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Purtell L.,Diabetes and Obesity Research Program | Jenkins A.,Diabetes and Obesity Research Program | Jenkins A.,University of Wollongong | Loughnan G.,Prader Willi Syndrome Clinic | And 8 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Prader-Willi syndrome (PWS) is associated with hyperphagia and obesity, without effective pharmacological treatment. Exenatide, recently developed for treatment of type 2 diabetes, induces appetite suppression and weight loss with common side effects. Objective: The objective of the study was to investigate the initial safety and effectiveness of exenatide in adult PWS subjects compared with obese controls (OBESE). Design, Setting, Patients, and Intervention: Eight PWS and 11 OBESE patients underwent standardized meal studies after a single sc injection of 10 μg exenatide or placebo in a single-blinded, crossover design. Main Outcome Measures: Glucose, insulin, C-peptide, glucagon, peptide YY (PYY; total)/PYY (3-36), glucagon-like peptide-1, and ghrelin (total) were measured fasting and postprandially. Appetite and satiety were assessed by visual analog scales. Energy expenditure (EE) was measured by indirect calorimetry. Side effects were screened during and for 24 h after the meal. Results: PWS and OBESE patients were matched for gender, age, body mass index, and central/total body fat. In both groups, exenatide increased satiety and lowered glucose and insulin levels but increased insulin secretion rate. Side effects were absent in PWS but common in OBESE patients. During the meal, PYY (total) and ghrelin were elevated in PWS patients. Exenatide decreased PYY (total) and glucagon-like peptide-1, whereas ghrelin remained unchanged. Energy expenditure was unchanged by exenatide. Conclusions: Our pilot study demonstrates that exenatide is well tolerated in PWS patients. It increases satiety independently of measured appetite hormones, exerting glucose lowering, and insulinotropic effects similarly in PWS and OBESE patients. Larger prospective studies should investigate whether chronic exenatide administration will reduce hyperphagia and overweight in PWS patients without side effects. Copyright © 2011 by The Endocrine Society. Source

Purtell L.,Garvan Institute of Medical Research | Jenkins A.,Garvan Institute of Medical Research | Jenkins A.,University of Wollongong | Viardot A.,Garvan Institute of Medical Research | And 8 more authors.
Clinical Endocrinology | Year: 2013

Context Individuals with Prader-Willi syndrome (PWS) have a high cardiovascular risk, the mechanism of which is unclear. There may be dysfunction in the autonomic nervous system (ANS) in PWS. Objective To measure, as indicators of cardiac autonomic function, postprandial heart rate variability (HRV) and arterial stiffness in adults with PWS. Methods Ten adults with PWS were compared with 11 matched healthy obese subjects and 9 healthy lean subjects. Electrocardiographic traces and arterial stiffness were recorded over a period of 10 minutes at -60, 0, 30, 60, 120 and 240 minutes after consumption of a standardized 600-kCal breakfast. Frequency domain analysis was performed using fast Fourier transform to estimate power spectral density in the full spectrum and in low-frequency (LF 0·04-0·15 Hz) and high-frequency (HF 0·15-0·40 Hz) bands. Results ANCOVA revealed a reduced LF HRV meal response in adults with PWS compared with obese controls, with no differences in HF HRV, LF/HF ratio, heart rate, total power or arterial stiffness meal responses. Conclusions This study assessed cardiac autonomic function in adults with PWS compared with matched obese and lean subjects in response to a meal. Results suggest impaired postprandial ANS responsiveness in PWS, which could contribute to both the known increased cardiovascular risk and obesity. © 2012 John Wiley & Sons Ltd. Source

Purtell L.,Garvan Institute of Medical Research | Sze L.,Kantonsspital St. Gallen | Loughnan G.,Prader Willi Syndrome Clinic | Smith E.,The Childrens Hospital | And 7 more authors.
Neuropeptides | Year: 2011

