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.

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

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/m(2) to 29.2 (25.1-35.0) kg/m(2), 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.

Leptin and insulin growth factor 1: diagnostic markers of the refeeding syndrome and mortality.

Refeeding syndrome is difficult to diagnose since the guidelines for identifying those at risk are largely based on subjective clinical parameters and there are no predictive biochemical markers. We examined the suitability of insulin-like growth factor 1 (IGF1) and leptin as markers to identify patients at risk of the refeeding syndrome before initiation of parenteral nutrition (PN). A total of thirty-five consecutive patients referred for commencement of PN were included. Serum leptin and IGF1 were measured before starting PN. Electrolytes, liver and renal function tests were conducted before and daily for 1 week after initiating PN. The primary outcome was a decrease in phosphate 12-36 h after initiating PN. 'Refeeding index' (RI) was defined as leptin × IGF1 divided by 2800 to produce a ratio of 1·0 in patients who are well nourished. RI had better sensitivity (78 %; 95 % CI 40, 97 %) and specificity (78 %; 95 % CI 40, 97 %) with a likelihood ratio of 3·4, at a cut-off value of 0·19 for predicting a ≥ 30 % decrease in phosphate concentration within 12-36 h after starting PN, compared with IGF1 or leptin alone. However, IGF1 was a better predictor of mortality than either leptin or the RI. The present study is the first to derive and test the 'RI', and find that it is a sensitive and specific predictor of the refeeding syndrome in hospitalised patients before starting PN.

Bile acid metabolism is altered in those with insulin resistance after gestational diabetes mellitus.

BACKGROUND: Bile acids (BAs) are known mediators of glucose metabolism that are altered in type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM). We hypothesised that post-prandial BA fractions are changed in women with Insulin resistance (IR) after recovery from GDM using homeostatic model assessment (HOMA-IR). METHODS: 45 women median age 44(31-47) with previous GDM, including 20 with HOMA-IR >2.8 and 25 age-matched controls with HOMA-IR ≤ 2.8 were studied. After an overnight fast, all underwent an oral glucose tolerance test. Blood samples were collected at baseline and every 30 min for 120 min and analysed for glucose on automated platform and for total BAs, their conjugates and fractions using liquid-chromatography tandem mass-spectrometry. Baseline samples were analysed for insulin on automated platform. Delta (Δ) change (difference between baseline and maximal post-prandial response) were calculated. Data is presented as median (IQR). RESULTS: Fasting primary and unconjugated BAs were higher in women with HOMA-IR >2.8 vs. those with HOMA-IR ≤ 2.8 [0.24 (0.16-0.33) vs 0.06(0.04-0.22) µmol/L and 0.91(0.56-1.84) µmol/L vs. 0.69(0.32-0.89) µmol/L respectively. ∆ taurine-conjugated BAs was higher in women with HOMA-IR ≤ 2.8 than those with HOMA-IR > 2.8 [0.33(0.20-0.54) vs 0.23(0.13-0.34) µmol/L]. Fasting glucose and non-12α-hydroxylated BAs were negatively correlated in women with HOMA-IR >2.8 (all p < 0.05). CONCLUSIONS: Following GDM, individuals with HOMA-IR >2.8 have altered conjugated and non-12α-hydroxylated fractions of BAs. It remains to be elucidated if the altered BA metabolism is a contributing factor to the pathogenesis or a consequence of GDM.

Suboptimal rise in awakening-induced cortisol is an accurate marker of cortisol insufficiency in patients with normal renal function (eGFR >60 mL/min).

