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1.  CPAP, Weight Loss, or Both for Obstructive Sleep Apnea 
The New England journal of medicine  2014;370(24):2265-2275.
Obesity and obstructive sleep apnea tend to coexist and are associated with inflammation, insulin resistance, dyslipidemia, and high blood pressure, but their causal relation to these abnormalities is unclear.
We randomly assigned 181 patients with obesity, moderate-to-severe obstructive sleep apnea, and serum levels of C-reactive protein (CRP) greater than 1.0 mg per liter to receive treatment with continuous positive airway pressure (CPAP), a weight-loss intervention, or CPAP plus a weight-loss intervention for 24 weeks. We assessed the incremental effect of the combined interventions over each one alone on the CRP level (the primary end point), insulin sensitivity, lipid levels, and blood pressure.
Among the 146 participants for whom there were follow-up data, those assigned to weight loss only and those assigned to the combined interventions had reductions in CRP levels, insulin resistance, and serum triglyceride levels. None of these changes were observed in the group receiving CPAP alone. Blood pressure was reduced in all three groups. No significant incremental effect on CRP levels was found for the combined interventions as compared with either weight loss or CPAP alone. Reductions in insulin resistance and serum triglyceride levels were greater in the combined-intervention group than in the group receiving CPAP only, but there were no significant differences in these values between the combined-intervention group and the weight-loss group. In per-protocol analyses, which included 90 participants who met prespecified criteria for adherence, the combined interventions resulted in a larger reduction in systolic blood pressure and mean arterial pressure than did either CPAP or weight loss alone.
In adults with obesity and obstructive sleep apnea, CPAP combined with a weight-loss intervention did not reduce CRP levels more than either intervention alone. In secondary analyses, weight loss provided an incremental reduction in insulin resistance and serum triglyceride levels when combined with CPAP. In addition, adherence to a regimen of weight loss and CPAP may result in incremental reductions in blood pressure as compared with either intervention alone.
PMCID: PMC4138510  PMID: 24918371
2.  Antipsychotic-Induced Insulin Resistance and Postprandial Hormonal Dysregulation Independent of Weight Gain or Psychiatric Disease 
Diabetes  2013;62(9):3232-3240.
Atypical antipsychotic (AAP) medications that have revolutionized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal challenge and a euglycemic-hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. We found that olanzapine, an AAP highly associated with weight gain, causes significant elevations in postprandial insulin, glucagon-like peptide 1 (GLP-1), and glucagon coincident with insulin resistance compared with placebo. Aripiprazole, an AAP considered metabolically sparing, induces insulin resistance but has no effect on postprandial hormones. Importantly, the metabolic changes occur in the absence of weight gain, increases in food intake and hunger, or psychiatric disease, suggesting that AAPs exert direct effects on tissues independent of mechanisms regulating eating behavior.
PMCID: PMC3749337  PMID: 23835329
3.  The Role of Obesity, Different Fat Compartments and Sleep Apnea Severity in Circulating Leptin Levels: The Icelandic Sleep Apnea Cohort Study 
To assess whether sleep apnea severity has an independent relationship with leptin levels in blood after adjusting for different measures of obesity and whether the relationship between OSA severity and leptin levels differs depending on obesity level.
Cross-sectional study of 452 untreated obstructive sleep apnea (OSA) patients (377 males and 75 females), in the Icelandic Sleep Apnea Cohort (ISAC), age 54.3±10.6 (mean±SD), BMI 32.7±5.3 kg/m2 and apnea-hypopnea index (AHI) 40.2 ± 16.1 events/hour. A sleep study and magnetic resonance imaging of abdominal visceral and subcutaneous fat volume were performed as well as fasting serum morning leptin levels measured.
