Mary Walter

Persistent metabolic adaptation 6 years after "The Biggest Loser" competition.

To measure long‐term changes in resting metabolic rate (RMR) and body composition in participants of “The Biggest Loser” competition.

Ingestion of Diet Soda Before a Glucose Load Augments Glucagon-Like Peptide-1 Secretion

OBJECTIVE The goal of this study was to determine the effect of artificial sweeteners on glucose, insulin, and glucagon-like peptide (GLP)-1 in humans. RESEARCH DESIGN AND METHODS For this study, 22 healthy volunteers (mean age 18.5 ± 4.2 years) underwent two 75-g oral glucose tolerance tests with frequent measurements of glucose, insulin, and GLP-1 for 180 min. Subjects drank 240 ml of diet soda or carbonated water, in randomized order, 10 min prior to the glucose load. RESULTS Glucose excursions were similar after ingestion of carbonated water and diet soda. Serum insulin levels tended to be higher after diet soda, without statistical significance. GLP-1 peak and area under the curve (AUC) were significantly higher with diet soda (AUC 24.0 ± 15.2 pmol/l per 180 min) versus carbonated water (AUC 16.2 ± 9.0 pmol/l per 180 min; P = 0.003). CONCLUSIONS Artificial sweeteners synergize with glucose to enhance GLP-1 release in humans. This increase in GLP-1 secretion may be mediated via stimulation of sweet-taste receptors on L-cells by artificial sweetener.

Calorie for Calorie, Dietary Fat Restriction Results in More Body Fat Loss than Carbohydrate Restriction in People with Obesity

Dietary carbohydrate restriction has been purported to cause endocrine adaptations that promote body fat loss more than dietary fat restriction. We selectively restricted dietary carbohydrate versus fat for 6 days following a 5-day baseline diet in 19 adults with obesity confined to a metabolic ward where they exercised daily. Subjects received both isocaloric diets in random order during each of two inpatient stays. Body fat loss was calculated as the difference between daily fat intake and net fat oxidation measured while residing in a metabolic chamber. Whereas carbohydrate restriction led to sustained increases in fat oxidation and loss of 53 ± 6 g/day of body fat, fat oxidation was unchanged by fat restriction, leading to 89 ± 6 g/day of fat loss, and was significantly greater than carbohydrate restriction (p = 0.002). Mathematical model simulations agreed with these data, but predicted that the body acts to minimize body fat differences with prolonged isocaloric diets varying in carbohydrate and fat.

Effects of Diet Soda on Gut Hormones in Youths With Diabetes

OBJECTIVE In patients with type 2 diabetes, but not type 1 diabetes, abnormal secretion of incretins in response to oral nutrients has been described. In healthy youths, we recently reported accentuated glucagon-like peptide 1 (GLP-1) secretion in response to a diet soda sweetened with sucralose and acesulfame-K. In this study, we examined the effect of diet soda on gut hormones in youths with diabetes. RESEARCH DESIGN AND METHODS Subjects aged 12–25 years with type 1 diabetes (n = 9) or type 2 diabetes (n = 10), or healthy control participants (n = 25) drank 240 mL cola-flavored caffeine-free diet soda or carbonated water, followed by a 75-g glucose load, in a randomized, cross-over design. Glucose, C-peptide, GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide Tyr-Tyr (PYY) were measured for 180 min. Glucose and GLP-1 have previously been reported for the healthy control subjects. RESULTS GLP-1 area under the curve (AUC) was 43% higher after ingestion of diet soda versus carbonated water in individuals with type 1 diabetes (P = 0.020), similar to control subjects (34% higher, P = 0.029), but was unaffected by diet soda in patients with type 2 diabetes (P = 0.92). Glucose, C-peptide, GIP, and PYY AUC were not statistically different between the two conditions in any group. CONCLUSIONS Ingestion of diet soda before a glucose load augmented GLP-1 secretion in type 1 diabetic and control subjects but not type 2 diabetic subjects. GIP and PYY secretion were not affected by diet soda. The clinical significance of this increased GLP-1 secretion, and its absence in youths with type 2 diabetes, needs to be determined.

