Jamshid Alaghband-Zadeh

Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding

Objectives Roux-en-Y gastric bypass (RYGB) has greater efficacy for weight loss in obese patients than gastric banding (BAND) surgery. We hypothesise that this may result from different effects on food hedonics via physiological changes secondary to distinct gut anatomy manipulations. Design We used functional MRI, eating behaviour and hormonal phenotyping to compare body mass index (BMI)-matched unoperated controls and patients after RYGB and BAND surgery for obesity. Results Obese patients after RYGB had lower brain-hedonic responses to food than patients after BAND surgery. RYGB patients had lower activation than BAND patients in brain reward systems, particularly to high-calorie foods, including the orbitofrontal cortex, amygdala, caudate nucleus, nucleus accumbens and hippocampus. This was associated with lower palatability and appeal of high-calorie foods and healthier eating behaviour, including less fat intake, in RYGB compared with BAND patients and/or BMI-matched unoperated controls. These differences were not explicable by differences in hunger or psychological traits between the surgical groups, but anorexigenic plasma gut hormones (GLP-1 and PYY), plasma bile acids and symptoms of dumping syndrome were increased in RYGB patients. Conclusions The identification of these differences in food hedonic responses as a result of altered gut anatomy/physiology provides a novel explanation for the more favourable long-term weight loss seen after RYGB than after BAND surgery, highlighting the importance of the gut–brain axis in the control of reward-based eating behaviour.

A COMPARISON OF FOLLICULAR FLUID LEVELS OF INSULIN‐LIKE GROWTH FACTOR‐1 IN NORMAL DOMINANT AND COHORT FOLLICLES, POLYCYSTIC AND MULTICYSTIC OVARIES

Fourteen ovulatory patients undergoing diagnostic laparoscopy had at least two samples of clear follicular fluid (FF) collected in the late follicular phase. The cohort concentrations of Insulin‐like Growth Factor‐1 (IGF1) were significantly correlated with serum IGF1 and dominant follicles contained significantly higher concentrations of IGF1 and oestradiol (E2) than their cohorts. After the LH surge, a further significant increase in dominant FF‐IGF1 occurred. FF‐(log)E2 was significantly correlated with both FF‐IGF1 and FF volume. Nine women with the polycystic ovary syndrome (PCOS) and one patient with multicystic ovaries (MCO) associated with weight‐loss related amenorrhoea also had follicular aspiration performed. The mean (SD) FF‐IGF1 in the PCOS group, 0.42 (0.15) U/ml, was not significantly different from that of the cohorts in the control group, 0.39 (0.13) U/ml. The patient with MCO had both serum and FF‐IGF1 concentrations < 10th centile. These results support the hypothesis that IGF1 has a paracrine (and possibly endocrine) role in the regulation of ovarian function in the human female.

Free cortisol index as a surrogate marker for serum free cortisol.

Background: The biologically active component of a hormone is the unbound or free fraction. Changes in cortisol-binding protein could give misleading results if only total cortisol is measured for the interpretation of dynamic function tests. Methods: This study aimed to measure serum free cortisol using a steady-state gel-filtration method and then to evaluate the correlation between the serum free cortisol and the free cortisol index (FCI), defined as serum total cortisol/cortisol-binding globulin (CBG). Results: Forty-eight serum samples from healthy volunteers undergoing a short Synacthen test were analysed for total cortisol, free cortisol and CBG. The FCI correlated well with a previously established, but more complex, calculation of serum free cortisol (R = 0·98, P <0·001) and with measured serum free cortisol (R = 0·90, P < 0·001). Conclusion: Free cortisol index is a reliable and user-friendly measure of serum free cortisol.

A Longitudinal Study of the Effect of Subcutaneous Estrogen Replacement on Bone in Young Women With Turner's Syndrome