Leptin levels were more highly correlated with body mass index (BMI), total abdominal and subcutaneous fat volume than visceral fat volume per se. No relationship was found between sleep apnea severity and leptin levels, assessed within three BMI groups (BMI<30, BMI 30–35 and BMI>35 kg/m2). In a multiple linear regression model, adjusted for gender, BMI explained 38.7% of the variance in leptin levels, gender explained 21.2% but OSA severity did not have a significant role and no interaction was found between OSA severity and BMI on leptin levels. However, hypertension had a significant effect on the interaction between OSA severity and obesity (p=0.04). In post-hoc analysis for nonhypertensive OSA subjects (n=249), the association between leptin levels and OSA severity explained a minor but significant variance (3.2%) in leptin levels. This relationship was greatest for nonobese nonhypertensive subjects (significant interaction with obesity level). No relationship of OSA severity and leptin levels was found for hypertensive subjects (n=199).
Obesity and gender are the dominant determinants of leptin levels. OSA severity is not related to leptin levels except to a minor degree in nonhypertensive nonobese OSA subjects.
PMCID: PMC3537909  PMID: 22964793
Obstructive sleep apnea; leptin; visceral fat; subcutaneous fat; obesity; hypertension
4.  Single Slice vs. Volumetric MR Assessment of Visceral Adipose Tissue - Reliability and Validity Among the Overweight and Obese 
Obesity (Silver Spring, Md.)  2012;20(10):2124-2132.
Visceral adipose tissue (VAT) is associated with abnormal cardiovascular and metabolic profiles. Total VAT volume of the abdominal compartment by MRI is the gold standard measurement for VAT but is costly and time consuming. Prior studies suggest VAT area on a single slice MR image may serve as a surrogate for total VAT volume but it is unknown if this relationship is maintained in overweight and obese males and females.
Untreated sleep apnea subjects enrolled into the Icelandic Sleep Apnea Cohort underwent abdominal MRI. VAT area and subcutaneous adipose tissue (SAT) area at the L2-L3 and L4-L5 interspaces and total VAT and SAT volumes were determined by manual examination using image analysis software.
N=539 males and N=129 females with mean ages of 54.1 and 58.8 years and mean body mass index of 32.2 kg/m2 and 33.7 kg/m2, respectively, were studied. Mean total VAT volume was 40% smaller and mean total subcutaneous adipose tissue (SAT) was 25% larger among females compared to males. The correlation with VAT volume was significantly larger for L2-L3 VAT area (r=0.96) compared to L4-L5 VAT area (r=0.83). The difference in correlation coefficients was statistically significant (non-parametric bootstrap p<0.001 with 95% CI for the difference from 0.11 to 0.15. VAT area at L2-L3 was also significantly better correlated with VAT volume than traditional anthropometric variables. Linear regression analyses demonstrated that L2-L3 area alone was sufficient for predicting total VAT volume and that the nature of the linear association was maintained across all levels of obesity and in both genders.
PMCID: PMC3743719  PMID: 22395811
5.  Obesity, diabetes, and exercise associated with sleep-related complaints in the American population 
Previous studies have demonstrated relationships between sleep and both obesity and diabetes. Additionally, exercise may improve sleep and daytime function, in addition to weight and metabolic function. The present study extends these findings by examining how general sleep-related complaints are associated with body mass index (BMI), diabetes diagnosis, and exercise in a large, nationally representative sample.
Subject and methods
Participants were respondents to the Behavioral Risk Factor Surveillance System (BRFSS). Sleep complaint (SC) was measured with “Over the last 2 weeks, how many days have you had trouble falling asleep or staying asleep or sleeping too much?” Daytime complaint (DC) was measured with “Over the last 2 weeks, how many days have you felt tired or had little energy?” Responses were dichotomized, with ≥6 days indicating complaint. Covariates included age, race/ethnicity, income, and education.
Being overweight was associated with DC in women only. Obesity was significantly associated with SC and DC in women, and DC in men. Diabetes was associated with SC and DC in both genders. Any exercise in the past 30 days did not attenuate any BMI or diabetes relationships, but was independently associated with a decrease in SC and DC in both men and women.
