Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study: newborn anthropometrics and childhood glucose metabolism.

AIMS/HYPOTHESIS: We aimed to examine associations of newborn anthropometric measures with childhood glucose metabolism with the hypothesis that greater newborn birthweight, adiposity and cord C-peptide are associated with higher childhood glucose levels and lower insulin sensitivity. METHODS: Data from the international, multi-ethnic, population-based Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study were used. The analytic cohort included 4155 children (mean age [SD], 11.4 [1.2] years; 51.0% male). Multiple linear regression was used to examine associations of primary predictors, birthweight, newborn sum of skinfolds (SSF) and cord C-peptide, from HAPO with continuous child glucose outcomes from the HAPO Follow-Up Study. RESULTS: In an initial model that included family history of diabetes and maternal BMI during pregnancy, birthweight and SSF demonstrated a significant, inverse association with 30 min and 1 h plasma glucose levels. In the primary model, which included further adjustment for maternal sum of glucose z scores from an oral glucose tolerance test during pregnancy, the associations were strengthened, and birthweight and SSF were inversely associated with fasting, 30 min, 1 h and 2 h plasma glucose levels. Birthweight and SSF were also associated with higher insulin sensitivity (Matsuda index) (ß = 1.388; 95% CI 0.870, 1.906; p < 0.001; ß = 0.792; 95% CI 0.340, 1.244; p < 0.001, for birthweight and SSF higher by 1 SD, respectively) in the primary model, while SSF, but not birthweight, was positively associated with the disposition index, a measure of beta cell compensation for insulin resistance (ß = 0.034; 95% CI 0.012, 0.056; p = 0.002). Cord C-peptide levels were inversely associated with Matsuda index (ß = -0.746; 95% CI -1.188, -0.304; p < 0.001 for cord C-peptide higher by 1 SD) in the primary model. CONCLUSIONS/INTERPRETATION: This study demonstrates that higher birthweight and SSF are associated with greater childhood insulin sensitivity and lower glucose levels following a glucose load, associations that were further strengthened after adjustment for maternal glucose levels during pregnancy. Graphical abstract.

One-step or 2-step testing for gestational diabetes: which is better?

In the United States, the common approach to detecting gestational diabetes mellitus is the 2-step protocol recommended by the American College of Obstetricians and Gynecologists. A 50 g, 1-hour glucose challenge at 24 to 28 weeks' gestation is followed by a 100 g, 3-hour oral glucose tolerance test when a screening test threshold is exceeded. Notably, 2 or more elevated values diagnose gestational diabetes mellitus. The 2-step screening test is administered without regard to the time of the last meal, providing convenience by eliminating the requirement for fasting. However, depending upon the cutoff used and population risk factors, approximately 15% to 20% of screened women require the 100 g, 3-hour oral glucose tolerance test. The International Association of Diabetes and Pregnancy Study Groups recommends a protocol of no screening test but rather a diagnostic 75 g, 2-hour oral glucose tolerance test. One or more values above threshold diagnose gestational diabetes mellitus. The 1-step approach requires that women be fasting for the test but does not require a second visit and lasts 2 hours rather than 3. Primarily because of needing only a single elevated value, the 1-step approach identifies 18% to 20% of pregnant women as having gestational diabetes mellitus, 2 to 3 times the rate with the 2-step procedure, but lower than the current United States prediabetes rate of 24% in reproductive aged women. The resources needed for the increase in gestational diabetes mellitus are parallel to the resources needed for the increased prediabetes and diabetes in the nonpregnant population. A recent randomized controlled trial sought to assess the relative population benefits of the above 2 approaches to gestational diabetes mellitus screening and diagnosis. The investigators concluded that there was no significant difference between the 2-step screening protocol and 1-step diagnostic testing protocol in their impact on population adverse short-term pregnancy outcomes. An accompanying editorial concluded that perinatal benefits of the 1-step approach to diagnosing gestational diabetes mellitus "appear to be insufficient to justify the associated patient and healthcare costs of broadening the diagnosis." We raise several concerns about this conclusion. The investigators posited that a 20% improvement in adverse outcomes among the entire pregnancy cohort would be necessary to demonstrate an advantage to the 1-step approach and estimated the sample size based on that presumption, which we believe to be unlikely given the number of cases that would be identified. In addition, 27% of the women randomized to the 1-step protocol underwent 2-step testing; 6% of the study cohort had no testing at all. A subset of women assigned to 2-step testing did not meet the criteria for gestational diabetes mellitus but were treated as such because of elevated fasting plasma glucose levels, presumably contributing to the reduction in adverse outcomes but not to the number of gestational diabetes mellitus identified, increasing the apparent efficacy of the 2-step approach. No consideration was given to long-term benefits for mothers and offspring. All these factors may have contributed to obscuring the benefits of 1-step testing; most importantly, the study was not powered to identify what we understand to be the likely impact of 1-step testing on population health.

