Teri L. Hernandez

Simvastatin Lowers C-Reactive Protein Within 14 Days An Effect Independent of Low-Density Lipoprotein Cholesterol Reduction

Background—The early response of C-reactive protein to initiation of a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) is not known. The purpose of this study was to determine the rate at which highly sensitive C-reactive protein (hsCRP) levels change after initiation of simvastatin and whether this occurs independently of the change in LDL cholesterol. Methods and Results—The study was a crossover, double-blind design including 40 subjects with elevated LDL cholesterol. Subjects were randomly assigned to 1 of 2 groups: simvastatin 40 mg for 14 days, then placebo for 14 days, or placebo first, then simvastatin. Simvastatin decreased LDL cholesterol by 56±4 mg/dL (P <0.0001) at day 7 and by an additional 8±3 mg/dL (P =0.02) at day 14. Baseline log(hsCRP) levels were similar in the 2 groups. By day 14, log(hsCRP) was significantly lower in patients on simvastatin when compared with placebo (P =0.011). Although there was no significant difference in fibrinogen levels, simvastatin produced a modest increase in log[lipoprotein(a)] (P =0.03) at days 7 and 14. There were no relationships between the decrease in LDL cholesterol and the decrease in hsCRP. Conclusions—Simvastatin lowers hsCRP by 14 days, independent of its effect on LDL cholesterol. This rapid impact of a statin on hsCRP has potential implications in the management of acute coronary syndromes.

Continuous Glucose Profiles in Obese and Normal-Weight Pregnant Women on a Controlled Diet Metabolic determinants of fetal growth

OBJECTIVE We sought to define 24-h glycemia in normal-weight and obese pregnant women using continuous glucose monitoring (CGM) while they consumed a habitual and controlled diet both early and late in pregnancy. RESEARCH DESIGN AND METHODS Glycemia was prospectively measured in early (15.7 ± 2.0 weeks’ gestation) and late (27.7 ± 1.7 weeks’ gestation) pregnancy in normal-weight (n = 22) and obese (n = 16) pregnant women on an ad libitum and controlled diet. Fasting glucose, triglycerides (early pregnancy only), nonesterified fatty acids (FFAs), and insulin also were measured. RESULTS The 24-h glucose area under the curve was higher in obese women than in normal-weight women both early and late in pregnancy despite controlled diets. Nearly all fasting and postprandial glycemic parameters were higher in the obese women later in pregnancy, as were fasting insulin, triglycerides, and FFAs. Infants born to obese mothers had greater adiposity. Maternal BMI (r = 0.54, P = 0.01), late average daytime glucose (r = 0.48, P < 0.05), and late fasting insulin (r = 0.49, P < 0.05) correlated with infant percentage body fat. However, early fasting triglycerides (r = 0.67, P < 0.001) and late fasting FFAs (r = 0.54, P < 0.01) were even stronger correlates. CONCLUSIONS This is the first study to demonstrate that obese women without diabetes have higher daytime and nocturnal glucose profiles than normal-weight women despite a controlled diet both early and late in gestation. Body fat in infants, not birth weight, was related to maternal BMI, glucose, insulin, and FFAs, but triglycerides were the strongest predictor. These metabolic findings may explain higher rates of infant macrosomia in obese women, which might be targeted in trials to prevent excess fetal growth.

Short-Term Triglyceride Lowering With Fenofibrate Improves Vasodilator Function in Subjects With Hypertriglyceridemia

Objective—The objective of this study was to investigate the effects of lowering plasma triglycerides (TGs) on endothelial function and gain insight into the role played by free fatty acids (FFAs) in hypertriglyceridemia-associated vascular dysfunction. Methods and Results—Eleven hypertriglyceridemic subjects without coronary artery disease, diabetes, elevated low-density lipoprotein cholesterol, tobacco use, or hypertension were studied using a randomized, double-blinded, crossover design (fenofibrate and placebo, 14 days). After each regimen, forearm blood flow was assessed by plethysmography in response to arterial acetylcholine, nitroprusside, and verapamil infusion. Hourly plasma TGs, FFA, glucose, and insulin were measured during a 24-hour feeding cycle to characterize the metabolic environment. Changes in plasma FFA after intravenous heparin were used to estimate typical FFA accumulation in the luminal endothelial microenvironment. Fenofibrate lowered plasma TG (P <0.001), total cholesterol (P <0.01), and apolipoprotein B (P <0.01) without altering high-density lipoprotein or low-density lipoprotein cholesterol concentrations. Forearm blood flow in response to acetylcholine (P <0.0001), nitroprusside (P <0.001), and verapamil (P <0.0001) improved after fenofibrate. Fenofibrate lowered 24-hour (P <0.0001) and post-heparin (P <0.001) TG and tended to lower 24-hour (P =0.054) and post-heparin (P =0.028) FFA. Conclusions—Vascular smooth muscle function significantly improves after lowering plasma TG without changes in confounding lipoproteins or insulin resistance. The data raise additional questions regarding the role of FFA in hypertriglyceridemia-associated vascular dysfunction.