Objective: Prader-Willi syndrome (PWS) is a leading genetic cause of obesity, characterized by hyperphagia, endocrine and developmental disorders. It is suggested that the intense hyperphagia could stem, in part, from impaired gut hormone signaling. Previous studies produced conflicting results, being confounded by differences in body composition between PWS and control subjects. Design: Fasting and postprandial gut hormone responses were investigated in a cross-sectional cohort study including 10 adult PWS, 12 obese subjects matched for percentage body fat and central abdominal fat, and 10 healthy normal weight subjects. Methods: PYY[total], PYY[3-36], GLP-1[active] and ghrelin[total] were measured by ELISA or radioimmunoassay. Body composition was assessed by dual energy X-ray absorptiometry. Visual analog scales were used to assess hunger and satiety. Results: In contrast to lean subjects (p<0.05), PWS and obese subjects were similarly insulin resistant and had similar insulin levels. Ghrelin[total] levels were significantly higher in PWS compared to obese subjects before and during the meal (p<0.05). PYY[3-36] meal responses were higher in PWS than in lean subjects (p=0.01), but not significantly different to obese (p=0.08), with an additional non-significant trend in PYY[total] levels. There were no significant differences in self-reported satiety between groups, however PWS subjects reported more hunger throughout (p=0.003), and exhibited a markedly reduced meal-induced suppression of hunger (p=0.01) compared to lean or obese subjects. Conclusions: Compared to adiposity-matched control subjects, hyperphagia in PWS is not related to a lower postprandial GLP-1 or PYY response. Elevated ghrelin levels in PWS are consistent with increased hunger and are unrelated to insulin levels. © 2011 Elsevier Ltd. Source

Viardot A.,Garvan Institute of Medical Research | Sze L.,University of Zurich | Purtell L.,Garvan Institute of Medical Research | Sainsbury A.,Garvan Institute of Medical Research | And 6 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Background: Subjects with Prader-Willi syndrome (PWS) have a reduced life expectancy due to cardiovascular disease. Increased systemic low-grade inflammation is postulated as a contributor, despite reported lower visceral fat mass and increased insulin sensitivity. Objectives: Our aim was to compare inflammatory markers and arterial stiffness in PWS and adiposity-matched obese control subjects. Design: We conducted a cross-sectional cohort study comparing 12 PWS subjects, 12 obese subjects matched for percentage body fat and central abdominal fat mass, and 10 healthy normal-weight subjects. Main Outcome Measures: Dual-energy x-ray absorptiometry was used to assess body composition, flow cytometry to quantify activation markers on immune cells, and ELISA for measurement of C-reactive protein, adiponectin, and IL-6. Insulin resistance was estimated by homeostasis model assessment and arterial stiffness by applanation tonometry. Results: PWS and obese subjects had similarly increased homeostasis model assessment and arterial stiffness. Nevertheless, PWS subjects showed significantly higher IL-6 (4.9 ± 1.0 vs. 2.5 ± 0.4 pg/ml; P = 0.02) and nonsignificantly higher C-reactive protein (10.5 ± 3.2 vs. 4.0 ± 1.0 ng/ml; P = 0.08). Neutrophil activation markers CD66b and CD11b were higher in PWS compared to obese subjects (P < 0.01), reflecting an activated innate immune system. These markers were positively related to central adiposity in lean and obese subjects (r = 0.49; P < 0.05), but not in PWS subjects. Conclusions: PWS subjects compared to adiposity-matched obese subjects demonstrate similar insulin resistance but increased low-grade inflammation. The dissociation of inflammation and central adiposity suggests that activation of innate immunity may be either a specific genetic feature of PWS or linked to the commonly associated obstructive sleep apnea syndrome, and might offer a treatment target to reduce cardiovascular disease. Copyright © 2010 by The Endocrine Society. Source

Purtell L.,Garvan Institute of Medical Research | Viardot A.,Garvan Institute of Medical Research | Sze L.,St Vincents Hospital Sydney | Loughnan G.,Kantonsspital St. Gallen | And 5 more authors.
Obesity | Year: 2015

Objective Individuals with Prader-Willi syndrome (PWS) are commonly restricted to 60-75% of height-appropriate calorie intake because they rapidly become obese on a normal diet. This study measured changes in energy expenditure, glucose and lipid homeostasis, and metabolic flexibility in response to a meal in PWS adults. Methods 11 adults with PWS were compared with 12 adiposity-matched and 10 lean subjects. Indirect calorimetry was conducted at baseline and 210 min after a standardized 600 kCal breakfast to assess energy expenditure and substrate utilization. Circulating glucose, insulin, C-peptide, glucagon, nonesterified fatty acids, and triglycerides were measured up to 240 min. Insulin sensitivity and insulin secretion rate were assessed by HOMA-IR and C-peptide deconvolution, respectively. Body composition was determined by dual-energy X-ray absorptiometry. Results The PWS group had lower lean mass than the obesity control group. Corrected for lean mass, there were no differences between the PWS and obesity groups in resting metabolic rate or metabolic flexibility. Total and abdominal fat mass, insulin sensitivity, and insulin secretion rate were also similar between these groups. Conclusions This study did not detect an intrinsic metabolic defect in individuals with PWS. Rather, lower lean mass, combined with lower physical activity, may contribute to weight gain on an apparent weight-maintenance diet. © 2015 The Obesity Society. Source

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