Association between egg intake and blood pressure in the USA: the INTERnational study on MAcro/micronutrients and blood Pressure (INTERMAP).

OBJECTIVES: To investigate associations of egg intake with blood pressure (BP) and the role of dietary variables and other macro- and micro-nutrients in the association. DESIGN: We used cross-sectional data for the USA as part of the INTERnational study on MAcro/micronutrients and blood Pressure (INTERMAP). INTERMAP was surveyed between 1996 and 1999, including four 24-h dietary recalls, two 24-h urine collections and eight measurements of systolic BP and diastolic BP (SBP, DBP). Average egg intake (g/d) was calculated. Multivariable linear regression models were used to estimate the association between egg intake (per each 50 g/d or per quintile) and BP. The roles of dietary variables and other macro- and micro-nutrients in this association were also investigated. SETTING: In the USA. PARTICIPANTS: In total, 2195 US INTERMAP men and women aged 40-59 years. RESULTS: Participants were 50 % female, 54 % non-Hispanic White and 16 % non-Hispanic Black. Mean egg intake (sd) in men and women was 30·4(29·8) and 21·6(20·5) g/d, respectively. Adjusting for demographics, socio-economics, lifestyle and urinary Na:K excretion ratios, we found non-linear associations with BP in non-obese women (P-quadratic terms: 0·004 for SBP and 0·035 for DBP).The associations remained after adjusting for dietary variables, macro/micro nutrients or minerals. Dietary cholesterol was highly correlated with egg intake and may factor in the association. No association was found in obese women and in obese or non-obese men. CONCLUSION: Egg intake was non-linearly associated with SBP and DBP in non-obese women, but not in obese women or men. Underlying mechanisms require additional study regarding the role of obesity and sex.

Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study.

AIMS/HYPOTHESIS: Maternal type 2 diabetes during pregnancy and gestational diabetes are associated with childhood adiposity; however, associations of lower maternal glucose levels during pregnancy with childhood adiposity, independent of maternal BMI, remain less clear. The objective was to examine associations of maternal glucose levels during pregnancy with childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. METHODS: The HAPO Study was an observational epidemiological international multi-ethnic investigation that established strong associations of glucose levels during pregnancy with multiple adverse perinatal outcomes. The HAPO Follow-up Study (HAPO FUS) included 4832 children from ten HAPO centres whose mothers had a 75 g OGTT at ~28 weeks gestation 10-14 years earlier, with glucose values blinded to participants and clinical caregivers. The primary outcome was child adiposity, including: (1) being overweight/obese according to sex- and age-specific cut-offs based on the International Obesity Task Force (IOTF) criteria; (2) IOTF-defined obesity only; and (3) measurements >85th percentile for sum of skinfolds, waist circumference and per cent body fat. Primary predictors were maternal OGTT and HbA1c values during pregnancy. RESULTS: Fully adjusted models that included maternal BMI at pregnancy OGTT indicated positive associations between maternal glucose predictors and child adiposity outcomes. For one SD difference in pregnancy glucose and HbA1c measures, ORs for each child adiposity outcome were in the range of 1.05-1.16 for maternal fasting glucose, 1.11-1.19 for 1 h glucose, 1.09-1.21 for 2 h glucose and 1.12-1.21 for HbA1c. Associations were significant, except for associations of maternal fasting glucose with offspring being overweight/obese or having waist circumference >85th percentile. Linearity was confirmed in all adjusted models. Exploratory sex-specific analyses indicated generally consistent associations for boys and girls. CONCLUSIONS/INTERPRETATION: Exposure to higher levels of glucose in utero is independently associated with childhood adiposity, including being overweight/obese, obesity, skinfold thickness, per cent body fat and waist circumference. Glucose levels less than those diagnostic of diabetes are associated with greater childhood adiposity; this may have implications for long-term metabolic health.