Background The insulin tolerance test is the gold standard for diagnosis of cortisol insufficiency. However, it is cumbersome, invasive, requires supervised hospital facilities and has unpleasant side-effects. A non-invasive outpatient-based test will be useful. We hypothesized that free cortisol concentrations in multiple spot urine samples can be used to diagnose cortisol insufficiency in patients with normal renal function (eGFR > 60 mL/min). Method Patients and controls provided urine samples at bedtime (S1), and first (S2) and second (S3) void the next day. Cortisol and creatinine were measured in all three samples, and cortisol:creatinine ratio (S1, S2 and S3) was used for further analysis. The sum of S1 + S2 + S3 was used to calculate total cortisol secretion (T). Variation (V) in cortisol secretion in response to circadian rhythm was calculated as the modulus of the difference between S1 and S2 and S2 and S3. Results Samples were collected from 96 controls and 11 patients. S1 was significantly lower vs . S2 and S3 in controls ( P < 0.0001) but not in patients. S2, S3, T and V were significantly lower in patients vs . controls ( P < 0.0001). ROC curve analysis using insulin tolerance test as gold standard showed that S2, S3, T and V were all equally accurate diagnostic markers for cortisol insufficiency (AUC: 0.87, NPV: 100%). The best balance of sensitivity and specificity was achieved using T (sensitivity: 100%, specificity: 58%). Conclusion Multiple spot urine samples test is an accurate, relatively inexpensive, non-invasive, convenient outpatient-based screening test for exclusion of cortisol insufficiency.

Clinical roles in clinical biochemistry: a national survey of practice in the UK.

Background Using an online survey, we collected data to present a picture of how clinical authorization is performed in the UK. Methods A 21-question survey was uploaded to www.surveymonkey.com , and responses were invited via the mail base of the Association for Clinical Biochemistry and Laboratory Medicine. The questionnaire examined the intensity and function of the duty biochemist role and how different types of authorization are used to handle and release results. Results Of 70 responses received, 60 were suitable for analysis. Responses were received from every region of the UK. A typical duty biochemist shift started on average at 8:50, and finished at 17:25. The mean duration was 8 h 58 min. Clinical scientists are the most abundantly represented group on duty biochemist rotas. Higher banded clinical scientists and chemical pathologists covered out-of-hours shifts. Results were handled differently depending on the level of abnormality and the requesting area. Normal results tended to be released either directly from the analyser or after technical then autoauthorization (90%). A greater preference for clinical authorization was seen for abnormal and critical results originating from outpatients (49% and 69%, respectively) or general practice (51% and 71%) than for inpatients (33% and 53%) or A&E (25% and 37%). Conclusions The handling and authorization of biochemistry results varies greatly between laboratories. The role is clearly heterogeneous in the UK. Guidance from the Association for Clinical Biochemistry and Royal College of Pathologists may help to clarify the essential roles of the duty biochemist.

Elevated fasting and postprandial C-terminal telopeptide after Roux-en-Y gastric bypass.

Background Roux-en-Y gastric bypass increases circulating bile acid concentrations, known mediators of postprandial suppression of markers of bone resorption. Long-term data, however, indicate that Roux-en-Y gastric bypass confers an increased risk of bone loss on recipients. Methods Thirty-six obese individuals, median age 44 (26-64) with median body mass index at baseline of 42.5 (40.4-46) were studied before and 15 months after Roux-en-Y gastric bypass. After an overnight fast, patients received a 400 kcal mixed meal. Blood samples were collected premeal then at 30-min periods for 120 min. Pre and postmeal samples were analysed for total bile acids, parathyroid hormone and C-terminal telopeptide. Results Body weight loss post Roux-en-Y gastric bypass was associated with a median 4.9-fold increase in peak postprandial total bile acid concentration, and a median 2.4-fold increase in cumulative food evoked bile acid response. Median fasting parathyroid hormone, postprandial reduction in parathyroid hormone and total parathyroid hormone release over 120 min remained unchanged after surgery. After surgery, median fasting C-terminal telopeptide increased 2.3-fold, peak postprandial concentrations increased 3.8-fold and total release was increased 1.9-fold. Conclusions Fasting and postprandial total bile acids and C-terminal telopeptide are increased above reference range after Roux-en-Y gastric bypass. These changes occur in spite of improved vitamin D status with supplementation. These results suggest that post-Roux-en-Y gastric bypass increases in total bile acids do not effectively oppose an ongoing resorptive signal operative along the gut-bone axis. Serial measurement of C-terminal telopeptide may be of value as a risk marker for long-term skeletal pathology in patients post Roux-en-Y gastric bypass.

