Gut Hormone Suppression Increases Food Intake After Esophagectomy With Gastric Conduit Reconstruction.

OBJECTIVES: To characterize the gut hormone profile and determine the effect of satiety gut hormone blockade on food intake in disease-free postesophagectomy patients. BACKGROUND: Improved oncologic outcomes for esophageal cancer have resulted in increased survivorship and a focus on health-related quality of life. Anorexia and early satiety are common, but putative causative factors, in particular the gut-brain hormonal axis, have not been systematically studied. METHODS: In a double-blind, placebo-controlled, randomized crossover study, disease-free patients at least 1 year postresection and gastric conduit reconstruction received either 1 mL 0.9% saline or 1 mL (100 µg) octreotide acetate subcutaneously followed by a standardized ad libitum meal on each of two assessments. Fasting and postprandial plasma glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin immunoreactivity were measured. Gut hormone responses and calorie intake postsaline versus octreotide were compared between experimental and control groups. RESULTS: Eighteen subjects [esophagectomy (ES), n = 10, 2.4 ±â€Š0.75 years postresection; and unoperated control subjects, n = 8] were studied. ES demonstrated significant weight loss at 3, 6, 12, and 24 months postoperatively (all P < 0.05). Ghrelin levels were similar (P = 0.58) for both groups, but postprandial GLP-1 and PYY responses were significantly (P < 0.001) greater among ES as compared with controls. After octreotide, ad libitum calorie intake increased among ES (1.5 ±â€Š0.2 fold-change, P = 0.02) but not controls (1.1 ±â€Š0.1 fold-change, P = 0.30). CONCLUSIONS: ES demonstrated an exaggerated postprandial satiety gut hormone response that was attenuated by octreotide, thus identifying a potential therapeutic target to modulate in the ES patient with early satiety.

Bariatric surgery and microvascular complications of type 2 diabetes mellitus.

Metabolic dysregulation is the defining characteristic of type 2 diabetes mellitus (T2DM) and can give rise to microvascular complications, specifically retinopathy, nephropathy and neuropathy. Pharmacological targeting of risk factors for microvascular complications can yield therapeutic gains, particularly in relation to retinopathy and nephropathy. Bariatric surgery is superior to intensified pharmacotherapy in relation to glycaemic control and can remediate dyslipidaemia and hypertension. Consequently, evidence of the effect of bariatric surgery on microvascular complications is now emerging in the literature. Examination of the recent published evidence base (covering the period 2011-2014) on the effects of bariatric surgery on microvascular complications reveals further evidence supportive of the efficacy of bariatric surgery in preventing the incidence and progression of albuminuria and arresting renal functional decline. Data on retinopathy are more ambivalent potentially representing the potential in some cases for a degree of surgery associated reactive hypoglycaemia to detract from the benefits of amelioration of hyperglycaemia. A significant gap in the literature remains in relation to the effects of surgery on diabetic neuropathy. Overall, there is a pressing need for prospective randomised controlled trials examining long-term microvascular outcomes following bariatric surgery in patients with T2DM.

Parallel assessment of albuminuria and plasma sTNFR1 in people with type 2 diabetes and advanced chronic kidney disease provides accurate prognostication of the risks of renal decline and death.

Identification of people with diabetes and chronic kidney disease at high-risk of early mortality is a priority to guide intensification of therapy. We aimed to investigate the complementary prognostic value of baseline urine albumin-to-creatinine ratio (uACR) and plasma soluble tumour necrosis factor receptor-1 (sTNFR1) with respect to early mortality and renal functional decline in a population with type 2 diabetes and advanced chronic kidney disease. We measured plasma sTNFR1 in people with type 2 diabetes (HbA1c ≥ 48 mmol/mol) at 2 hospital sites in Dublin between October 15th, 2014 and July 17th, 2015. In a subgroup of patients with advanced chronic kidney disease at baseline (estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/BSA) (n = 118), we collected clinical and longitudinal laboratory data to investigate relationships between sTNFR1 and renal and mortality endpoints by multivariable linear mixed-effects models and Cox proportional hazards regression models. The cohort was 64% male and 97% Caucasian. Mean age was 74 years, with a median type 2 diabetes duration of 16 years. Mean CKD-EPI eGFR was 42 mL/min/BSA and median [IQR] uACR was 3 [11] mg/mmol. Twenty-three (39%) people in quartiles 3 and 4 for plasma sTNFR1 died over 4-year follow-up. After adjustment for clinical variables, annual CKD-EPI eGFR decreased by - 0.56 mL/min/BSA/year for each logarithm unit increase in baseline uACR, corresponding to an annual loss of renal function of 3% per year. Furthermore, elevated uACR, but not sTNFR1, increased the risk of ≥ 40% decline in CKD-EPI eGFR (HR 1.5, p = 0.001) and doubling of serum creatinine (HR 2.0, p < 0.001). Plasma sTNFR1 did not predict a more negative trajectory in eGFR slope. However, for those people in quartiles 3 and 4 for plasma sTNFR1, an increased risk of incident mortality was detected (HR 4.9, p = 0.02). No such association was detected for uACR. In this elderly cohort of patients with type 2 diabetes and chronic kidney disease, sTNFR1 predicted short-to-medium term mortality risk but not risk of progressive renal functional decline. In contrast, parallel assessment of uACR predicted renal functional decline but not mortality, highlighting the complementary prognostic information provided by both parameters.