Association of Gestational Diabetes With Maternal Disorders of Glucose Metabolism and Childhood Adiposity.

Importance: The sequelae of gestational diabetes (GD) by contemporary criteria that diagnose approximately twice as many women as previously used criteria are unclear. Objective: To examine associations of GD with maternal glucose metabolism and childhood adiposity 10 to 14 years' postpartum. Design, Setting, and Participants: The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study established associations of glucose levels during pregnancy with perinatal outcomes and the follow-up study evaluated the long-term outcomes (4697 mothers and 4832 children; study visits occurred between February 13, 2013, and December 13, 2016). Exposures: Gestational diabetes was defined post hoc using criteria from the International Association of Diabetes and Pregnancy Study Groups consisting of 1 or more of the following 75-g oral glucose tolerance test results (fasting plasma glucose ≥92 mg/dL; 1-hour plasma glucose level ≥180 mg/dL; 2-hour plasma glucose level ≥153 mg/dL). Main Outcomes and Measures: Primary maternal outcome: a disorder of glucose metabolism (composite of type 2 diabetes or prediabetes). Primary outcome for children: being overweight or obese; secondary outcomes: obesity, body fat percentage, waist circumference, and sum of skinfolds (>85th percentile for latter 3 outcomes). Results: The analytic cohort included 4697 mothers (mean [SD] age, 41.7 [5.7] years) and 4832 children (mean [SD] age, 11.4 [1.2] years; 51.0% male). The median duration of follow-up was 11.4 years. The criteria for GD were met by 14.3% (672/4697) of mothers overall and by 14.1% (683/4832) of mothers of participating children. Among mothers with GD, 52.2% (346/663) developed a disorder of glucose metabolism vs 20.1% (791/3946) of mothers without GD (odds ratio [OR], 3.44 [95% CI, 2.85 to 4.14]; risk difference [RD], 25.7% [95% CI, 21.7% to 29.7%]). Among children of mothers with GD, 39.5% (269/681) were overweight or obese and 19.1% (130/681) were obese vs 28.6% (1172/4094) and 9.9% (405/4094), respectively, for children of mothers without GD. Adjusted for maternal body mass index during pregnancy, the OR was 1.21 (95% CI, 1.00 to 1.46) for children who were overweight or obese and the RD was 3.7% (95% CI, -0.16% to 7.5%); the OR was 1.58 (95% CI, 1.24 to 2.01) for children who were obese and the RD was 5.0% (95% CI, 2.0% to 8.0%); the OR was 1.35 (95% CI, 1.08 to 1.68) for body fat percentage and the RD was 4.2% (95% CI, 0.9% to 7.4%); the OR was 1.34 (95% CI, 1.08 to 1.67) for waist circumference and the RD was 4.1% (95% CI, 0.8% to 7.3%); and the OR was 1.57 (95% CI, 1.27 to 1.95) for sum of skinfolds and the RD was 6.5% (95% CI, 3.1% to 9.9%). Conclusions and Relevance: Among women with GD identified by contemporary criteria compared with those without it, GD was significantly associated with a higher maternal risk for a disorder of glucose metabolism during long-term follow-up after pregnancy. Among children of mothers with GD vs those without it, the difference in childhood overweight or obesity defined by body mass index cutoffs was not statistically significant; however, additional measures of childhood adiposity may be relevant in interpreting the study findings.

The chromosome 3q25 genomic region is associated with measures of adiposity in newborns in a multi-ethnic genome-wide association study.