These results suggest that for both men and women diabetes is a significant predictor of sleep and daytime complaints, and there is a relationship between obesity and sleep and complaints for women to a greater extent than men. Finally, exercise was associated with much fewer sleep and daytime complaints in both genders.
PMCID: PMC3392306  PMID: 22791935
Sleep; Sleep disturbance; Obesity; Diabetes; Exercise
6.  Atypical antipsychotics and the neural regulation of food intake and peripheral metabolism 
Physiology & behavior  2011;104(4):590-598.
The atypical antipsychotics (AAPs) are associated with weight gain and an increased incidence of metabolic disease including type 2 diabetes mellitus. Epidemiological, cross-sectional and prospective studies suggest that two of the AAPs, olanzapine and clozapine, cause the most dramatic weight gain and metabolic impairments including increased fasting glucose, insulin and triglycerides. Relative to the other AAPs, both olanzapine and clozapine exhibit a particularly high antagonistic affinity for histamine and muscarinic receptors which have been hypothesized as mediators of the reported increase in weight and glucose abnormalities. In this article, we review the current evidence for the AAP associated weight gain and abnormal glucose metabolism. We postulate that the effects of the AAPs on food intake and peripheral metabolism are initially independently regulated but with increasing body adiposity, the early AAP-induced impairments in peripheral metabolism will be exacerbated, thereby establishing a vicious cycle such that the effects of the AAP are magnified by the known pathophysiological consequences of obesity. Furthermore, we examine how inhibition of the histaminergic pathway may mediate increases in food intake and the potential role of the vagus nerve in the reported peripheral metabolic effects.
PMCID: PMC3139777  PMID: 21664918
histamine; vagus; insulin; glucose; weight gain; obesity
7.  Metabolic Syndrome, Components, and Cardiovascular Disease Prevalence in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study 
American Journal of Nephrology  2011;33(6):477-484.
Metabolic syndrome may increase the risk for incident cardiovascular disease (CVD) and all-cause mortality in the general population. It is unclear whether, and to what degree, metabolic syndrome is associated with CVD in chronic kidney disease (CKD). We determined metabolic syndrome prevalence among individuals with a broad spectrum of kidney dysfunction, examining the role of the individual elements of metabolic syndrome and their relationship to prevalent CVD.
We evaluated four models to compare metabolic syndrome or its components to predict prevalent CVD using prevalence ratios in the Chronic Renal Insufficiency Cohort (CRIC) Study.
Among 3,939 CKD participants, the prevalence of metabolic syndrome was 65% and there was a significant association with prevalent CVD. Metabolic syndrome was more common in diabetics (87.5%) compared with non-diabetics (44.3%). Hypertension was the most prevalent component, and increased triglycerides the least prevalent. Using the bayesian information criterion, we found that the factors defining metabolic syndrome, considered as a single interval-scaled variable, was the best of four models of metabolic syndrome, both for CKD participants overall and for diabetics and non-diabetics separately.
The predictive value of this model for future CVD outcomes will subsequently be validated in longitudinal analyses.
PMCID: PMC3095834  PMID: 21525746
Cardiovascular disease; Chronic kidney disease; Chronic Renal Insufficiency Cohort (CRIC) Study; Metabolic syndrome
8.  How neural mediation of anticipatory and compensatory insulin release helps us tolerate food 
Physiology & behavior  2011;103(1):44-50.
Learned anticipatory and compensatory responses allow the animal and human to maintain metabolic homeostasis during periods of nutritional challenges, either acutely within each meal or chronically during periods of overnutrition. This paper discusses the role of neurally-mediated anticipatory responses in humans and their role in glucoregulation, focusing on cephalic phase insulin and pancreatic polypeptide release as well as compensatory insulin release during the etiology of insulin resistance. The necessary stimuli required to elicit CPIR and vagal activation are discussed and the role of CPIR and vagal efferent activation in intra-meal metabolic homeostasis and during chronic nutritional challenges are reviewed.