Patterns of Glycemia in Normal Pregnancy: Should the current therapeutic targets be challenged?

Despite the well-known influence of maternal glucose on infant birth weight (BW), the prevalence of large for gestational age (LGA) infants (≥90th percentile for age) has been increasing steadily over decades, particularly in pregnancies complicated by pregestational or gestational diabetes mellitus (1). Although the overall prevalence of macrosomia (BW ≥4,000 g) is 17–29% in women with untreated gestational diabetes, the majority of macrosomic infants are born to women with obesity but no gestational diabetes (2,3). Moreover, epidemiologic data show that a higher BW is associated with higher BMI and glucose intolerance later in life (4,5), suggesting life-long metabolic implications for offspring. Recent data from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study suggested that concentrations of maternal glucose below the previously accepted diagnostic thresholds for gestational diabetes are predictive of LGA and fetal hyperinsulinemia (6). On the basis of this landmark study, the International Association of Diabetes in Pregnancy Study Group and the American Diabetes Association (ADA) recommended new lower diagnostic criteria for gestational diabetes (7,8). However, a significant number of women with gestational diabetes whose glucose values are within the current targeted therapeutic ranges deliver macrosomic infants (9). Although glucose plays a major role in fetal growth, this paradox underscores the likely role of other nutrients in fetal growth, but also the need to critically reexamine our definition of “normal” maternal patterns of glycemia and the effects on fetal growth. The new diagnostic criteria recommended by the International Association of Diabetes in Pregnancy Study Group and ADA are expected to increase the prevalence of gestational diabetes to 18%. Thus, treatment targets may need to be reevaluated. Historically, the treatment goal in pregnancies complicated by diabetes has been to mimic patterns of glycemia in normal pregnancy (1). Although the HAPO study better defined abnormal …

Fat redistribution following suction lipectomy: defense of body fat and patterns of restoration.

No randomized studies in humans have examined whether fat returns after removal or where it returns. We undertook a prospective, randomized‐controlled trial of suction lipectomy in nonobese women to determine if adipose tissue (AT) is defended and if so, the anatomic pattern of redistribution. Healthy women with disproportionate AT depots (lower abdomen, hips, or thighs) were enrolled. Baseline body composition measurements included dual‐energy X‐ray absorptiometry (DXA) (a priori primary outcome), abdominal/limb circumferences, subcutaneous skinfold thickness, and magnetic resonance imaging (MRI) (torso/thighs). Participants (n = 32; 36 ± 1 year) were randomized to small‐volume liposuction (n = 14, mean BMI: 24 ± 2 kg/m2) or control (n=18, mean BMI: 25 ± 2) following baseline. Surgery group participants underwent liposuction within 2–4 weeks. Identical measurements were repeated at 6 weeks, 6 months, and 1 year later. Participants agreed not to make lifestyle changes while enrolled. Between‐group differences were adjusted for baseline level of the outcome variable. After 6 weeks, percent body fat (%BF) by DXA was decreased by 2.1% in the lipectomy group and by 0.28% in the control group (adjusted difference (AD): −1.82%; 95% confidence interval (CI): −2.79% to −0.85%; P = 0.0002). This difference was smaller at 6 months, and by 1 year was no longer significant (0.59% (control) vs. −0.41% (lipectomy); AD: −1.00%; CI: −2.65 to 0.64; P = 0.23). AT reaccumulated differently across various sites. After 1 year the thigh region remained reduced (0.77% (control) vs. −1.83% (lipectomy); AD: −2.59%; CI: −3.91 to −1.28; P = 0.0001), but AT reaccumulated in the abdominal region (0.64% (control) vs. 0.42% (lipectomy); AD: −0.22; CI: −2.35 to 1.91; P = 0.84). Following suction lipectomy, BF was restored and redistributed from the thigh to the abdomen.

