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Background\ud Duodenal mucosal resurfacing (DMR) is a novel day-case endoscopic intervention which results in weight loss-independent reductions in HbA1c in patient with type 2 diabetes mellitus (T2DM). We hypothesized that DMR works by increasing insulin sensitivity and we aimed to investigate the mechanism of action of DMR through longitudinal metabolic phenotyping in humans.\ud \ud Methods\ud Thirty-two insulin-resistant women with polycystic ovary syndrome (PCOS) and obesity were randomised in a double-blinded manner to DMR or sham endoscopy. They underwent measurements of insulin sensitivity using euglycaemic hyperinsulinaemic clamps, insulin secretion using oral glucose tolerance tests and reproductive function using weekly reproductive hormone profiles and ovarian ultrasonography for 6 months post-intervention.\ud \ud Results\ud A small increase in total body insulin sensitivity measured by the clamp was observed in both groups at week 12. An increase in insulin sensitivity, as measured by HOMA-IR, was observed in both groups at week 24. There was an increase in the number of menses (median 2 DMR, 0.5 sham). There were no significant differences between the two groups in these outcomes or insulin secretion.\ud \ud Conclusions\ud These findings suggest that DMR does not work by increasing insulin sensitivity in euglycaemic, insulin resistant women with PCOS. The procedure may exert its effects only in the context of hyperglycaemia or pathologically hyperplastic, insulin-desensitised duodenal mucosa.

Summary Background Many patients with type 2 diabetes do not achieve sustained diabetes remission after metabolic (bariatric) surgery for the treatment of obesity. Liraglutide, a glucagon-like peptide-1 analogue, improves glycaemic control and reduces bodyweight in patients with type 2 diabetes. Our aim was to assess the safety and efficacy of liraglutide 1·8 mg in patients with persistent or recurrent type 2 diabetes after metabolic surgery. Methods In the GRAVITAS randomised double-blind, placebo-controlled trial, we enrolled adults who had undergone Roux-en-Y gastric bypass or vertical sleeve gastrectomy and had persistent or recurrent type 2 diabetes with HbA1c levels higher than 48 mmol/mol (6·5%) at least 1 year after surgery from five hospitals in London, UK. Participants were randomly assigned (2:1) via a computer-generated sequence to either subcutaneous liraglutide 1·8 mg once daily or placebo, both given together with a reduced-calorie diet, aiming for a 500 kcal per day deficit from baseline energy intake, and increased physical activity. The primary outcome was the change in HbA1c from baseline to the end of the study period at 26 weeks, assessed in patients who completed the trial. Safety was assessed in the safety analysis population, consisting of all participants who received either liraglutide or placebo. This trial is registered with EudraCT, number 2014-003923-23, and the ISRCTN registry, number ISRCTN13643081. Findings Between Jan 29, 2016, and May 2, 2018, we assigned 80 patients to receive either liraglutide (n=53) or placebo (n=27). 71 (89%) participants completed the study and were included in the principal complete-cases analysis. In a multivariable linear regression analysis, with baseline HbA1c levels and surgery type as covariates, liraglutide treatment was associated with a difference of −13·3 mmol/mol (−1·22%, 95% CI −19·7 to −7·0; p=0·0001) in HbA1c change from baseline to 26 weeks, compared with placebo. Type of surgery had no significant effect on the outcome. 24 (45%) of 53 patients assigned to liraglutide and 11 (41%) of 27 assigned to placebo reported adverse effects: these were mainly gastrointestinal and in line with previous experience with liraglutide. There was one death during the study in a patient assigned to the placebo group, which was considered unrelated to study treatment. Interpretation These findings support the use of adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery. Funding JP Moulton Foundation.