Predicting refeeding hypophosphataemia: insulin growth factor 1 (IGF-1) as a diagnostic biochemical marker for clinical practice.

BACKGROUND: Refeeding syndrome (RS) is a potentially fatal condition that can occur following the re-introduction of nutrition after a period of starvation. Hypophosphataemia following the reintroduction of nutrition is often the only reliable biochemical marker of RS. Refeeding index (RI) generated from baseline insulin-like growth factor-1 (IGF-1) and leptin has been proposed as a useful biochemical marker for the identification of patients at risk of developing refeeding hypophosphataemia (RH). METHODS: A prospective study included 52 patients referred for parenteral nutrition (PN). The sensitivity and specificity of IGF-1 measured using a sensitive assay was compared to the RI in predicting the development of RH (a ≥ 30% drop in PO4 during the first 36-h of PN administration). Leptin and IGF-1 were analysed on baseline samples using a quantitative enzyme-linked immunoassay. Daily blood samples were collected from all patients for routine biochemistry for the full duration of PN administration. RESULTS: High sensitivity IGF-1 measurement alone was comparable with the RI, using receiver-operating characteristic (ROC) curve analysis, with areas under the curve being 0.79 and 0.80, respectively, and superior to leptin alone (0.72) for predicting ≥ 30% drop in PO4. The cut-off value for IGF-1 that gave best sensitivity (91% [95% CI 75-98%]) and specificity (65% [95% CI 41-85%]) was 63.7 µg/L, with a likelihood ratio of 2.59. CONCLUSION: Baseline IGF-1 is an objective, sensitive and specific biochemical marker in identifying patients who are at high risk of developing RH prior to PN administration and therefore may have a role in clinical practice.

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 Turner's 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 microm at baseline to 40.9 microm 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 Turner's syndrome and low bone mass.

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.

Urine bile acids relate to glucose control in patients with type 2 diabetes mellitus and a body mass index below 30 kg/m2.

Bile acids are important endocrine signalling molecules, modulating glucose homeostasis through activation of cell surface and nuclear receptors. Bile acid metabolism is altered in type 2 diabetes mellitus; however, whether this is of pathogenic consequence is not fully established. In this study urinary bile acid excretion in individuals with type 2 diabetes and matched healthy volunteers was assessed. Urinary bile acid excretion in type 2 diabetes patients was considered in the context of prevailing glycaemia and the patient body mass index. Urine bile acids were measured by liquid chromatography-tandem mass spectrometry, allowing individual quantification of 15 bile acid species. Urinary bile acid excretion in patients with type 2 diabetes who were normal weight (BMI 18.5-24.9 kg/m2) and overweight (BMI 25-29.9 kg/m2) were elevated compared to healthy normal weight volunteers, both p<0.0001. In obese (BMI ≥ 30 kg/m2) type 2 diabetes patients, urinary bile acid excretion was significantly lower than in the normal and overweight type 2 diabetes groups (both p<0.01). Total bile acid excretion positively correlated with HbA1c in normal (rs=0.85, p=<0.001) and overweight (rs=0.61, p=0.02) but not obese type 2 diabetes patients (rs=-0.08, p=0.73). The glycaemia-associated increases in urine bile acid excretion in normal weight and overweight type 2 diabetes seen in this study may represent compensatory increases in bile acid signalling to maintain glucose homeostasis. As such alterations appear blunted by obesity; further investigation of weight-dependent effects of bile acid signalling on type 2 diabetes pathogenesis is warranted.

Higher circulating bile acid concentrations in obese patients with type 2 diabetes.