Women With Gestational Diabetes Mellitus Randomized to a Higher–Complex Carbohydrate/Low-Fat Diet Manifest Lower Adipose Tissue Insulin Resistance, Inflammation, Glucose, and Free Fatty Acids: A Pilot Study

OBJECTIVE Diet therapy in gestational diabetes mellitus (GDM) has focused on carbohydrate restriction but is poorly substantiated. In this pilot randomized clinical trial, we challenged the conventional low-carbohydrate/higher-fat (LC/CONV) diet, hypothesizing that a higher–complex carbohydrate/lower-fat (CHOICE) diet would improve maternal insulin resistance (IR), adipose tissue (AT) lipolysis, and infant adiposity. RESEARCH DESIGN AND METHODS At 31 weeks, 12 diet-controlled overweight/obese women with GDM were randomized to an isocaloric LC/CONV (40% carbohydrate/45% fat/15% protein; n = 6) or CHOICE (60%/25%/15%; n = 6) diet. All meals were provided. AT was biopsied at 37 weeks. RESULTS After ∼7 weeks, fasting glucose (P = 0.03) and free fatty acids (P = 0.06) decreased on CHOICE, whereas fasting glucose increased on LC/CONV (P = 0.03). Insulin suppression of AT lipolysis was improved on CHOICE versus LC/CONV (56 vs. 31%, P = 0.005), consistent with improved IR. AT expression of multiple proinflammatory genes was lower on CHOICE (P < 0.01). Infant adiposity trended lower with CHOICE (10.1 ± 1.4 vs. 12.6 ± 2%, respectively). CONCLUSIONS A CHOICE diet may improve maternal IR and infant adiposity, challenging recommendations for a LC/CONV diet.

A Higher-Complex Carbohydrate Diet in Gestational Diabetes Mellitus Achieves Glucose Targets and Lowers Postprandial Lipids: A Randomized Crossover Study

OBJECTIVE The conventional diet approach to gestational diabetes mellitus (GDM) advocates carbohydrate restriction, resulting in higher fat (HF), also a substrate for fetal fat accretion and associated with maternal insulin resistance. Consequently, there is no consensus about the ideal GDM diet. We hypothesized that, compared with a conventional, lower-carbohydrate/HF diet (40% carbohydrate/45% fat/15% protein), consumption of a higher-complex carbohydrate (HCC)/lower-fat (LF) Choosing Healthy Options in Carbohydrate Energy (CHOICE) diet (60/25/15%) would result in 24-h glucose area under the curve (AUC) profiles within therapeutic targets and lower postprandial lipids. RESEARCH DESIGN AND METHODS Using a randomized, crossover design, we provided 16 GDM women (BMI 34 ± 1 kg/m2) with two 3-day isocaloric diets at 31 ± 0.5 weeks (washout between diets) and performed continuous glucose monitoring. On day 4 of each diet, we determined postprandial (5 h) glucose, insulin, triglycerides (TGs), and free fatty acids (FFAs) following a controlled breakfast meal. RESULTS There were no between-diet differences for fasting or mean nocturnal glucose, but 24-h AUC was slightly higher (∼6%) on the HCC/LF CHOICE diet (P = 0.02). The continuous glucose monitoring system (CGMS) revealed modestly higher 1- and 2-h postprandial glucose on CHOICE (1 h, 115 ± 2 vs. 107 ± 3 mg/dL, P ≤ 0.01; 2 h, 106 ± 3 vs. 97 ± 3 mg/dL, P = 0.001) but well below current targets. After breakfast, 5-h glucose and insulin AUCs were slightly higher (P < 0.05), TG AUC was no different, but the FFA AUC was significantly lower (∼19%; P ≤ 0.01) on the CHOICE diet. CONCLUSIONS This highly controlled study randomizing isocaloric diets and using a CGMS is the first to show that liberalizing complex carbohydrates and reducing fat still achieved glycemia below current treatment targets and lower postprandial FFAs. This diet strategy may have important implications for preventing macrosomia.

Induction of Circadian Gene Expression in Human Subcutaneous Adipose‐derived Stem Cells

Objective: Genes encoding the circadian transcriptional apparatus exhibit robust oscillatory expression in murine adipose tissues. This study tests the hypothesis that human subcutaneous adipose‐derived stem cells (ASCs) provide an in vitro model in which to monitor the activity of the core circadian transcriptional apparatus.