OBJECTIVE Roux-en-Y gastric bypass (RYGB) characteristically enhances postprandial levels of glucagon-like peptide 1 (GLP-1), a mechanism that contributes to its profound glucose-lowering effects. This enhancement is thought to be triggered by bypass of food to the distal small intestine with higher densities of neuroendocrine L-cells. We hypothesized that if this is the predominant mechanism behind the enhanced secretion of GLP-1, a longer intestinal bypass would potentiate the postprandial peak in GLP-1, translating into higher insulin secretion and, thus, additional improvements in glucose tolerance. To investigate this, we conducted a mechanistic study comparing two variants of RYGB that differ in the length of intestinal bypass. RESEARCH DESIGN AND METHODS A total of 53 patients with type 2 diabetes (T2D) and obesity were randomized to either standard limb RYGB (50-cm biliopancreatic limb) or long limb RYGB (150-cm biliopancreatic limb). They underwent measurements of GLP-1 and insulin secretion following a mixed meal and insulin sensitivity using euglycemic hyperinsulinemic clamps at baseline and 2 weeks and at 20% weight loss after surgery. RESULTS Both groups exhibited enhancement in postprandial GLP-1 secretion and improvements in glycemia compared with baseline. There were no significant differences in postprandial peak concentrations of GLP-1, time to peak, insulin secretion, and insulin sensitivity. CONCLUSIONS The findings of this study demonstrate that lengthening of the intestinal bypass in RYGB does not affect GLP-1 secretion. Thus, the characteristic enhancement of GLP-1 response after RYGB might not depend on delivery of nutrients to more distal intestinal segments.

Objective: The objective of this study was to assess the utility of the 2-hour oral glucose tolerance test (OGTT) value to discriminate between different cardiometabolic profiles and examine the role of body composition in predicting the associated increased risk for glucose impairment, beta-cell dysfunction, and cardiovascular disease (CVD). Methods: Subjects with normal fasting glucose completed a 2-hour OGTT and were categorized to the carbohydrate metabolism alterations (CMAs) or the control group based on a 2-hour glucose threshold of 7.8 mmol/L. Body composition, visceral adipose tissue, OGTT-based parameters, and cardiovascular risk factors (CVRFs) such as hypertension, dyslipidemia, obstructive sleep apnea, nonalcoholic fatty liver disease, and smoking status were measured. Results: Subjects with CMAs exhibited a significantly higher 1-hour postload glucose level and a greater decline in beta-cell function and CVRF profiles. After multivariate adjustment, an excess of total body and visceral fat was associated with an increased risk of CMAs, beta-cell dysfunction, CVRFs, and lower whole-body insulin sensitivity. Conclusions: These data support the etiopathogenic role of body and visceral fat in the development of glucose derangements and CVRFs early on in the metabolic dysregulation process. Thus, body composition analysis and OGTT assessment performed in individuals with normal fasting glucose enable a better identification of patients at risk of developing type 2 diabetes and CVD.

BACKGROUND: An excessively long-blind end of the alimentary limb following a Roux-en-Y gastric bypass (RYGB), known as a 'candy cane' (CC), may cause symptoms including abdominal pain, regurgitation and vomiting. Very few studies have examined the efficacy of surgical resection of the CC. OBJECTIVES: The aim of this study was to assess sensitivity of preoperative diagnostic tools for CC, as well as perioperative outcomes and symptom resolution after CC revision surgery. SETTING: High volume bariatric centre of excellence, United Kingdom. METHODS: Observational study of CC revisions from 2010 to 2017. RESULTS: Twenty-eight CC revision cases were identified (mean age 45 ± 9 years, female preponderance 9:1). Presenting symptoms were abdominal pain (86%), regurgitation/vomiting (43%), suboptimal weight loss (36%) and acid reflux (21%). Preoperative tests provided correct diagnosis in 63% of barium contrast swallows, 50% of upper gastrointestinal endoscopies and 29% computed tomographies. Patients presenting with pain had significantly higher CC size as compared with pain-free group (4.2 vs. 2 cm, p = 0.001). Perioperative complications occurred in 25% of cases. Complete or partial symptom resolution was documented in 73% of patients undergoing CC revision. Highest success rates were recorded in the regurgitation/vomiting group (67%). CONCLUSION: Surgical revision of CC is associated with good symptom resolution in the majority of patients, especially those presenting with regurgitation/vomiting. However, it carries certain risk of complications. CC diagnosis may frequently be missed; hence more than one diagnostic tool should be considered when investigating symptomatic patients after RYGB.