Newborns characterized as large and small for gestational age are at risk for increased mortality and morbidity during the first year of life as well as for obesity and dysglycemia as children and adults. The intrauterine environment and fetal genes contribute to the fetal size at birth. To define the genetic architecture underlying the newborn size, we performed a genome-wide association study (GWAS) in 4281 newborns in four ethnic groups from the Hyperglycemia and Adverse Pregnancy Outcome Study. We tested for association with newborn anthropometric traits (birth length, head circumference, birth weight, percent fat mass and sum of skinfolds) and newborn metabolic traits (cord glucose and C-peptide) under three models. Model 1 adjusted for field center, ancestry, neonatal gender, gestational age at delivery, parity, maternal age at oral glucose tolerance test (OGTT); Model 2 adjusted for Model 1 covariates, maternal body mass index (BMI) at OGTT, maternal height at OGTT, maternal mean arterial pressure at OGTT, maternal smoking and drinking; Model 3 adjusted for Model 2 covariates, maternal glucose and C-peptide at OGTT. Strong evidence for association was observed with measures of newborn adiposity (sum of skinfolds model 3 Z-score 7.356, P = 1.90×10⁻¹³, and to a lesser degree fat mass and birth weight) and a region on Chr3q25.31 mapping between CCNL and LEKR1. These findings were replicated in an independent cohort of 2296 newborns. This region has previously been shown to be associated with birth weight in Europeans. The current study suggests that association of this locus with birth weight is secondary to an effect on fat as opposed to lean body mass.

Odds, risks and appropriate diagnosis of gestational diabetes.

The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) diagnostic process and criteria for gestational diabetes mellitus (GDM) have been recommended by the World Health Organization for adoption and were widely introduced into clinical practice in Australia from January 2015 - in Queensland, the Australian Capital Territory and variably across other states. The IADPSG criteria identify women at increased risk of a range of adverse pregnancy outcomes related to maternal hyperglycaemia. The relationship between maternal hyperglycaemia and adverse outcomes is continuous; however, one elevated glucose value is sufficient to impart a higher risk of pregnancy complications. We outline the background and statistical foundations of the IADPSG approach and refute the inference that invalid statistical reasoning underlies the IADPSG approach. The prevalence of GDM diagnosed by IADPSG criteria may be higher or lower than with other criteria, depending on the underlying population prevalence of fasting and post-glucose load hyperglycaemia, which in turn vary with ethnicity. Studies comparing previous Australian criteria to the IADPSG criteria suggest GDM prevalence may decrease or may increase by up to 35% in specific populations with the planned change in criteria. Pregnancy complications have multiple potential underlying causes. No set of glucose criteria will ever be able to fully separate women and babies at risk of pregnancy complications from those who are not.

Counterpoint: Establishing consensus in the diagnosis of GDM following the HAPO study.

The International Association of Diabetes in Pregnancy Study Groups (IADPSG) recommended a new protocol of 1-step testing with a 75 g oral glucose tolerance test for gestational diabetes in 2010. Since that time, these recommendations have been carefully scrutinized and accepted by a variety of organizations, but challenged or rejected by others. In the current review, we present more details regarding the background to the development of the IADPSG recommendations and seek to place them in context with the available epidemiologic and randomized controlled trial data. In this "counterpoint," we also provide specific rebuttal for errors of fact and disputed contentions provided by Long and Cundy in their 2013 article in Current Diabetes Reports.

Estimating 24-hour urinary sodium excretion from casual urinary sodium concentrations in Western populations: the INTERSALT study.

High intakes of dietary sodium are associated with elevated blood pressure levels and an increased risk of cardiovascular disease. National and international guidelines recommend reduced sodium intake in the general population, which necessitates population-wide surveillance. We assessed the utility of casual (spot) urine specimens in estimating 24-hour urinary sodium excretion as a marker of sodium intake in the International Cooperative Study on Salt, Other Factors, and Blood Pressure. There were 5,693 participants recruited in 1984-1987 at the ages of 20-59 years from 29 North American and European samples. Participants were randomly assigned to test or validation data sets. Equations derived from casual urinary sodium concentration and other variables in the test data were applied to the validation data set. Correlations between observed and estimated 24-hour sodium excretion were 0.50 for individual men and 0.51 for individual women; the values were 0.79 and 0.71, respectively, for population samples. Bias in mean values (observed minus estimated) was small; for men and women, the values were -1.6 mmol per 24 hours and 2.3 mmol per 24 hours, respectively, at the individual level and -1.8 mmol per 24 hours and 2.2 mmol per 24 hours, respectively, at the population level. Proportions of individuals with urinary 24-hour sodium excretion above the recommended levels were slightly overestimated by the models. Casual urine specimens may be a useful, low-burden, low-cost alternative to 24-hour urine collections for estimation of population sodium intakes; ongoing calibration with study-specific 24-hour urinary collections is recommended to increase validity.

Use of fasting plasma glucose to determine the approach for diagnosing gestational diabetes mellitus.