Metabolic Effects of Chronic Cannabis Smoking

OBJECTIVE We examined if chronic cannabis smoking is associated with hepatic steatosis, insulin resistance, reduced β-cell function, or dyslipidemia in healthy individuals. RESEARCH DESIGN AND METHODS In a cross-sectional, case-control study, we studied cannabis smokers (n = 30; women, 12; men, 18; 27 ± 8 years) and control subjects (n = 30) matched for age, sex, ethnicity, and BMI (27 ± 6). Abdominal fat depots and intrahepatic fat content were quantified by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. Insulin-sensitivity indices and various aspects of β-cell function were derived from oral glucose tolerance tests (OGTT). RESULTS Self-reported cannabis use was: 9.5 (2–38) years; joints/day: 6 (3–30) [median (range)]. Carbohydrate intake and percent calories from carbohydrates, but not total energy intake, were significantly higher in cannabis smokers. There were no group differences in percent total body fat, or hepatic fat, but cannabis smokers had a higher percent abdominal visceral fat (18 ± 9 vs. 12 ± 5%; P = 0.004). Cannabis smokers had lower plasma HDL cholesterol (49 ± 14 vs. 55 ± 13 mg/dL; P = 0.02), but fasting levels of glucose, insulin, total cholesterol, LDL cholesterol, triglycerides, or free fatty acids (FFA) were not different. Adipocyte insulin resistance index and percent FFA suppression during an OGTT was lower (P < 0.05) in cannabis smokers. However, oral glucose insulin sensitivity index, measures of β-cell function, or incretin concentrations did not differ between the groups. CONCLUSIONS Chronic cannabis smoking was associated with visceral adiposity and adipose tissue insulin resistance but not with hepatic steatosis, insulin insensitivity, impaired pancreatic β-cell function, or glucose intolerance.

Obstructive Sleep Apnea Is a Predictor of Abnormal Glucose Metabolism in Chronically Sleep Deprived Obese Adults

Context Sleep abnormalities, including obstructive sleep apnea (OSA), have been associated with insulin resistance. Objective To determine the relationship between sleep, including OSA, and glucose parameters in a prospectively assembled cohort of chronically sleep-deprived obese subjects. Design Cross-sectional evaluation of a prospective cohort study. Setting Tertiary Referral Research Clinical Center. Main Outcome Measure(s) Sleep duration and quality assessed by actigraphy, sleep diaries and questionnaires, OSA determined by a portable device; glucose metabolism assessed by oral glucose tolerance test (oGTT), and HbA1c concentrations in 96 obese individuals reporting sleeping less than 6.5 h on a regular basis. Results Sixty % of subjects had an abnormal respiratory disturbance index (RDI≥5) and 44% of these subjects had abnormal oGTT results. Severity of OSA as assessed by RDI score was associated with fasting glucose (R = 0.325, p = 0.001) and fasting insulin levels (ρ = 0.217, p = 0.033). Subjects with moderate to severe OSA (RDI>15) had higher glucose concentrations at 120 min than those without OSA (RDI<5) (p = 0.017). Subjects with OSA also had significantly higher concentrations of plasma ACTH (p = 0.009). Several pro-inflammatory cytokines were higher in subjects with OSA (p<0.050). CRP levels were elevated in this sample, suggesting increased cardiovascular risk. Conclusions OSA is associated with impaired glucose metabolism in obese, sleep deprived individuals. Since sleep apnea is common and frequently undiagnosed, health care providers should be aware of its occurrence and associated risks. Trial Registration This study was conducted under the NIDDK protocol 06-DK-0036 and is listed in ClinicalTrials.gov NCT00261898

Increased 24-hour ad libitum food intake is associated with lower plasma irisin concentrations the following morning in adult humans.