Alterations in human milk leptin and insulin are associated with early changes in the infant intestinal microbiome

BACKGROUND Increased maternal body mass index (BMI) is a robust risk factor for later pediatric obesity. Accumulating evidence suggests that human milk (HM) may attenuate the transfer of obesity from mother to offspring, potentially through its effects on early development of the infant microbiome. OBJECTIVES Our objective was to identify early differences in intestinal microbiota in a cohort of breastfeeding infants born to obese compared with normal-weight (NW) mothers. We also investigated relations between HM hormones (leptin and insulin) and both the taxonomic and functional potentials of the infant microbiome. DESIGN Clinical data and infant stool and fasting HM samples were collected from 18 NW [prepregnancy BMI (in kg/m(2)) <24.0] and 12 obese (prepregnancy BMI >30.0) mothers and their exclusively breastfed infants at 2 wk postpartum. Infant body composition at 2 wk was determined by air-displacement plethysmography. Infant gastrointestinal microbes were estimated by using 16S amplicon and whole-genome sequencing. HM insulin and leptin were determined by ELISA; short-chain fatty acids (SCFAs) were measured in stool samples by using gas chromatography. Power was set at 80%. RESULTS Infants born to obese mothers were exposed to 2-fold higher HM insulin and leptin concentrations (P < 0.01) and showed a significant reduction in the early pioneering bacteria Gammaproteobacteria (P = 0.03) and exhibited a trend for elevated total SCFA content (P < 0.06). Independent of maternal prepregnancy BMI, HM insulin was positively associated with both microbial taxonomic diversity (P = 0.03) and Gammaproteobacteria (e.g., Enterobacteriaceae; P = 0.04) and was negatively associated with Lactobacillales (e.g., Streptococcaceae; P = 0.05). Metagenomic analysis showed that HM leptin and insulin were associated with decreased bacterial proteases, which are implicated in intestinal permeability, and reduced concentrations of pyruvate kinase, a biomarker of pediatric gastrointestinal inflammation. CONCLUSION Our results indicate that, although maternal obesity may adversely affect the early infant intestinal microbiome, HM insulin and leptin are independently associated with beneficial microbial metabolic pathways predicted to increase intestinal barrier function and reduce intestinal inflammation. This trial was registered at clinicaltrials.gov as NCT01693406.

Lack of suppression of circulating free fatty acids and hypercholesterolemia during weight loss on a high-fat, low-carbohydrate diet

BACKGROUND Little is known about the comparative effect of weight-loss diets on metabolic profiles during dieting. OBJECTIVE The purpose of this study was to compare the effect of a low-carbohydrate diet (< or =20 g/d) with a high-carbohydrate diet (55% of total energy intake) on fasting and hourly metabolic variables during active weight loss. DESIGN Healthy, obese adults (n = 32; 22 women, 10 men) were randomly assigned to receive either a carbohydrate-restricted diet [High Fat; mean +/- SD body mass index (BMI; in kg/m(2)): 35.8 +/- 2.9] or a calorie-restricted, low-fat diet (High Carb; BMI: 36.7 +/- 4.6) for 6 wk. A 24-h in-patient feeding study was performed at baseline and after 6 wk. Glucose, insulin, free fatty acids (FFAs), and triglycerides were measured hourly during meals, at regimented times. Remnant lipoprotein cholesterol was measured every 4 h. RESULTS Patients lost a similar amount of weight in both groups (P = 0.57). There was an absence of any diet treatment effect between groups on fasting triglycerides or on remnant lipoprotein cholesterol, which was the main outcome. Fasting insulin decreased (P = 0.03), and both fasting (P = 0.040) and 24-h FFAs (P < 0.0001) increased within the High Fat group. Twenty-four-hour insulin decreased (P < 0.05 for both groups). Fasting LDL cholesterol decreased in the High Carb group only (P = 0.003). In both groups, the differences in fasting and 24-h FFAs at 6 wk were significantly correlated with the change in LDL cholesterol (fasting FFA: r = 0.41, P = 0.02; 24-h FFA: r = 0.52, P = 0.002). CONCLUSIONS Weight loss was similar between diets, but only the high-fat diet increased LDL-cholesterol concentrations. This effect was related to the lack of suppression of both fasting and 24-h FFAs.