BACKGROUND: Bile acids (BAs) play an important role in releasing incretin hormones via the enteroendocrine L-cell surface TGR5 receptors. The aim of this study was to investigate the difference in BA concentration at baseline and in response to a meal stimulus between type 2 diabetes mellitus (T2DM) and a matched normoglycaemic group. MATERIALS AND METHODS: A cross-sectional study of 12 patients with known T2DM and 12 matched normoglycaemic controls compared BA fractions after an overnight fast and following a standard meal. RESULTS: The T2DM group had higher baseline glucose (P < 0.001), but baseline total BA, total glycine conjugated BAs (GCBA) and total taurine conjugated BA (TCBA) were similar between both groups. The T2DM group compared to the normoglycaemic group had a higher post-prandial peak change in total BAs 4.28 (3.51-5.38) µmol/L vs. 0.88 (0.60-1.57) µmol/L (P < 0.001) and peak total GCBA 2.77 (1.07-4.19) µmol/L vs. 0.94 (0.34-1.15) µmol/L (P < 0.0001), but similar peak total TCBA 0.36 (0.02-0.76) µmol/L vs. 0.08 (0.04-0.22) µmol/L (P=0.91). CONCLUSION: The post-prandial bile acid response is elevated in obese patients with T2DM compared to matched normoglycaemic individuals.

Postprandial bone turnover is independent of calories above 250 kcal.

BACKGROUND: The mechanisms causing bone turnover after food intake have not yet been elucidated. Several gut hormones are secreted in the postprandial phase, proportional to meal calorie content, and possibly one or more of these could influence bone turnover. The aim of this study was to investigate bone turnover in proportion to graded-calorie and fixed calcium containing meals. METHODS: A group of healthy volunteers were given six meals with calories varying from 250 to 3000 kcal on different occasions. All the meals contained 500 mg of calcium. C-telopeptide type I collagen (CTX) was measured before and 180 min after each meal. RESULTS: All meals significantly reduced CTX between 35.8 +/- 5.6% and 44.8 +/- 3.8%. No significant difference in CTX was however apparent for the different calorie containing meals. Observed differences suggest a trend to greater CTX suppression with lower protein and higher fat content of meals. CONCLUSION: Changes in CTX are not proportional to calorie contents when the meals contain 500 mg of calcium. Further studies should now determine whether patients with increased bone resorption would benefit from multiple small meals to slow down the rate of bone loss.

Serum total cortisol and free cortisol index give different information regarding the hypothalamus-pituitary-adrenal axis reserve in patients with liver impairment.

BACKGROUND: The short synacthen test (SST) is used to investigate patients with suspected hypothalamus-pituitary-adrenal (HPA) axis pathology. A rise of serum total cortisol (total cortisol) above 550 nmol/L is accepted as sufficient adrenal reserve. In total, 80% of cortisol is bound to cortisol-binding globulin (CBG) and 10% to albumin. In the acute phase responses CBG concentrations decrease and can influence the interpretation of SST. The free cortisol index (FCI) is a surrogate marker for free cortisol and is defined as total cortisol (nmol/L)/CBG (mg/L) with an FCI > 12 representing sufficient adrenal reserve. The aim of this study was to compare total cortisol and FCI in the interpretation of SST in patients with liver impairment. METHOD: SST was done on 26 patients with liver impairment. Total cortisol was measured on Advia Centaur; serum CBG by radioimmunoassay and FCI calculated. RESULTS: Eleven (42%) patients had a total cortisol >550 nmol/L (range 555-2070) and FCI > 12 (12.0-68.9) suggesting sufficient cortisol reserve. Three patients (13%) had total cortisol <550 nmol/L (268-413) and FCI < 12 (3.5-11.6) consistent with cortisol deficiency. Twelve patients (46%) had a total cortisol <550 nmol/L (144-529), but an FCI > 12 (12.0-52.9). None of the patients had a total cortisol >550 nmol/L and FCI < 12. CONCLUSION: When total cortisol alone is used to interpret SST in patients with liver impairment, 46% may have been classified as having adrenal insufficiency because of low CBG. FCI may be better for the evaluation of HPA axis insufficiency in patients with liver impairment.