Prospective Associations of Systemic and Urinary Choline Metabolites with Incident Type 2 Diabetes

Svingen, G.F.T.; Schartum-Hansen, Hall; Pedersen, Eva Kristine Ringdal; Ueland, Per Magne; Tell, Grethe S.; Mellgren, Gunnar; Njølstad, Pål R.; Seifert, Reinhard; Strand, Elin; Karlsson, Therese; Nygård, Ottar

doi:10.1373/clinchem.2015.250761

Cited by 73 publications

(78 citation statements)

References 42 publications

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“…For example, we showed that subjects with highest plasma phosphatidylcholine concentrations had lower odds of type 2 diabetes, which somewhat countered the findings of a brief report on dietary intake data from 3 ongoing cohorts in the United States that showed an increase in the risk of type 2 diabetes that was associated with increased dietary choline from phosphatidylcholine (29). However, our data were consistent with recent prospective studies from both a Norwegian sample of patients with suspected stable angina pectoris (30) and an American generalpopulation sample (31) that showed an inverse relation between plasma betaine and the presence of type 2 diabetes. In addition, analyses of 4 other cohorts showed no relation between dietary intake of betaine or choline and the incidence of peripheral artery disease (32), incidence of coronary heart disease (33), or cardiovascular disease risk (34).…”

Section: Discussionsupporting

confidence: 84%

Choline and its metabolites are differently associated with cardiometabolic risk factors, history of cardiovascular disease, and MRI-documented cerebrovascular disease in older adults,

Roe

Zhang

Bhadelia

et al. 2017

The American Journal of Clinical Nutrition

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Background: There is a potential role of choline in cardiovascular and cerebrovascular disease through its involvement in lipid and one-carbon metabolism. Objective: We evaluated the associations of plasma choline and choline-related compounds with cardiometabolic risk factors, history of cardiovascular disease, and cerebrovascular pathology. Design: A cross-sectional subset of the Nutrition, Aging, and Memory in Elders cohort who had undergone MRI of the brain (n = 296; mean 6 SD age: 73 6 8.1 y) was assessed. Plasma concentrations of free choline, betaine, and phosphatidylcholine were measured with the use of liquid-chromatography-stable-isotope dilutionmultiple-reaction monitoring-mass spectrometry. A volumetric analysis of MRI was used to determine the cerebrovascular pathology (white-matter hyperintensities and small-and large-vessel infarcts). Multiple linear and logistic regression models were used to examine relations of plasma measures with cardiometabolic risk factors, history of cardiovascular disease, and radiologic evidence of cerebrovascular pathology. Results: Higher concentrations of plasma choline were associated with an unfavorable cardiometabolic risk-factor profile [lower highdensity lipoprotein (HDL) cholesterol, higher total homocysteine, and higher body mass index (BMI)] and greater odds of large-vessel cerebral vascular disease or history of cardiovascular disease but lower odds of small-vessel cerebral vascular disease. Conversely, higher concentrations of plasma betaine were associated with a favorable cardiometabolic risk-factor profile [lower low-density lipoprotein (LDL) cholesterol and triglycerides] and lower odds of diabetes. Higher concentrations of plasma phosphatidylcholine were associated with characteristics of both a favorable cardiometabolic risk-factor profile (higher HDL cholesterol, lower BMI, lower C-reactive protein, lower waist circumference, and lower odds of hypertension and diabetes) and an unfavorable profile (higher LDL cholesterol and triglycerides). Conclusion: Choline and its metabolites have differential associations with cardiometabolic risk factors and subtypes of vascular disease, thereby suggesting differing roles in the pathogenesis of cardiovascular and cerebral large-vessel disease compared with that of small-vessel disease.Am J Clin Nutr 2017;105:1283-90.

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Section: Discussionsupporting

confidence: 84%

Choline and its metabolites are differently associated with cardiometabolic risk factors, history of cardiovascular disease, and MRI-documented cerebrovascular disease in older adults,

Roe

Zhang

Bhadelia

et al. 2017

The American Journal of Clinical Nutrition

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“…Plasma TMAO concentrations were found to be higher in patients with diabetes with or without cardiovascular comorbidities (5,20,24), but these studies did not investigate the associations between plasma TMAO and type 2 diabetes after adjustment for other confounding factors. Svingen and colleagues (18) found increased plasma TMAO in patients with type 2 diabetes, but no significant association was observed in their investigation. In a recent metabolomic study of type 2 diabetes risk in 2 cohorts of Chinese adults, the pooled result of the association between plasma TMAO and type 2 diabetes risk did not reach significance, although the associations showed the same positive direction in both cohorts (19).…”

Section: Discussionmentioning

confidence: 76%

“…A recent prospective study indicated that higher intake of phosphatidylcholine, the precursor to the generation of TMAO, was independently associated with an increased risk of type 2 diabetes in 3 US populations (16). Previous studies have yielded inconsistent associations between plasma TMAO and type 2 diabetes (5,(17)(18)(19), and whether the association varies by FMO3 genetic variations has not yet been investigated. Our aim, therefore, was to determine the association of plasma TMAO with type 2 diabetes and to examine whether the association may be modified by a common FMO3 genetic variation in a casecontrol study.…”