Validating the association between plasma tumour necrosis factor receptor 1 levels and the presence of renal injury and functional decline in patients with Type 2 diabetes.

AIMS: Elevated plasma soluble tumour necrosis factor receptor 1 (TNFR1) predicts long-term progression of chronic kidney disease. We investigated the association between elevated TNFR1 and the presence of renal disease in patients with Type 2 diabetes mellitus registering a haemoglobin A1c (HbA1c) >48mmol/mol despite medical therapy. METHODS: Using sensitivity, specificity and regression analyses we interrogated the association between plasma TNFR1 and presence of chronic kidney disease as assessed by the presence of microalbuminuria and/or an estimated glomerular filtration rate of less than 60ml/min/1.73m2 (stages 3-5 chronic kidney disease). The association of TNFR1 with C-reactive protein and leptin-adiponectin ratio as plasma markers of systemic inflammation and adipose stress respectively was also investigated. RESULTS: Upper quartile TNFR1 is independently associated with elevated urinary albumin-creatinine ratios, reductions in eGFR and strongly predicts the presence of stages 3-5 chronic kidney disease in regression modelling. Elevated TNFR1 levels are associated with increased plasma C-reactive protein and augmented leptin-adiponectin ratio. CONCLUSIONS: Our study confirms plasma TNFR1 as a surrogate of renal structural and functional impairment in patients with type 2 diabetes mellitus. Association of TNFR1 with markers of systemic inflammation and adipose stress indicates that TNFR1 may be a biomarker of these processes as components of the pathogenesis of diabetic kidney disease.

Link Between Increased Satiety Gut Hormones and Reduced Food Reward After Gastric Bypass Surgery for Obesity.

CONTEXT: Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weight loss maintenance, reducing appetite, and also food reward, via unclear mechanisms. OBJECTIVE: To investigate the role of elevated satiety gut hormones after RYGB, we examined food hedonic-reward responses after their acute post-prandial suppression. DESIGN: These were randomized, placebo-controlled, double-blind, crossover experimental medicine studies. PATIENTS: Two groups, more than 5 months after RYGB for obesity (n = 7-11), compared with nonobese controls (n = 10), or patients after gastric banding (BAND) surgery (n = 9) participated in the studies. INTERVENTION: Studies were performed after acute administration of the somatostatin analog octreotide or saline. In one study, patients after RYGB, and nonobese controls, performed a behavioral progressive ratio task for chocolate sweets. In another study, patients after RYGB, and controls after BAND surgery, performed a functional magnetic resonance imaging food picture evaluation task. MAIN OUTCOME MEASURES: Octreotide increased both appetitive food reward (breakpoint) in the progressive ratio task (n = 9), and food appeal (n = 9) and reward system blood oxygen level-dependent signal (n = 7) in the functional magnetic resonance imaging task, in the RYGB group, but not in the control groups. RESULTS: Octreotide suppressed postprandial plasma peptide YY, glucagon-like peptide-1, and fibroblast growth factor-19 after RYGB. The reduction in plasma peptide YY with octreotide positively correlated with the increase in brain reward system blood oxygen level-dependent signal in RYGB/BAND subjects, with a similar trend for glucagon-like peptide-1. CONCLUSIONS: Enhanced satiety gut hormone responses after RYGB may be a causative mechanism by which anatomical alterations of the gut in obesity surgery modify behavioral and brain reward responses to food.

Maternal C-reactive protein in early pregnancy.

