weight loss, 18.4% had 4% to 10% weight loss, and 5.3% had >10% weight gain. Over the following 3 years of the trial, >10% weight loss was strongly associated with major macrovascular events (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.26-2.44), cardiovascular mortality (HR, 2.76; 95% CI, 1.87-4.09), all-cause mortality (HR, 2.79; 95% CI, 2.10-3.71), but not major microvascular events (HR, 0.91; 95% CI, 0.61-1.36), compared with stable weight. There was no evidence of effect modification by baseline body mass index, age, or type of diabetes medication. Conclusions In the absence of substantial lifestyle changes, weight loss may be a warning sign of poor health meriting further workup in patients 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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Snoring frequency and risk of type 2 diabetes mellitus: a prospective cohort study

BMJ Open ◽

10.1136/bmjopen-2020-042469 ◽

2021 ◽

Vol 11 (5) ◽

pp. e042469

Author(s):

Ningbin Dai ◽

Qianwen Shi ◽

Yujie Hua ◽

Yu Guo ◽

Zheng Bian ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Cohort Study ◽

Interaction Effect ◽

Chinese Population ◽

Cox Regression ◽

Baseline Survey ◽

Increased Risk

ObjectiveTo evaluate the association between snoring frequency and type 2 diabetes mellitus (T2DM) according to age and gender in Chinese population.DesignA cohort study was performed in Suzhou site of the China Kadoorie Biobank. Residents who didn’t suffer from T2DM at baseline survey (2004–2008) and in half a year after baseline were enrolled in this study and followed cause-specific morbidity until 31 December 2013. All participants were requested to complete a detailed questionnaire and undergo anthropometric measurements. Cox regression models were used to estimate HRs and 95% CIs for the snoring and T2DM association.SettingWuzhong district, Suzhou, China.ParticipantsA total of 49 453 participants (men: 41.8%; mean age: 51.14±10.28 years) were enrolled in this study.Outcome measuresT2DM cases were defined as International Classification of Diseases 10th Revision code of E11 and were identified through disease registries and health insurance databases.ResultsDuring a media of 7.18 years follow-up, 1120 T2DM cases were identified. Higher T2DM incidence was observed in participants with frequent and occasional snoring compared with those without (4.80 and 2.87 vs 2.39 per 1000 person-years). The multivariable-adjusted model found snoring was independently associated with T2DM (HR 1.28, 95% CI 1.20 to 1.38), both in men (HR 1.25, 95% CI 1.10 to 1.41) and women (HR 1.28, 95% CI 1.17 to 1.39). Moreover, a significant multiplicative interaction effect between snoring and age was detected on T2DM risk (p=0.015).ConclusionsSnoring was independently associated with an increased risk of T2DM in Chinese population, both in men and women. Meanwhile, there was an interaction effect between snoring and age on T2DM risk.

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