Adela Hruby

Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis

OBJECTIVE To conduct a systematic review of cross-sectional and prospective human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on prediabetes and type 2 diabetes. RESEARCH DESIGN AND METHODS We searched MEDLINE and EMBASE databases through August 2015. We conducted a qualitative review of cross-sectional and prospective studies. Additionally, meta-analyses of metabolite markers, with data estimates from at least three prospective studies, and type 2 diabetes risk were conducted, and multivariable-adjusted relative risks of type 2 diabetes were calculated per study-specific SD difference in a given metabolite. RESULTS We identified 27 cross-sectional and 19 prospective publications reporting associations of metabolites and prediabetes and/or type 2 diabetes. Carbohydrate (glucose and fructose), lipid (phospholipids, sphingomyelins, and triglycerides), and amino acid (branched-chain amino acids, aromatic amino acids, glycine, and glutamine) metabolites were higher in individuals with type 2 diabetes compared with control subjects. Prospective studies provided evidence that blood concentrations of several metabolites, including hexoses, branched-chain amino acids, aromatic amino acids, phospholipids, and triglycerides, were associated with the incidence of prediabetes and type 2 diabetes. We meta-analyzed results from eight prospective studies that reported risk estimates for metabolites and type 2 diabetes, including 8,000 individuals of whom 1,940 had type 2 diabetes. We found 36% higher risk of type 2 diabetes per study-specific SD difference for isoleucine (pooled relative risk 1.36 [1.24–1.48]; I2 = 9.5%), 36% for leucine (1.36 [1.17–1.58]; I2 = 37.4%), 35% for valine (1.35 [1.19–1.53]; I2 = 45.8%), 36% for tyrosine (1.36 [1.19–1.55]; I2 = 51.6%), and 26% for phenylalanine (1.26 [1.10–1.44]; I2 = 56%). Glycine and glutamine were inversely associated with type 2 diabetes risk (0.89 [0.81–0.96] and 0.85 [0.82–0.89], respectively; both I2 = 0.0%). CONCLUSIONS In studies using high-throughput metabolomics, several blood amino acids appear to be consistently associated with the risk of developing type 2 diabetes.

Meta-Analysis Investigating Associations Between Healthy Diet and Fasting Glucose and Insulin Levels and Modification by Loci Associated With Glucose Homeostasis in Data From 15 Cohorts

Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 U.S. and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (β = -0.004 mmol/L, 95% confidence interval: -0.005, -0.003) and FI (β = -0.008 ln-pmol/L, 95% confidence interval: -0.009, -0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.

Higher magnesium intake reduces risk of impaired glucose and insulin metabolism, and progression from prediabetes to diabetes in middle-aged Americans

OBJECTIVE To assess 7-year associations between magnesium intake and incident prediabetes and/or insulin resistance (IR), and progression from these states to type 2 diabetes. RESEARCH DESIGN AND METHODS In 2,582 community-dwelling participants 26–81 years old at baseline, magnesium intake and risk of incident “metabolic impairment,” defined as impaired fasting glucose (FG) (≥5.6 to <7.0 mmol/L), impaired glucose tolerance (2-h postload glucose ≥7.8 to <11.1 mmol/L), IR, or hyperinsulinemia (≥90th percentile of homeostasis model assessment of IR or fasting insulin, respectively), was estimated among those with normal baseline status, and risk of incident diabetes was estimated among those with baseline metabolic impairment. In participants without incident diabetes, we examined magnesium intake in relation to 7-year changes in fasting and postload glucose and insulin, IR, and insulin sensitivity. RESULTS After adjusting for age, sex, and energy intake, compared with those with the lowest magnesium intake, those with the highest intake had 37% lower risk of incident metabolic impairment (P trend = 0.02), and in those with baseline metabolic impairment, higher intake was associated with 32% lower risk of incident diabetes (P trend = 0.05). In the combined population, the risk in those with the highest intake was 53% (P trend = 0.0004) of those with the lowest intake. Adjusting for risk factors and dietary fiber attenuated associations in the baseline normal population but did not substantially affect associations in the metabolically impaired. Higher magnesium intake tended to associate with lower follow-up FG and IR, but not fasting insulin, postload values, or insulin sensitivity. CONCLUSIONS Magnesium intake may be particularly beneficial in offsetting risk of developing diabetes among those at high risk. Magnesium’s long-term associations with non–steady-state (dynamic) measures deserve further research.