Section: Introductionmentioning

confidence: 99%

Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes

Shan

Sun

Huang

et al. 2017

The American Journal of Clinical Nutrition

156

111

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Background: The association of trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite from dietary choline and carnitine, with type 2 diabetes was inconsistent. Objective: We evaluated the association of plasma TMAO with newly diagnosed type 2 diabetes and the potential modification of TMAO-generating enzyme flavin monooxygenase 3 (FMO3) polymorphisms. Design: This was an age-and sex-matched case-control study of 2694 participants: 1346 newly diagnosed cases of type 2 diabetes and 1348 controls. Concentrations of plasma TMAO were measured, and FMO3 E158K polymorphisms (rs2266782) were genotyped. Results: Medians (IQRs) of plasma TMAO concentration were 1.47 mmol/L (0.81-2.20 mmol/L) for controls and 1.77 mmol/L (1.09-2.80 mmol/L) for type 2 diabetes cases. From the lowest to the highest quartiles of plasma TMAO, the multivariable adjusted ORs of type 2 diabetes were 1.00 (reference), 1.38 (95% CI: 1.08, 1.77), 1.64 (95% CI: 1.28, 2.09), and 2.55 (95% CI: 1.99, 3.28) (Ptrend , 0.001); each SD of ln-transformed plasma TMAO was associated with a 38% (95% CI: 26%, 51%) increment in ORs of type 2 diabetes. The FMO3 rs2266782 polymorphism was not associated with type 2 diabetes. The positive association between plasma TMAO and type 2 diabetes was consistent in each rs2266782 genotype group, and no significant interaction was observed (P = 0.093). Conclusions: Our results suggested that higher plasma TMAO was associated with increased odds of newly diagnosed type 2 diabetes and that this association was not modified by the FMO3 rs2266782 polymorphism. This study was registered at clinicaltrials.gov as NCT03130894.Am J Clin Nutr 2017;106:888-94.

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“…Moreover, the association between betaine and AF risk was less strong in patients with suspected stable angina pectoris than in the general population. This may due to complex interactions of choline oxidation with extensive use of medications among the WECAC patients 44. Fourth, intravascular volume status may alter the susceptibility to AF 45.…”

Section: Discussionmentioning

confidence: 99%

“…However, the risk estimates in NORVIT were in general similar to those observed in HUSK and WECAC, making it less likely that the choline and betaine AF risk associations in NORVIT merely reflected persistent or recurrent AF present at baseline. Moreover, the within‐person reproducibility for neither plasma betaine nor choline is excellent 44, 49. Therefore, the risk associations explored based on baseline samples may be underestimated due to regression dilution bias 50…”

Section: Discussionmentioning

confidence: 99%

Plasma Concentrations and Dietary Intakes of Choline and Betaine in Association With Atrial Fibrillation Risk: Results From 3 Prospective Cohorts With Different Health Profiles

Zuo

Svingen

Tell

et al. 2018

JAHA

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BackgroundAlthough choline metabolism has been associated with atherosclerotic heart disease, less research attention has been paid to the associations of choline and its oxidative metabolite betaine with cardiac arrhythmias.Methods and ResultsWe evaluated associations of plasma concentrations and dietary intakes of choline and betaine with long‐term atrial fibrillation (AF) risk in a community‐based cohort, HUSK ([the Hordaland Health Study] n=6949), and validated the findings in 2 patient cohorts: the Western Norway Coronary Angiography Cohort (n=4164) and the NORVIT (Norwegian B‐Vitamin) Trial (n=3733). Information on AF was obtained from the CVDNOR (Cardiovascular Disease in Norway) project. In HUSK, WECAC (Western Norway Coronary Angiography Cohort), and NORVIT, 552, 411, and 663 AF cases were identified during a median follow‐up time of 10.9, 7.3, and, 8.7 years, respectively. Plasma concentrations of choline and betaine were significantly positively associated with later AF risk after multivariable adjustments in HUSK. Such associations were independently replicated in the 2 external prospective patient cohorts. The pooled hazard ratio was 1.13 (95% confidence interval 1.08‐1.19, P<0.001) and 1.16 (95% confidence interval 1.10‐1.22, P<0.001) per SD increment for log‐transformed choline and betaine, respectively. Moreover, dietary intake of choline was marginally associated with AF risk (pooled hazard ratio 1.29, 95% confidence interval 1.01‐1.66, fifth versus first quintile), whereas no significant association was observed between dietary betaine and AF risk.ConclusionsOur findings indicate that plasma concentrations as well as dietary intake of choline, but not betaine, are associated with subsequent risk of AF, suggesting a potential role of choline metabolism in the pathogenesis of AF.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov.Unique identifier: NCT00671346.

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Prospective Associations of Systemic and Urinary Choline Metabolites with Incident Type 2 Diabetes

Abstract: BACKGROUND: Several compounds in the choline oxidation pathway are associated with insulin resistance and prevalent diabetes; however, prospective data are scarce.

Cited by 73 publications

References 42 publications

Choline and its metabolites are differently associated with cardiometabolic risk factors, history of cardiovascular disease, and MRI-documented cerebrovascular disease in older adults,

Choline and its metabolites are differently associated with cardiometabolic risk factors, history of cardiovascular disease, and MRI-documented cerebrovascular disease in older adults,

Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes

Plasma Concentrations and Dietary Intakes of Choline and Betaine in Association With Atrial Fibrillation Risk: Results From 3 Prospective Cohorts With Different Health Profiles

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