AIMS: Estimate the impact of OGTTs only on women with a screening FPG of 4.5-5.0 mmol/L using data from HAPO. METHODS: HAPO participants had 75-g OGTTs (24-32 weeks' gestation). At follow-up, children had adiposity assessed (overweight/obesity, obesity) and mothers and children had OGTTs. GDM was defined retrospectively using IADPSG criteria. Odds for neonatal (birthweight, percent neonatal fat, sum of skinfolds, cord C-peptide > 90th percentiles) and follow-up outcomes were assessed in those with HAPO FPG ≤ 4.4 or > 4.4 mmol/L and GDM or no GDM focusing on women with FPG > 4.4 and no GDM (Group 3) vs women with GDM and FPG ≤ 4.4 (Group 2). RESULTS: This strategy would miss a diagnosis of GDM in 14.7%. Odds for neonatal outcomes in Groups 2 and 3 were not different (ORs: 1.14 to 1.29). Odds at follow-up for type 2 diabetes and disorders of glucose metabolism in mothers were higher in Group 2 (ORs: 3.51, 2.57). Odds for childhood impaired glucose tolerance or adiposity outcomes were not different for Groups 2 and 3. CONCLUSIONS: HAPO mothers whose GDM diagnosis would be missed were not at greater risk for adverse neonatal and childhood outcomes than mothers with FPG of 4.5-5.0 without GDM.

Nutrient and food intakes of middle-aged adults at low risk of cardiovascular disease: the international study of macro-/micronutrients and blood pressure (INTERMAP).

PURPOSE: Individuals with favorable levels of readily measured cardiovascular disease (CVD) risk factors (low risk, LR) experience low long-term rates of CVD mortality and greater longevity. The purpose of the current study was to compare nutrient/food intakes of LR participants with participants not LR in the INTERMAP study. METHODS: Men and women (40-59 years) from 17 population samples in four countries (China, Japan, UK, US) provided four 24-h dietary recalls and two timed 24-h urine collections. LR was defined as meeting all of the following CVD risk criteria: systolic/diastolic blood pressure (BP) ≤ 120/ ≤ 80 mmHg; no drug treatment for high BP, hyperlipidemia, or CVD; non-smoking; BMI <25.0 kg/m(2) (US, UK) or <23.0 kg/m(2) (China, Japan); alcohol consumption <26.0 g/day (men)/<13.0 g/day (women); and no history of diabetes or CVD. Multivariate logistic regression was used to examine associations of nutrient/food intakes with LR. RESULTS: LR individuals reported higher intake of vegetable protein, fiber, magnesium, non-heme iron, potassium; lower energy intake; lower intake of cholesterol, saturated fatty acids, animal protein; and lower 24-h urinary sodium compared with individuals not LR. With regard to foods, LR individuals reported higher intake of fruits, vegetables, grains, pasta/rice, fish; lower intakes of meats, processed meats, high-fat dairy, and sugar-sweetened beverages than individuals not LR. CONCLUSIONS: Lower energy intake and differential intake of multiple specific nutrients and foods are characteristic of individuals at low risk for developing CVD. Identification of dietary habits associated with LR is important for further development of public health efforts aimed at reduction/prevention of CVD.

Lifetime risk and years lived free of total cardiovascular disease.