Plasma Branched-Chain Amino Acids and Incident Cardiovascular Disease in the PREDIMED Trial

BACKGROUND The role of branched-chain amino acids (BCAAs) in cardiovascular disease (CVD) remains poorly understood. We hypothesized that baseline BCAA concentrations predict future risk of CVD and that a Mediterranean diet (MedDiet) intervention may counteract this effect. METHODS We developed a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED), with 226 incident CVD cases and 744 noncases. We used LC-MS/MS to measure plasma BCAAs (leucine, isoleucine, and valine), both at baseline and after 1 year of follow-up. The primary outcome was a composite of incident stroke, myocardial infarction, or cardiovascular death. RESULTS After adjustment for potential confounders, baseline leucine and isoleucine concentrations were associated with higher CVD risk: the hazard ratios (HRs) for the highest vs lowest quartile were 1.70 (95% CI, 1.05-2.76) and 2.09 (1.27-3.44), respectively. Stronger associations were found for stroke. For both CVD and stroke, we found higher HRs across successive quartiles of BCAAs in the control group than in the MedDiet groups. With stroke as the outcome, a significant interaction (P = 0.009) between baseline BCAA score and intervention with MedDiet was observed. No significant effect of the intervention on 1-year changes in BCAAs or any association between 1-year changes in BCAAs and CVD were observed. CONCLUSIONS Higher concentrations of baseline BCAAs were associated with increased risk of CVD, especially stroke, in a high cardiovascular risk population. A Mediterranean-style diet had a negligible effect on 1-year changes in BCAAs, but it may counteract the harmful effects of BCAAs on stroke.

Higher Magnesium Intake Is Associated with Lower Fasting Glucose and Insulin, with No Evidence of Interaction with Select Genetic Loci, in a Meta-Analysis of 15 CHARGE Consortium Studies

Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = -0.009 mmol/L (95% CI: -0.013, -0.005), P < 0.0001] and insulin [-0.020 ln-pmol/L (95% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.

Plasma Ceramides, Mediterranean Diet, and Incident Cardiovascular Disease in the Predimed Trial

Background: Although in vitro studies and investigations in animal models and small clinical populations have suggested that ceramides may represent an intermediate link between overnutrition and certain pathological mechanisms underlying cardiovascular disease (CVD), no prospective studies have investigated the association between plasma ceramides and risk of CVD. Methods: The study population consisted of 980 participants from the PREDIMED trial (Prevención con Dieta Mediterránea), including 230 incident cases of CVD and 787 randomly selected participants at baseline (including 37 overlapping cases) followed for ⩽7.4 years. Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Plasma ceramide concentrations were measured on a liquid chromatography tandem mass spectrometry metabolomics platform. The primary outcome was a composite of nonfatal acute myocardial infarction, nonfatal stroke, or cardiovascular death. Hazard ratios were estimated with weighted Cox regression models using Barlow weights to account for the case-cohort design. Results: The multivariable hazard ratios (HR) and 95% confidence intervals (CIs) comparing the extreme quartiles of plasma concentrations of C16:0, C22:0, C24:0, and C24:1 ceramides were 2.39 (1.49–3.83, Ptrend<0.001), 1.91 (1.21–3.01, Ptrend=0.003), 1.97 (1.21–3.20, Ptrend=0.004), and 1.73 (1.09–2.74, Ptrend=0.011), respectively. The ceramide score, calculated as a weighted sum of concentrations of four ceramides, was associated with a 2.18-fold higher risk of CVD across extreme quartiles (HR, 2.18; 95% CI, 1.36–3.49; Ptrend<0.001). The association between baseline ceramide score and incident CVD varied significantly by treatment groups (Pinteraction=0.010). Participants with a higher ceramide score and assigned to either of the 2 active intervention arms of the trial showed similar CVD risk to those with a lower ceramide score, whereas participants with a higher ceramide score and assigned to the control arm presented significantly higher CVD risk. Changes in ceramide concentration were not significantly different between Mediterranean diet and control groups during the first year of follow-up. Conclusions: Our study documented a novel positive association between baseline plasma ceramide concentrations and incident CVD. In addition, a Mediterranean dietary intervention may mitigate potential deleterious effects of elevated plasma ceramide concentrations on CVD. Clinical Trial Registration: URL: http://www.isrctn.com. Unique identifier: ISRCTN35739639.