Background and aims Obesity is associated with impaired glucose tolerance which is a risk factor for cardiovascular risk. However, the oral glucose tolerance test (OGTT) is not usually performed in patients with normal fasting glycaemia, thus offering false reassurance to patients with overweight or obesity who may have post-prandial hyperglycaemia. As an alternative to resource demanding OGTTs, we aimed to examine the predictive value of anthropometric measures of total and central fat distribution for post-prandial hyperglycaemia in patients with overweight and obesity with normal fasting glycaemia enrolled in the DICAMANO study. Methods We studied 447 subjects with overweight/obesity with a fasting glucose value ≤ 5.5 mmol l−1 (99 mg dl−1) and BMI ≥ 25 kg/m2 who underwent a 75-g OGTT. Post-prandial hyperglycaemia was defined as a glucose level ≥ 7.8 mmol l−1 (140 mg dl−1) 2-h after the OGTT. The anthropometric measurements included body mass index, body adiposity index, waist circumference, neck circumference, waist-to-hip ratio and waist-to-height ratio. Results The prevalence of post-prandial hyperglycaemia was 26%. Mean 1-h OGTT glucose levels, insulin resistance and beta cell dysfunction was higher in those subjects in the highest tertile for each anthropometric measurement, irrespective of fasting glucose level. Central fat depot anthropometric measurements were strongly and independently associated with an increased risk of post-prandial hyperglycaemia. After multivariable-adjustment for fasting plasma glucose level, smoking, and physical activity level, the odds ratio (95% confidence intervals) for the presence of post-prandial hyperglycaemia for neck circumference, waist circumference and waist-to-height ratio were 3.3 (1.4, 7.7), 2.4 (1.4, 4.4) and 2.5 (1.4, 4.5), respectively. Conclusions In this large and comprehensively phenotyped cohort, one in four subjects had post-prandial hyperglycaemia despite normal fasting glycaemia. Anthropometric indices of central fat distribution were strongly and independently associated with an increased risk of post-prandial hyperglycaemia. These results support the association between central adiposity and glucose derangements and demonstrate the clinical usefulness of anthropometric measurements as screening tools for the selection of patients who are most likely to benefit from an OGTT. Trial registration ClinicalTrials.gov Identifier: NCT03506581. Registered 24 April 2018—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03506581

Highlights • Biliopancreatic diversion (BPD) is one of the most effective surgical procedures for obesity. • BPD is associated with long-term complications such as protein malnutrition and vitamin deficiencies due to malabsorption. • Robust multidisciplinary lifelong surgical and medical follow-up is needed in all BPD patients. • BPD complications can be minimised and recognised early with patient and healthcare staff education on the importance of lifetime follow-up and adherence to dietary and supplement regimes., Context Bariatric surgery has beneficial effects on obesity and associated comorbidities such as glycaemic control in type 2 diabetes, dyslipidaemia, hypertension, and renal and hepatic function. Nevertheless, this surgery is not free of complications and possible side effects due to restrictive and/or malabsorptive related components. Case description We report the case of a 60-year-old woman whose past medical history included morbid obesity, hypertension and Scopinaro biliopancreatic diversion (BPD) with duodenal switch in 1998. In 2015, she attended the emergency department hypotensive with bad general condition and reporting chronic constitutional symptoms. A wide variety of tests were performed including endoscopic studies as her symptoms were not immediately correlated with the BPD surgery. Finally, she was diagnosed from gastrojejunal stricture which caused her severe malnutrition. The patient underwent successful surgical management. Discussion BPD is one of the most effective surgical procedures for obesity, with an overall 5-year loss of excess body weight higher than 72%. Nonetheless, it is associated with long-term complications such as protein malnutrition and vitamin deficiencies due to malabsorption. Being surgically challenging, with high risk of nutritional complications and lifelong needed for the follow-up, BPD is rarely performed nowadays. Conclusions Bariatric Surgery is a well-known effective therapeutic measure to improve obesity and cardiovascular related disease. However, this case highlights the importance of robust multidisciplinary lifelong surgical and medical follow-up in all BPD patients. BPD complications can be minimised and recognised early with patient and healthcare staff education on the importance of lifetime follow-up and adherence to dietary and supplement regimes.