OBJECTIVE: To compare maternal C-reactive protein concentration in the first 18 weeks of pregnancy with the nonpregnant adult reference range. STUDY DESIGN: Serum samples from healthy women with a pregnancy <18 weeks' gestation were retrieved from a Hospital biological resource bank. C-reactive protein was measured using an immunoturbidimetric assay. Clinical and sociodemographic details were retrieved from the Hospital's computerized database. RESULTS: Of the 146 women, 85 (58.2%) were nulliparous, 11 (7.5%) were smokers and 22 (15.1%) were obese. Mean gestational age at phlebotomy was 12.5 (range 8.1-17.4) weeks. Median C-reactive protein was 3.2 (interquartile range 0.3-12.1)mg/L. There were 74 women (50.7%) with C-reactive protein level >3.0mg/L which is above the nonpregnant adult reference range. C-reactive protein levels were positively correlated with increasing Body Mass Index. No relationship was found between C-reactive protein and age, smoking or gestational age. CONCLUSION: C-reactive protein concentration in a well-characterized population in early pregnancy was higher than that cited for the nonpregnant adult, and C-reactive protein was positively associated with Body Mass Index. Therefore, caution is needed in the use and interpretation of C-reactive protein measurements in early pregnancy to avoid unnecessary interventions in women with suspected illness.

Beyond weight loss: evaluating the multiple benefits of bariatric surgery after Roux-en-Y gastric bypass and adjustable gastric band.

BACKGROUND: Despite the evidence for benefits beyond weight loss following bariatric surgery, assessments of surgical outcomes are often limited to changes in weight and remission of type 2 diabetes mellitus. To address this shortfall in assessment, the King's Obesity Staging System was developed. This system evaluates the individual in severity stages of physical, psychological, socio-economic and functional disease. These are categorised into disease domains arranged so as to allow an alphabetic mnemonic as Airways, Body Mass Index (BMI), Cardiovascular, Diabetes, Economic, Functional, Gonadal, Health Status (perceived) and (body) Image. METHODS: In this cohort study, patients were assessed before and 12 months after surgery using the modified King's Obesity Staging Score. We studied 217 consecutive patients undergoing Roux-en-Y gastric bypass (RYGB; N = 148) and laparoscopic adjustable gastric band (LAGB; N = 69) using the modified King's Obesity Staging System to determine health benefits after bariatric surgery. RESULTS: Preoperatively, the groups had similar BMI, but the RYGB group had worse Airways, Cardiovascular, and Diabetes scores (p < 0.05). After surgery, RYGB and LAGB produced improvements in all scores. In a subgroup paired analysis matched for preoperative Airways, BMI, Cardiovascular, and Diabetes scores, both procedures showed similar improvements in all scores, except for BMI where RYGB had a greater reduction than LAGB (p < 0.05). CONCLUSIONS: Both RYGB and LAGB deliver multiple benefits to patients as evaluated by the modified King's Obesity Staging System beyond BMI and glycaemic markers. A validated staging score such as the modified King's Obesity Staging System can be used to quantify these benefits.

Gastric bypass surgery for obesity decreases the reward value of a sweet-fat stimulus as assessed in a progressive ratio task.

BACKGROUND: Obesity is among the leading causes of disease and death. Bariatric surgery is the most effective treatment of obesity. There is increasing evidence that after gastric bypass surgery, patients and animal models show a decreased preference for sweet and fatty foods. The underlying mechanism may include alterations in taste function. OBJECTIVE: We hypothesize that a gastric bypass reduces the reward value of sweet and fat tastes. DESIGN: In this prospective case-control study, 11 obese patients who were scheduled to undergo a gastric bypass and 11 normal-weight control subjects in the fed state clicked a computer mouse to receive a sweet and fatty candy on a progressive ratio schedule 10 wk apart (in patients, testing took place 2 wk before and 8 wk after gastric bypass surgery). Subjects worked progressively harder to obtain a food reward (reinforcer) until they stopped clicking (ie, the breakpoint), which was a measure of the reinforcer value. Breakpoints were assessed by the number of mouse clicks in the last completed ratio. The experiment was repeated in a different cohort by using vegetable pieces as the reinforcer. RESULTS: Breakpoints in the test sessions of control subjects correlated highly for both reinforcers. The median breakpoint for candies, but not vegetables, was reduced by 50% in the obese group after gastric bypass. Patients with the largest reduction in the breakpoint had the largest decrease in BMI. CONCLUSIONS: Gastric bypass surgery resulted in the selective reduction of the reward value of a sweet and fat tastant. This application of the progressive ratio task provided an objective and reliable evaluation of taste-driven motivated behavior for food stimuli after obesity surgery.