It is desirable that young women with primary ovarian failure achieve normal peak bone mass to reduce the subsequent risk of osteoporosis, and that there are management strategies to replace bone that is already lost. While estrogen (E2) is generally considered to prevent bone loss by suppressing bone resorption, it is now recognized that estrogen also exerts an anabolic effect on the human skeleton. In this study, we tested whether estrogen could increase bone mass in women with primary ovarian failure. We studied the mechanism underlying this by analyzing biochemical markers of bone turnover and iliac crest biopsy specimens obtained before and 3 years after E2 replacement. Twenty‐one women with Turners syndrome, aged 20‐40 years, were studied. The T scores of bone mineral density at lumbar spine and proximal femur at baseline were −1.4 and ‐1.1, respectively. Hormone replacement was given as subcutaneous E2 implants (50 mg every 6 months) with oral medroxy progesterone. Serum E2 levels increased incrementally from 87.5 pM at baseline to 323, 506, 647, and 713 pM after 6 months and 1, 2, and 3 years of hormone replacement therapy (HRT), respectively. The bone mineral density at the lumbar spine and proximal femur increased after 3 years to T scores of ‐0.2 and ‐0.4, respectively. The cancellous bone volume increased significantly from 13.4% to 18.8%. There was a decrease in activation frequency, but the active formation period was increased by HRT. There was a significant increase in the wall thickness from 33.4 μm at baseline to 40.9 μm after 3 years of HRT, reflecting an increase in bone formed at individual remodeling units. Although there was an early increase in biochemical markers of bone formation, these declined thereafter. Our results show that estrogen is capable of exerting an anabolic effect in the skeleton of young women with Turners syndrome and low bone mass.

Enhanced fasting and post-prandial plasma bile acid responses after Roux-en-Y gastric bypass surgery

Abstract Objective. Exogenous bile acid (BA) administration is associated with beneficial metabolic effects very similar to those seen after Roux-en-Y gastric bypass (RYGB) surgery. Re-routing of bile into a biliopancreatic limb with simultaneous exclusion of food occurs after RYGB, with subsequent increased fasting plasma BAs. The study assessed fasting and post-prandial plasma BA response before and 15 months after RYGB. Material and methods. The prospective study recruited 63 obese individuals (43 females), aged 43 (36–56) [median (IQR)] years. Blood samples were collected before and every 30 min for 120 min after a standard 400 kcal meal. Fasting and post-prandial plasma BAs, glucagons like peptide-1 (GLP-1), –tyrosine (PYY), fasting C-reactive protein (CRP), glucose and insulin were measured and homeostasis model assessment-insulin resistance (HOMA-IR) was calculated. Results. Following RYGB, body mass index, CRP, fasting glucose and HOMA-IR decreased; 43.7 (39.3–49.2) kg/m2 to 29.2 (25.1–35.0) kg/m2, 7.9 (4.1–11.9) mg/L to 0.4 (0.2–1.0) mg/L, 5.5 (5.0–6.0) mmol/L to 4.6 (4.3–4.9) mmol/L and 5.9 (3.5–9.2) to 1.7 (1.1–2.2), respectively, all P < 0.001. Fasting total BAs, GLP-1 and PYY increased after RYGB; 1.69 (0.70–2.56) µmol/L to 2.43 (1.23–3.82) µmol/L (P = 0.02), 6.8 (1.5–15.3) pmol/L to 17.1 (12.6–23.9) pmol/L (P < 0.001) and 4.0 (1.0–7.1) pmol/L to 15.2 (10.0–28.3) pmol/L (P < 0.001), respectively. The area under the curve for post-prandial total BAs, total glycine-conjugated BAs, GLP-1 and PYY were greater after RYGB; 486 (312–732) µmol/L/min versus 1012 (684–1921) µmol/L/min, 315 (221–466) µmol/L/min versus 686 (424–877) µmol/L/min, 3679 (3162–4537) pmol/L/min versus 5347 (4727–5781) pmol/L/min and 1887 (1423–2092) pmol/L/min versus 3296 (2534–3834) pmol/L/min, respectively, all P < 0.0001. Conclusion. Weight loss following RYGB is associated with an increase in post-prandial plasma BA response due to larger amounts of glycine-conjugated BAs. This suggests up regulation of BA production and conjugation after RYGB.

Postprandial plasma bile acid responses in normal weight and obese subjects

Background Bile acids can act as signalling molecules via various receptors including the nuclear farnesoid X receptor (FXR) and pregnane X receptor (PXR), and the cell surface G-protein-coupled receptor TGR5. The signalling has been implicated in the release of peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), which improves glycaemic control and energy expenditure. We investigated whether morbidly obese subjects have altered postprandial bile acid responses in comparison to normal weight subjects. Method Blood samples were taken every 30 min from 0 to 180 min following a 400 kcal test meal. Samples were taken from 12 normal weight subjects with a body mass index (BMI) of 23.2 (2.8) kg/m2 (median [interquartile range (IQR)]) and seven obese patients with a BMI of 47.2 (7.2) kg/m2. Fractionated bile acids were measured on these samples using high-performance liquid chromatography tandem mass spectrometry. Results The obese subjects showed a lower postprandial response in total bile acids compared with the normal weight subjects. An increase of 6.4 (5.0) and 2.6 (3.3) μmol/L (median [IQR]) in normal weight and obese subjects was observed, respectively (P = 0.02). The difference was predominantly due to the glycine-conjugated fraction (P = 0.03). There was no difference in the increase of the unconjugated or taurine-conjugated fractions. Conclusions The decreased postprandial bile acid response in obese subjects compared with normal weight subjects may partly explain the suboptimal GLP-1 and PYY responses and could affect appetite, glycaemic control and energy expenditure.