BACKGROUND The relationship between food intake and irisin concentrations in humans is unclear. OBJECTIVES To determine whether the previous days intake impacts fasting plasma irisin concentrations, or whether fasting irisin concentrations associate with subsequent ad libitum food intake. METHODS Sixty-six nondiabetic adults (42 men) were admitted for a study of the determinants of energy intake. After 6 days of a weight maintaining diet, ad libitum energy intake over 3 days was assessed using a vending machine paradigm. Fasting plasma irisin concentrations were measured on the morning of the second day of the vending period. RESULTS There were no correlations between irisin and demographic or anthropometric parameters. On day 1, subjects consumed 144 ± 52% of weight maintaining energy needs. Every additional 500 kcal consumed on day 1 associated with a 3.4% lower irisin concentration the following morning (95% CI -6.2, -0.4%, p = 0.01; adjusted for age, sex and race). If energy intake was expressed as a percentage of weight maintaining energy needs, every 10% increase associated with a 1.9% lower irisin concentration (95% CI -3.7, -0.1%; adjusted p = 0.02). A 100 kcal increase in carbohydrate or fat consumption associated with a 1.3% (95% CI -2.5, -0.1%, p = 0.01) and a 0.6% (95% CI -1.1, -0.0%, p = 0.02) lower irisin concentration, respectively. There was no association between fasting irisin concentrations and subsequent energy intake on day 2 (r = 0.19, p = 0.1). CONCLUSIONS Higher ad libitum 24 h energy intake was associated with lower fasting irisin concentrations the following morning, but fasting irisin concentrations did not predict subsequent energy intake. The decrease in irisin concentrations with increased energy intake is consistent with the detrimental metabolic effects of overeating.

Effects of Metreleptin in Pediatric Patients With Lipodystrophy

Context Lipodystrophy syndromes are rare disorders of deficient adipose tissue. Metreleptin, a human analog of leptin, improved metabolic abnormalities in mixed cohorts of children and adults with lipodystrophy and low leptin. Objective Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin. Design Prospective, single-arm, open-label studies with continuous enrollment since 2000. Setting National Institutes of Health, Bethesda, Maryland. Patients Fifty-three patients aged 6 months to <18 years with lipodystrophy, leptin level <8 ng/mL (male patients) or <12 ng/mL (female patients), and ≥1 metabolic abnormality (diabetes, insulin resistance, or hypertriglyceridemia). Intervention Subcutaneous metreleptin injections (0.04 to 0.19 mg/kg/d). Main Outcome Measures Change in A1c, lipid, and transaminase levels after a mean ± standard deviation (SD) of 12 ± 0.2 months and 61 ± 39 months. Changes in liver histology, growth, and pubertal development throughout treatment. Results After 12 months, the A1c level (mean ± SD) decreased from 8.3% ± 2.4% to 6.5% ± 1.8%, and median triglyceride level decreased from 374 mg/dL [geometric mean (25th,75th percentile), 190, 1065] to 189 mg/dL (112, 334; P < 0.0001), despite decreased glucose- and lipid-lowering medications. The median [geometric mean (25th,75th percentile)] alanine aminotransferase level decreased from 73 U/L (45, 126) to 41 U/L (25, 59; P = 0.001), and that of aspartate aminotransferase decreased from 51 U/L (29, 90) to 26 U/L (18, 42; P = 0.0002). These improvements were maintained over long-term treatment. In 17 patients who underwent paired biopsies, the NAFLD activity score (mean ± SD) decreased from 4.5 ± 2.0 to 3.4 ± 2.0 after 3.3 ± 3.2 years of metreleptin therapy (P = 0.03). There were no clinically significant changes in growth or puberty. Conclusion Metreleptin lowered A1c and triglyceride levels, and improved biomarkers of NAFLD in pediatric patients with lipodystrophy. These improvements are likely to reduce the lifetime burden of disease.