CONTEXT: Estimates of lifetime risk for total cardiovascular disease (CVD) may provide projections of the future population burden of CVD and may assist in clinician-patient risk communication. To date, no lifetime risk estimates of total CVD have been reported. OBJECTIVES: To calculate lifetime risk estimates of total CVD by index age (45, 55, 65, 75 years) and risk factor strata and to estimate years lived free of CVD across risk factor strata. DESIGN, SETTING, AND PARTICIPANTS: Pooled survival analysis of as many as 905,115 person-years of data from 1964 through 2008 from 5 National Heart, Lung, and Blood Institute-funded community-based cohorts: Framingham Heart Study, Framingham Offspring Study, Atherosclerosis Risk in Communities Study, Chicago Heart Association Detection Project in Industry Study, and Cardiovascular Health Study. All participants were free of CVD at baseline with risk factor data (blood pressure [BP], total cholesterol [TC], diabetes, and smoking status) and total CVD outcome data. MAIN OUTCOME MEASURES: Any total CVD event (including fatal and nonfatal coronary heart disease, all forms of stroke, congestive heart failure, and other CVD deaths). RESULTS: At an index age of 45 years, overall lifetime risk for total CVD was 60.3% (95% CI, 59.3%-61.2%) for men and 55.6% (95% CI, 54.5%-56.7%) for women. Men had higher lifetime risk estimates than women across all index ages. At index ages 55 and 65 years, men and women with at least 1 elevated risk factor (BP, 140-149/90-99 mm Hg; or TC, 200-239 mg/dL; but no diabetes or smoking), 1 major risk factor, or at least 2 major risk factors (BP, ≥160/100 mm Hg or receiving treatment; TC, ≥240 mg/dL or receiving treatment; diabetes mellitus; or current smoking) had lifetime risk estimates to age 95 years that exceeded 50%. Despite an optimal risk factor profile (BP, <120/80 mm Hg; TC, <180 mg/dL; and no smoking or diabetes), men and women at the index age of 55 years had lifetime risks (through 85 years of age) for total CVD of greater than 40% and 30%, respectively. Compared with participants with at least 2 major risk factors, those with an optimal risk factor profile lived up to 14 years longer free of total CVD. CONCLUSIONS: Lifetime risk estimates for total CVD were high (>30%) for all individuals, even those with optimal risk factors in middle age. However, maintenance of optimal risk factor levels in middle age was associated with substantially longer morbidity-free survival.

Association of weight status with mortality in adults with incident diabetes.

CONTEXT: Type 2 diabetes in normal-weight adults (body mass index [BMI] <25) is a representation of the metabolically obese normal-weight phenotype with unknown mortality consequences. OBJECTIVE: To test the association of weight status with mortality in adults with new-onset diabetes in order to minimize the influence of diabetes duration and voluntary weight loss on mortality. DESIGN, SETTING, AND PARTICIPANTS: Pooled analysis of 5 longitudinal cohort studies: Atherosclerosis Risk in Communities study, 1990-2006; Cardiovascular Health Study, 1992-2008; Coronary Artery Risk Development in Young Adults, 1987-2011; Framingham Offspring Study, 1979-2007; and Multi-Ethnic Study of Atherosclerosis, 2002-2011. A total of 2625 participants with incident diabetes contributed 27,125 person-years of follow-up. Included were men and women (age >40 years) who developed incident diabetes based on fasting glucose 126 mg/dL or greater or newly initiated diabetes medication and who had concurrent measurements of BMI. Participants were classified as normal weight if their BMI was 18.5 to 24.99 or overweight/obese if BMI was 25 or greater. MAIN OUTCOME MEASURES: Total, cardiovascular, and noncardiovascular mortality. RESULTS: The proportion of adults who were normal weight at the time of incident diabetes ranged from 9% to 21% (overall 12%). During follow-up, 449 participants died: 178 from cardiovascular causes and 253 from noncardiovascular causes (18 were not classified). The rates of total, cardiovascular, and noncardiovascular mortality were higher in normal-weight participants (284.8, 99.8, and 198.1 per 10,000 person-years, respectively) than in overweight/obese participants (152.1, 67.8, and 87.9 per 10,000 person-years, respectively). After adjustment for demographic characteristics and blood pressure, lipid levels, waist circumference, and smoking status, hazard ratios comparing normal-weight participants with overweight/obese participants for total, cardiovascular, and noncardiovascular mortality were 2.08 (95% CI, 1.52-2.85), 1.52 (95% CI, 0.89-2.58), and 2.32 (95% CI, 1.55-3.48), respectively. CONCLUSION: Adults who were normal weight at the time of incident diabetes had higher mortality than adults who are overweight or obese.

Blood pressure interactions with the DASH dietary pattern, sodium, and potassium: The International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP).