PMCID: PMC3056926  PMID: 21256146
Vagus nerve; cephalic phase insulin; pancreatic polypeptide; insulin resistance
9.  Insulin Sensitivity, Food Intake, and Cravings with Premenstrual Syndrome: A Pilot Study 
Journal of Women's Health  2008;17(4):657-665.
The objective of this pilot study was to evaluate possible differences in insulin sensitivity, food intake, and cravings between the follicular and luteal phases of the menstrual cycle in women with premenstrual syndrome (PMS).
Subjects were screened for PMS using the Penn Daily Symptom Rating (DSR) scale. Each subject had two overnight admissions (once in each cycle phase) to the Hospital of the University of Pennsylvania. They performed 3-day diet histories prior to each hospitalization. After admission, subjects received dinner and a snack, then were fasted until morning, when they underwent a frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity was determined by Minimal Model analysis. Blinded analysis of diet histories and inpatient food intake was performed by a registered dietitian.
There was no difference found in insulin sensitivity between cycle phases (n = 7). There were also no differences in proportions of macronutrients or total kilocalories by cycle phase, despite a marked difference in food cravings between cycle phase, with increased food cravings noted in the luteal phase (p = 0.002). Total DSR symptom scores decreased from a mean of 186 (± 29.0) in the luteal phase to 16.6 (± 14.2) in the follicular phase. Women in this study consumed relatively high proportions of carbohydrates (55%–64%) in both cycle phases measured.
These findings reinforce the suggestion that although the symptom complaints of PMS are primarily confined to the luteal phase, the neuroendocrine background for this disorder may be consistent across menstrual cycle phases.
PMCID: PMC3319142  PMID: 18447765
10.  Cephalic Phase Pancreatic Polypeptide Responses to Liquid and Solid Stimuli in Humans 
Physiology & behavior  2009;99(3):317-323.
The hormone, pancreatic polypeptide (PP) is postulated to be involved in body weight regulation. PP release is dependent on vagal activation and is a marker of vagal efferent activity. Because vagal activity plays a role in glucose homeostasis, elucidating the conditions of activation has important implications for nutrient metabolism. In humans, modified sham-feeding is known to elicit vagally-mediated hormonal responses. We present results of 3 studies in which healthy human subjects tasted various stimuli including sweet and salty liquids, unflavored and flavored gum and mixed nutrient foods flavored with either sweet or salt and rendered palatable or unpalatable. We examined the effects of these stimuli on PP levels relative to fasting. We found that liquids flavored with either glucose or salt, did not elicit an increase in PP levels greater than fasting. Similarly, chewing gum, whether unflavored or flavored with a non-nutritive sweetener or the sweetener paired with a mint flavor, did not significantly increase PP levels. In contrast, when subjects tasted mixed nutrient foods, these reliably elicited increases in PP levels at 4 min post stimulus (sweet palatable, p<0.002; sweet unpalatable, p<0.001; salty, palatable, p<0.05, salty unpalatable, p<0.05). The magnitude of release was influenced by the flavor, i.e. a sweet palatable stimulus (320.1±93.7 pg/ml/30 min) elicited the greatest increase in PP compared with a salty palatable stimulus (142.4±88.7 pg/ml/30 min; P<0.05). These data suggest that liquids and chewing gum do not provide adequate stimulation for vagal efferent activation in humans and that mixed nutrient foods are the optimal stimuli.
PMCID: PMC2834473  PMID: 19944113
vagal; cephalic phase; taste; parasympathetic; hormone; pre-absorptive hormones; sensory
11.  48-h Glucose infusion in humans: effect on hormonal responses, hunger and food intake 
Physiology & behavior  2007;90(5):733-743.