Myocardial Fat Accumulation Is Independent of Measures of Insulin Sensitivity

BACKGROUND Myocardial steatosis, an independent predictor of diastolic dysfunction, is frequently present in type 2 diabetes mellitus. High free fatty acid flux, hyperglycemia, and hyperinsulinemia may play a role in myocardial steatosis. There are no prior studies examining the relationship between insulin sensitivity (antilipolytic and glucose disposal actions of insulin) and cardiac steatosis. OBJECTIVE Using a cross-sectional study design of individuals with and without metabolic syndrome (MetSyn), we examined the relationships between cardiac steatosis and the sensitivity of the antilipolytic and glucose disposal actions of insulin. METHODS Pericardial fat (PF) volume, intramyocardial and hepatic fat (MF and HF) content, visceral fat (VF) and sc fat content were assessed by magnetic resonance imaging in 77 subjects (49 without MetSyn and 28 with MetSyn). In a subset of the larger cohort (n = 52), peripheral insulin sensitivity index (SI) and adipocyte insulin sensitivity (Adipo-SI) were determined from an insulin-modified frequently sampled iv glucose tolerance test. The Quantitative Insulin Sensitivity Check Index was used as a surrogate for hepatic insulin sensitivity. RESULTS Individuals with the MetSyn had significantly higher body mass index, total body fat, and MF, PF, HF, and VF content. HF and VF, but not MF, were negatively correlated with the Quantitative Insulin Sensitivity Check Index, Adipo-SI, and SI. Stepwise regression revealed that waist circumference and serum triglyceride levels independently predicted MF and PF, respectively. Adipo-SI and serum triglyceride levels independently predict HF. CONCLUSION Myocardial steatosis is unrelated to hepatic, adipocyte, or peripheral insulin sensitivity. Although it is frequently observed in insulin-resistant subjects, further studies are necessary to identify and delineate pathogenic mechanisms that differentially affect cardiac and hepatic steatosis.

Lipoprotein Particles in Adolescents and Young Women With PCOS Provide Insights Into Their Cardiovascular Risk

CONTEXT Adult women with polycystic ovarian syndrome (PCOS) have an increased risk for cardiovascular disease, but the evidence for this is controversial in adolescents and young women with PCOS. Measurement of low-density lipoprotein (LDL) particle number, measured by nuclear magnetic resonance spectroscopy is a novel technology to assess cardiovascular risk. OBJECTIVE The objective of the study was to evaluate lipoprotein particle number and size in young women with PCOS and its relationship with insulin resistance and hyperandrogenism. DESIGN This was a cross-sectional case control study. SETTING The study was conducted at a clinical research center. PARTICIPANTS Women with PCOS (n = 35) and normal controls (n = 20) participated in the study. INTERVENTIONS Blood samples and anthropometric measures were obtained. MAIN OUTCOME MEASURES LDL particle size and number were measured using nuclear magnetic resonance spectroscopy. A secondary outcome was to investigate the correlation of LDL particle number with high-sensitivity C-reactive protein, waist to hip ratio, hyperandrogenism, insulin resistance, and adiponectin. RESULTS Women with PCOS had higher LDL particle number when compared with healthy controls (935 ± 412 vs 735 ± 264, P = .032); LDL particle number correlated strongly with high-sensitivity C-reactive protein (r = 0.37, P = .006) and waist-to-hip (r = 0.57, P = .0003). The higher LDL particle number was driven mainly due to differences in the small LDL particle number (sLDLp), with PCOS patients having more sLDLp (348 ± 305 vs 178 ± 195, P = .015). The sLDLp correlated with the Matsuda index (r = -0.51, P = .0001), homeostasis model assessment index of insulin resistance (r = 0.41, P = .002), and adiponectin (r = -0.46, P = .0004) but not with T. CONCLUSION Adolescent and young women with PCOS have an atherogenic lipoprotein profile suggestive of increased cardiovascular risk that appears to be driven by the degree of visceral adiposity and insulin resistance.