BACKGROUND: Adherence to the Dietary Approaches to Stop Hypertension (DASH) diet enhances potassium intake and reduces sodium intake and blood pressure (BP), but the underlying metabolic pathways are unclear. OBJECTIVES: Among free-living populations, we delineated metabolic signatures associated with the DASH diet adherence, 24-hour urinary sodium and potassium excretions, and the potential metabolic pathways involved. METHODS: We used 24-hour urinary metabolic profiling by proton nuclear magnetic resonance spectroscopy to characterize the metabolic signatures associated with the DASH dietary pattern score (DASH score) and 24-hour excretion of sodium and potassium among participants in the United States (n = 2164) and United Kingdom (n = 496) enrolled in the International Study of Macro- and Micronutrients and Blood Pressure (INTERMAP). Multiple linear regression and cross-tabulation analyses were used to investigate the DASH-BP relation and its modulation by sodium and potassium. Potential pathways associated with DASH adherence, sodium and potassium excretion, and BP were identified using mediation analyses and metabolic reaction networks. RESULTS: Adherence to the DASH diet was associated with urinary potassium excretion (correlation coefficient, r = 0.42; P < 0.0001). In multivariable regression analyses, a 5-point higher DASH score (range, 7 to 35) was associated with a lower systolic BP by 1.35 mmHg (95% CI, -1.95 to -0.80 mmHg; P = 1.2 × 10-5); control of the model for potassium but not sodium attenuated the DASH-BP relation. Two common metabolites (hippurate and citrate) mediated the potassium-BP and DASH-BP relationships, while 5 metabolites (succinate, alanine, S-methyl cysteine sulfoxide, 4-hydroxyhippurate, and phenylacetylglutamine) were found to be specific to the DASH-BP relation. CONCLUSIONS: Greater adherence to the DASH diet is associated with lower BP and higher potassium intake across levels of sodium intake. The DASH diet recommends greater intake of fruits, vegetables, and other potassium-rich foods that may replace sodium-rich processed foods and thereby influence BP through overlapping metabolic pathways. Possible DASH-specific pathways are speculated but confirmation requires further study. INTERMAP is registered as NCT00005271 at www.clinicaltrials.gov.

Relation of urinary calcium and magnesium excretion to blood pressure: The International Study Of Macro- And Micro-nutrients And Blood Pressure and The International Cooperative Study On Salt, Other Factors, And Blood Pressure.

Data indicate an inverse association between dietary calcium and magnesium intakes and blood pressure (BP); however, much less is known about associations between urinary calcium and magnesium excretion and BP in general populations. The authors assessed the relation of BP to 24-hour excretion of calcium and magnesium in 2 cross-sectional studies. The International Study of Macro- and Micro-Nutrients and Blood Pressure (INTERMAP) comprised 4,679 persons aged 40-59 years from 17 population samples in China, Japan, the United Kingdom, and the United States, and the International Cooperative Study on Salt, Other Factors, and Blood Pressure (INTERSALT) comprised 10,067 persons aged 20-59 years from 52 samples around the world. Timed 24-hour urine collections, BP measurements, and nutrient data from four 24-hour dietary recalls (INTERMAP) were collected. In multiple linear regression analyses, urinary calcium excretion was directly associated with BP. After adjustment for multiple confounders (including weight, height, alcohol intake, calcium intake, urinary sodium level, and urinary potassium intake), systolic BP was 1.9 mm Hg higher per each 4.1 mmol per 24 hours (2 standard deviations) of higher urinary calcium excretion (associations were smaller for diastolic BP) in INTERMAP. Qualitatively similar associations were observed in INTERSALT analyses. Associations between magnesium excretion and BP were small and nonsignificant for most of the models examined. The present data suggest that altered calcium homoeostasis, as exhibited by increased calcium excretion, is associated with higher BP levels.

Hyperglycemia and adverse pregnancy outcomes.

BACKGROUND: It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes. METHODS: A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded if the fasting plasma glucose level was 105 mg per deciliter (5.8 mmol per liter) or less and the 2-hour plasma glucose level was 200 mg per deciliter (11.1 mmol per liter) or less. Primary outcomes were birth weight above the 90th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90th percentile. Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia. RESULTS: For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter]), an increase in the 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter [1.7 mmol per liter]), and an increase in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter [1.3 mmol per liter]). For birth weight above the 90th percentile, the odds ratios were 1.38 (95% confidence interval [CI], 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55 (95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesarean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and 1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Significant associations were also observed for secondary outcomes, although these tended to be weaker. CONCLUSIONS: Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels.

Newborn Adiposity and Cord Blood C-Peptide as Mediators of the Maternal Metabolic Environment and Childhood Adiposity.