Experimentally-induced hyperglycemia by prolonged glucose infusion allows investigation of the effects of sustained stimulation of the pancreatic β-cell on insulin secretion and sensitivity. Hormonal responses to a meal following prolonged glucose infusions have not been investigated. To determine if a 48-h glucose infusion alters hormonal responses to a test meal as well as food intake and hunger in normal weight individuals, 16 subjects (8 men, 8 women, age 18–30 y, mean BMI=21.7±1.6 kg/m2) were infused for 48-h with either saline (50 ml/h) or 15% glucose (200 mg/m2/min). Subjects ingested a 600 kcal mixed nutrient meal 3-h after infusion termination. Blood samples were taken during the 48-h and for 4 hours following food ingestion. The 48-h glucose infusion elicited a metabolic profile of a glucose intolerant obese subjects, with increased plasma glucose, insulin and leptin (all P<0.01) and increased HOMA-IR (P<0.001). During meal ingestion, early insulin secretion was increased (P<0.05) but postprandial glucose (P<0.01) and insulin (P<0.01) excursions were lower following the glucose infusion. Postprandial plasma triglyceride concentrations were increased after glucose compared with saline. Food intake and hunger ratings were not different between the two conditions. Plasma leptin levels were inversely correlated with hunger (P<0.03) in both conditions and with food intake (P<0.003) during the glucose condition only. Thus, a 48-h glucose infusion does not impair postprandial hormonal responses, alter food intake or hunger in normal weight subjects. The glucose-induced increases in plasma leptin result in a stronger inverse relationship between plasma leptin and hunger as well as food intake. These data are the first to demonstrate a relationship between leptin and hunger in normal weight, non-calorically restricted human subjects.
PMCID: PMC2834966  PMID: 17275862
leptin; insulin; food intake; insulin sensitivity; triglycerides
12.  Exploring human/animal intersections: Converging lines of evidence in comparative models of aging 
At a symposium convened on March 8, 2007 by the Institute on Aging at the University of Pennsylvania, researchers from the University’s Schools of Medicine and Veterinary Medicine explored the convergence of aging research emerging from the two schools. Studies in human patients, animal models, and companion animals have revealed different but complementary aspects of the aging process, ranging from fundamental biologic aspects of aging to the treatment of age-related diseases, both experimentally and in clinical practice. Participants concluded that neither animal nor human research alone will provide answers to most questions about the aging process. Instead, an optimal translational research model supports a bidirectional flow of information from animal models to clinical research.
PMCID: PMC2665932  PMID: 18631944
Organ specific mechanisms of aging in humans and animals; Model systems for aging research; Normal aging; Aging related diseases
13.  Acute Alcohol Consumption Disrupts the Hormonal Milieu of Lactating Women 
Despite the lack of scientific evidence to support the claim that alcohol is a galactagogue, lactating women have been advised to drink alcohol as an aid to lactation for centuries. To test the hypothesis that alcohol consumption affects the hormonal response in lactating women, we conducted a within-subjects design study in which 17 women consumed a 0.4 g/kg dose of alcohol in orange juice during one test session and an equal volume of orange juice during the other. Changes in plasma prolactin, oxytocin, and cortisol levels during and after breast stimulation, lactational performance, and mood states were compared under the two experimental conditions. Oxytocin levels significantly decreased, whereas prolactin levels and measures of sedation, dysphoria, and drunkenness significantly increased, during the immediate hours after alcohol consumption. Changes in oxytocin were related to measures of lactational performance such as milk yield and ejection latencies, whereas changes in prolactin were related to self-reported measures of drunkenness. Although alcohol consumption resulted in significantly higher cortisol when compared with the control condition, cortisol levels were not significantly correlated with any of the indices of lactational performance or self-reported drug effects. Moreover, cortisol levels steadily decreased on the control day, indicating that the procedures were not stressful to the subjects. In conclusion, recommending alcohol as an aid to lactation may be counterproductive. In the short term, mothers may be more relaxed, but the hormonal milieu underlying lactational performance is disrupted, and, in turn, the infant’s milk supply is diminished.
PMCID: PMC1351273  PMID: 15623810

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