The relationship between postprandial bile acid concentration, GLP-1, PYY and ghrelin

Background  Gut hormones peptide YY (PYY) and glucagon‐like peptide‐1 (GLP‐1) play an integral role in appetite control and energy homeostasis. Entero‐endocrine L‐cells can be stimulated by nutrients and or bile acids to co‐secrete PYY and GLP‐1. The aim of this study was to determine the response of bile acids, PYY, GLP‐1 and ghrelin after a test meal.

Temporal changes in bile acid levels and 12α-hydroxylation after Roux-en-Y gastric bypass surgery in type 2 diabetes

Introduction:Gastric bypass surgery (GBP) leads to sustained weight loss and significant improvement in type 2 diabetes (T2DM). Bile acids (BAs), signaling molecules which influence glucose metabolism, are a potential mediator for the improvement in T2DM after GBP. This study sought to investigate the effect of GBP on BA levels and composition in individuals with T2DM.Methods:Plasma BA levels and composition and fibroblast growth factor (FGF)-19 levels were measured during fasting and in response to an oral glucose load before and at 1 month and 2 years post GBP in 13 severely obese women with T2DM.Results:A striking temporal change in BA levels and composition was observed after GBP. During the fasted state, BA concentrations were generally reduced at 1 month, but increased 2 years post GBP. Postprandial BA levels were unchanged 1 month post GBP, but an exaggerated postprandial peak was observed 2 years after the surgery. A significant increase in the 12α-hydroxylated/non12α-hydroxylated BA ratio during fasting and postprandially at 2 years, but not 1 month, post GBP was observed. Significant correlations between BAs vs FGF-19, body weight, the incretin effect and peptide YY (PYY) were also found.Conclusions:This study provides evidence that GBP temporally modifies the concentration and composition of circulating BAs in individuals with T2DM, and suggests that BAs may be linked to the improvement in T2DM after GBP.

Changes in bone density and biochemical markers of bone turnover in pregnancy‐associated osteoporosis

* Gautam Khastgir Research Fellow (Wellbeing Grant), * John W. W. Studd Consultant Gynaecologist, * Hilary King Senior Radiographer, * Hossam Abdaila Consultant Gynaecologist, ** Julia Jones Senior Scientist, ** Graham Carter Consultant Biochemist, ** Jamshid Alaghband-Zadeh Consultant Endocrinologist * Fertility and Endocrinology Centre, Lister Hospital and Academic Department of Obstetrics and Gynaecology, Chelsea & Westminster Hospital, London ; ** Endocrine Laboratory, Charing Cross Hospital, London

Anabolic effect of long-term estrogen replacement on bone collagen in elderly postmenopausal women with osteoporosis.

Abstract: Estrogen has been shown to stimulate osteoblasts in cell culture and increase bone formation in animal models. Such an anabolic effect of estrogen replacement therapy (ERT) would be beneficial to postmenopausal women with osteoporosis. Hence, we assessed the total collagen content and collagen crosslink maturity in iliac crest bone biopsy from 18 such women before and after 6 years of higher-dose ERT. These results were compared with the serum estradiol level and bone mineral density (BMD). Total collagen content of both cortical and cancellous bone increased, showing a median (95% CI) percent change of 6.7 (0.3–14.2) and 25.6 (13.5–33.8), respectively. Increase in collagen synthesis was supported by a rise in intermediate crosslinks in both cortical and cancellous bone, and mature crosslinks in cortical bone only. At the same time, BMD showed a substantial rise both at the lumbar spine and proximal femur with a median (95% CI) percent change of 28.6 (19.8–37.3) and 14.5 (8.4–20.7), respectively. Serum estradiol and BMD results correlated with cortical bone collagen levels. Our results suggest that long-term higher-dose ERT has a therapeutic role due to its anabolic effect on bone in postmenopausal women with osteoporosis.