OBJECTIVE: Excessive childhood adiposity is a risk factor for adverse metabolic health. The objective was to investigate associations of newborn body composition and cord C-peptide with childhood anthropometrics and explore whether these newborn measures mediate associations of maternal midpregnancy glucose and BMI with childhood adiposity. RESEARCH DESIGN AND METHODS: Data on mother/offspring pairs (N = 4,832) from the epidemiological Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and HAPO Follow-up Study (HAPO FUS) were analyzed. Linear regression was used to study associations between newborn and childhood anthropometrics. Structural equation modeling was used to explore newborn anthropometric measures as potential mediators of the associations of maternal BMI and glucose during pregnancy with childhood anthropometric outcomes. RESULTS: In models including maternal glucose and BMI adjustments, newborn adiposity as measured by the sum of skinfolds was associated with child outcomes (adjusted mean difference, 95% CI, P value) BMI (0.26, 0.12-0.39, <0.001), BMI z-score (0.072, 0.033-0.11, <0.001), fat mass (kg) (0.51, 0.26-0.76, <0.001), percentage of body fat (0.61, 0.27-0.95, <0.001), and sum of skinfolds (mm) (1.14, 0.43-1.86, 0.0017). Structural equation models demonstrated significant mediation by newborn sum of skinfolds and cord C-peptide of maternal BMI effects on childhood BMI (proportion of total effect 2.5% and 1%, respectively), fat mass (3.1%, 1.2%), percentage of body fat (3.6%, 1.8%), and sum of skinfolds (2.9%, 1.8%), and significant mediation by newborn sum of skinfolds and cord C-peptide of maternal glucose effects on child fat mass (proportion of total association 22.0% and 21.0%, respectively), percentage of body fat (15.0%, 18.0%), and sum of skinfolds (15.0%, 20.0%). CONCLUSIONS: Newborn adiposity is independently associated with childhood adiposity and, along with fetal hyperinsulinemia, mediates, in part, associations of maternal glucose and BMI with childhood adiposity.

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: paving the way for new diagnostic criteria for gestational diabetes mellitus.

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study was performed in response to the need for internationally agreed upon diagnostic criteria for gestational diabetes, based upon their predictive value for adverse pregnancy outcome. Increases in each of the 3 values on the 75-g, 2-hour oral glucose tolerance test are associated with graded increases in the likelihood of pregnancy outcomes such as large for gestational age, cesarean section, fetal insulin levels, and neonatal fat content. Based upon an iterative process of decision making, a task force of the International Association of Diabetes and Pregnancy Study Groups recommends that the diagnosis of gestational diabetes be made when any of the following 3 75-g, 2-hour oral glucose tolerance test thresholds are met or exceeded: fasting 92 mg/dL, 1-hour 180 mg/dL, or 2 hours 153 mg/dL. Various authoritative bodies around the world are expected to deliberate the adoption of these criteria.

The ankle-brachial index is associated with the magnitude of impaired walking endurance among men and women with peripheral arterial disease.

Previous reports suggest that the severity of peripheral arterial disease (PAD), measured by the ankle-brachial index (ABI), is not associated with the magnitude of walking impairment, measured by treadmill testing. These prior studies have had small sample sizes and included only PAD participants with symptoms of intermittent claudication. We studied the association of the ABI with diverse measures of walking performance in a cross-sectional study of 156 participants with PAD with and without intermittent claudication symptoms. Outcomes included the Gardner-Skinner treadmill test, 6-minute walk, 4-meter walking velocity at usual and fastest pace, and the walking impairment questionnaire (WIQ). Adjusting for age, sex, race, comorbidities, leg symptoms, and other confounders, lower ABI values were associated with shorter distance achieved in the 6-minute walk (ABI < 0.50: 286 meters; ABI 0.50-0.70: 316 meters; ABI 0.71-0.95: 355 meters, p trend < 0.001), shorter maximal treadmill walking time (ABI < 0.50: 6.0 minutes; ABI 0.50-0.70: 6.9 minutes; ABI 0.71-0.95: 8.3 minutes, p trend = 0.009), and lower WIQ distance scores (p trend = 0.007) among PAD participants. The ABI was not associated significantly with walking velocity over 4 meters, treadmill time to onset of leg symptoms, or the WIQ speed or stair-climbing scores. In conclusion, among 156 participants with PAD with and without intermittent claudication, lower ABI values are associated significantly with poorer walking endurance, assessed by three distinct measures. Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique identifier: NCT00106327.