Perspective: The Case for an Evidence-Based Reference Interval for Serum Magnesium: The Time Has Come

The 2015 Dietary Guidelines Advisory Committee indicated that magnesium was a shortfall nutrient that was underconsumed relative to the Estimated Average Requirement (EAR) for many Americans. Approximately 50% of Americans consume less than the EAR for magnesium, and some age groups consume substantially less. A growing body of literature from animal, epidemiologic, and clinical studies has demonstrated a varied pathologic role for magnesium deficiency that includes electrolyte, neurologic, musculoskeletal, and inflammatory disorders; osteoporosis; hypertension; cardiovascular diseases; metabolic syndrome; and diabetes. Studies have also demonstrated that magnesium deficiency is associated with several chronic diseases and that a reduced risk of these diseases is observed with higher magnesium intake or supplementation. Subclinical magnesium deficiency can exist despite the presentation of a normal status as defined within the current serum magnesium reference interval of 0.75-0.95 mmol/L. This reference interval was derived from data from NHANES I (1974), which was based on the distribution of serum magnesium in a normal population rather than clinical outcomes. What is needed is an evidenced-based serum magnesium reference interval that reflects optimal health and the current food environment and population. We present herein data from an array of scientific studies to support the perspective that subclinical deficiencies in magnesium exist, that they contribute to several chronic diseases, and that adopting a revised serum magnesium reference interval would improve clinical care and public health.

The Circulating Concentration and 24-h Urine Excretion of Magnesium Dose- and Time-Dependently Respond to Oral Magnesium Supplementation in a Meta-Analysis of Randomized Controlled Trials

BACKGROUND Accurate determination of Mg status is important for improving nutritional assessment and clinical risk stratification. OBJECTIVE We aimed to quantify the overall responsiveness of Mg biomarkers to oral Mg supplementation among adults without severe diseases and their dose- and time responses using available data from randomized controlled trials (RCTs). METHODS We identified 48 Mg supplementation trials (n = 2131) through searches of MEDLINE and the Cochrane Library up to November 2014. Random-effects meta-analysis was used to estimate weighted mean differences of biomarker concentrations between intervention and placebo groups. Restricted cubic splines were used to determine the dose- and time responses of Mg biomarkers to supplementation. RESULTS Among the 35 biomarkers assessed, serum, plasma, and urine Mg were most commonly measured. Elemental Mg supplementation doses ranged from 197 to 994 mg/d. Trials ranged from 3 wk to 5 y (median: 12 wk). Mg supplementation significantly elevated circulating Mg by 0.04 mmol/L (95% CI: 0.02, 0.06) and 24-h urine Mg excretion by 1.52 mmol/24 h (95% CI: 1.20, 1.83) as compared to placebo. Circulating Mg concentrations and 24-h urine Mg excretion responded to Mg supplementation in a dose- and time-dependent manner, gradually reaching a steady state at doses of 300 mg/d and 400 mg/d, or after ~20 wk and 40 wk, respectively (all P-nonlinearity ≤ 0.001). The higher the circulating Mg concentration at baseline, the lower the responsiveness of circulating Mg to supplementation, and the higher the urinary excretion (all P-linearity < 0.05). In addition, RBC Mg, fecal Mg, and urine calcium were significantly more elevated by Mg supplementation than by placebo (all P-values < 0.05), but there is insufficient evidence to determine their responses to increasing Mg doses. CONCLUSIONS This meta-analysis of RCTs demonstrated significant dose- and time responses of circulating Mg concentration and 24-h urine Mg excretion to oral Mg supplementation.

Dietary Magnesium and Genetic Interactions in Diabetes and Related Risk Factors: A Brief Overview of Current Knowledge

Nutritional genomics has exploded in the last decade, yielding insights—both nutrigenomic and nutrigenetic—into the physiology of dietary interactions and our genes. Among these are insights into the regulation of magnesium transport and homeostasis and mechanisms underlying magnesium’s role in insulin and glucose handling. Recent observational evidence has attempted to examine some promising research avenues on interaction between genetics and dietary magnesium in relation to diabetes and diabetes risk factors. This brief review summarizes the recent evidence on dietary magnesium’s role in diabetes and related traits in the presence of underlying genetic risk, and discusses future potential research directions.

Trends in overweight and obesity in soldiers entering the US Army, 1989-2012.

The US Army recruits new soldiers from an increasingly obese civilian population. The change in weight status at entry into the Army between 1989 and 2012 and the demographic characteristics associated with overweight/obesity at entry were examined.