RESUMEN Fundamento. Un adecuado control de la glucemia y de los factores de riesgo cardiovascular (FRCV) es fundamental en los pacientes con diabetes mellitus tipo 2 (DM2). Sin embargo, diversos estudios han demostrado que el porcentaje de pacientes que alcanzan dichos objetivos es escaso. Hemos evaluado el grado de control de FRCV en pacientes DM2 que acuden con regularidad a una consulta monográfica de diabetes. Pacientes y métodos. Se han estudiado los pacientes con DM2 que acudían a revisión al departamento de Endocrinología de la Clínica Universidad de Navarra con un seguimiento mínimo de un año. Se presentan las características clínicas, complicaciones crónicas y tratamiento médico, así como la clasificación en grupos según el cumplimiento de los objetivos de hemoglobina glicada (HbA1c), perfil lipídico (LDL-colesterol) y presión arterial (PA) individualizados según comorbilidades y años de evolución de la DM2. Resultados. Se han analizado 137 pacientes (75% hombres) con DM2, 67 años de edad media y 12,7 años de evolución. Durante el seguimiento, se encontraron dentro del rango objetivo individualizado de HbA1c el 83,9% de los pacientes, el 67,2% en cuanto a LDL-colesterol y el 76,6% considerando PA. Además, el 68% presentaron las tres variables principales dentro del objetivo. Conclusiones. En nuestra población de DM2 la consecución de objetivos de HbA1c, LDL-colesterol y PA se alcanza en una importante proporción de pacientes (67-91%). Posiblemente la intensa e individualizada atención ofrecida a través de una unidad de diabetes especializada pueda explicar estos resultados. ABSTRACT Background. Achieving an adequate control of glycaemic and cardiovascular risk factors (CVRFs) is essential in patients with type 2 diabetes mellitus (T2DM). However, several studies have shown that the percentage of patients achieving these goals is scarce. We evaluated the degree of control of CVRFs target goals in T2DM patients who regularly attend a specialized diabetic clinic. Methods. We studied T2DM patients who attended the specialized Diabetic Unit at the Department of Endocrinology of Clínica Universidad de Navarra with a minimum follow-up of one year. Clinical characteristics, chronic complications and treatments were collected and patients were classified into groups according to the fulfilment of target glycated haemoglobin (HbA1c), LDL cholesterol and blood pressure (BP) levels, predefined according to the presence of different comorbidities and the duration of T2DM. Results. We analysed 137 patients (75% men) with T2DM, with an average age of 67 years and a 12.7 year duration of diabetes. During follow-up, 83.9% of the patients were within the individualized HbA1c target, 76.6% considering BP and 67.2% in terms of LDL-cholesterol. In addition, 68% had concomitantly the three main variables within the target. Conclusions. In our population of T2DM, HbA1c, LDL cholesterol and BP targets were achieved in a substantial proportion of patients (67-91%). Perhaps the intense and individualized care offered through a specialized diabetes unit may explain these results.

The prevalence of obesity is increasing exponentially worldwide, becoming an international public health issue that affects quality of life, increases the risk of illness and raises healthcare costs in countries in all parts of the world. In this editorial, we analyse the latest progress in the management of obesity and associated cardiovascular risk factors, and summarise the latest randomised controlled trials that have had the biggest influence on the current changes we are experiencing in obesity management.

The most common cause of organic fasting hypoglycemia in adults is the presence of an insulin-producing pancreatic adenoma, but when high insulin levels are not found, the differential diagnosis is challenging. Misdiagnosis can lead to an unnecessary pancreatectomy. Insulin concentrations may be low in some cases despite a clinical history suggestive of insulinoma. In these cases, a proinsulinoma should be suspected, although the rarity of this condition requires an extensive workup before reaching a final diagnosis. We describe an unusual case of a 38-year-old man with a severe hypoglycemic syndrome due to a proinsulin-secreting pancreatic adenoma. Insulin was measured by the specific assay and suppressed under the lower detection limit during fasting hypoglycemia. Serum proinsulin and C-peptide levels were abnormally elevated, and further tests revealed an islet cell tumor. The tumor was surgically removed, relieving the fasting hypoglycemia. Histopathological study showed a conventional well-differentiated neuroendocrine tumor with high immunoreactivity against proinsulin and with lesser intensity against insulin. Interestingly, GS-9A8 antibody clone used for immunostaining proinsulin did not cross-react with human insulin or C-peptide, providing an unbiased picture of proinsulin secretion. The resolution of symptoms, the fall of proinsulin concentrations after tumor removal and the histopathology study confirmed the diagnosis of proinsulinoma.

A 69 year old woman was treated with an intravenous infusion of iron polymaltose (1800 mg in 500 mL normal saline). Within minutes of …