Non-functional alpha-cell hyperplasia with glucagon-producing NET: a case report.

Introduction: Alpha-cell hyperplasia (ACH) is a rare pancreatic endocrine condition. Three types of ACH have been described: functional or nonglucagonoma hyperglucagonemic glucagonoma syndrome, reactive or secondary to defective glucagon signaling, and non-functional. Few cases of ACH with concomitant pancreatic neuroendocrine tumors (pNETs) have been reported and its etiology remains poorly understood. A case report of non-functional ACH with glucagon-producing NET is herein presented. Case report: A 72-year-old male was referred to our institution for a 2 cm single pNET incidentally found during imaging for acute cholecystitis. The patient's past medical history included type 2 diabetes (T2D) diagnosed 12 years earlier, for which he was prescribed metformin, dapagliflozin, and semaglutide. The pNET was clinically and biochemically non-functioning, apart from mildly elevated glucagon 217 pg/ml (<209), and 68Ga-SSTR PET/CT positive uptake was only found at the pancreatic tail (SUVmax 11.45). The patient underwent a caudal pancreatectomy and the post-operative 68Ga-SSTR PET/CT was negative. A multifocal well-differentiated NET G1, pT1N0M0R0 (mf) strongly staining for glucagon on a background neuroendocrine alpha-cell hyperplasia with some degree of acinar fibrosis was identified on pathology analysis. Discussion and conclusion: This case reports the incidental finding of a clinically non-functioning pNET in a patient with T2D and elevated glucagon levels, unexpectedly diagnosed as glucagon-producing NET and ACH. A high level of suspicion was required to conduct the glucagon immunostaining, which is not part of the pathology routine for a clinically non-functioning pNET, and was key for the diagnosis that otherwise would have been missed. This case highlights the need to consider the diagnosis of glucagon-producing pNET on an ACH background even in the absence of glucagonoma syndrome.

Anti-Müllerian hormone a surrogate of follicular fluid oxidative stress in polycystic ovary syndrome?

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women at childbearing age. Anti-Müllerian hormone (AMH) is a widely accepted sensitive marker of ovarian reserve, which has been suggested that could also act as biomarker of ovarian morphology for PCOS diagnosis. Oxidative stress (OS) is known to be associated and have a negative impact factor in several reproductive conditions, including PCOS. However, the relationship between circulating AMH and OS within the follicular fluid (FF), and its potential impact on in vitro fertilization (IVF) outcomes of women with PCOS, remains largely unexplored. A total of 84 women, with PCOS (n = 30) or ovulatory controls (n = 54), were enrolled in this study. Women underwent individualized controlled ovarian stimulation for oocyte retrieval. Blood and FF obtained from mature follicles were collected at the time of oocyte retrieval, for measuring total testosterone, ∆4-androstenedione, progesterone, sex hormone binding globulin (SHBG) and AMH. OS in the FF was assessed by measuring total antioxidant capacity (TAC) through the ferric reducing antioxidant power (FRAP) and lipid peroxidation (LPO) by quantification of malondialdehyde (MDA) levels. Our results demonstrated that women with PCOS had significantly higher plasma levels of AMH, ∆4-androstenedione, total testosterone and a free androgen index (FAI) than observed in non-PCOS controls. In women with PCOS, total testosterone and AMH levels in the FF were also higher, while TAC was lower compared to non-PCOS. Furthermore, circulating AMH levels were positively correlated with ∆4-androstenedione, albeit negatively correlated with TAC. In this study we demonstrated that the susceptibility to OS, as assessed by the total antioxidant capacity in the FF, is higher in women with PCOS and inversely related to AMH levels. This study results lead us to forge the reasonable hypothesis that the greater susceptibility to OS within the follicle microenvironment is potentially at the end of a roadway that starts with elevated ∆4-androstenedione and AMH within the FF, which in turn are mirrored by circulating AMH and androgen levels. Thus, suggesting that circulating AMH levels could act as a surrogate biomarker of follicular fluid oxidative stress in women with PCOS.

Gestational Diabetes Risk and Low Birth Weight After Metabolic Bariatric Surgery: a Complex Interplay to be Balanced.

INTRODUCTION: Metabolic bariatric surgery (MBS) is known to improve the obstetric outcomes of women with obesity and to prevent gestational diabetes (GD). To what extent does MBS decreases GD, without incurring at additional risks is a matter of concern. METHODS: A retrospective case-control study to compare the pregnancy outcomes of women previously submitted to MBS to those of age and preconception body mass index (PC BMI) matched non-operated controls. RESULTS: Pregnancies of women after MBS (n = 79) and matched controls (n = 79) were included. GD was significantly less frequent after MBS (7.6% vs. 19%; p = 0.03). Fasting blood glucose (76.90 ± 0.77 vs 80.37 ± 1.15 mg/dl, p < 0.05; 70.08 ± 1.34 vs. 76.35 ± 0.95 mg/dl; p < 0.05, first and second trimesters respectively) and birth weight (2953.67 ± 489.51 g vs. 3229.11 ± 476.21 g; p < 0.01) were significantly lower after MBS when compared to controls. The occurrence of small-for-gestational-age (SGA) was more frequent after MBS (22.8% vs. 6.3%; p < 0.01), but no longer significant after controlling for smoking habits (15.5% vs. 6%, p = 0.14). There were no significant differences in gestational weight gain, prematurity rate nor mode of delivery between groups. CONCLUSION: MBS was associated with a lower prevalence of GD than observed in non-operated women with the same age and BMI. After controlling for smoking, this occurred at the expense of a lower birth weight. Our data reinforces the hypothesis that MBS has body weight independent effects on glucose kinetics during pregnancy with distinctive impacts for mother and offspring, which need to be balanced.

Beyond Restrictive: Sleeve Gastrectomy to Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy as a Spectrum of One Single Procedure.

INTRODUCTION: Single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) is a restrictive/hypoabsorptive procedure recommended for patients with obesity class 3. For safety reasons, SADI-S can be split into a two-step procedure by performing a sleeve gastrectomy (SG) first. This stepwise approach also provides an unprecedented opportunity to disentangle the weight loss mechanisms triggered by each component. The objective was to compare weight trajectories and post-prandial endocrine and metabolic responses of patients with obesity class 3 submitted to SADI-S or SG as the first step of SADI-S. METHODS: Subjects submitted to SADI-S (n = 7) or SG (n = 7) at a tertiary referral public academic hospital underwent anthropometric evaluation and a liquid mixed meal tolerance test (MMTT) pre-operatively and at 3, 6, and 12 months post-operatively. RESULTS: Anthropometric parameters, as well as metabolic and micronutrient profiles, were not significantly different between groups, neither before nor after surgery. There were no significant differences in fasting or post-prandial glucose, insulin, C-peptide, ghrelin, insulin secretion rate, and insulin clearance during the MMTT between subjects submitted to SADI-S and SG. There was no lost to follow-up. CONCLUSIONS: The restrictive component seems to be the main driver for weight loss and metabolic adaptations observed during the first 12 months after SADI-S, given that the weight trajectories and metabolic profiles do not differ from SG. These data provide support for surgeons' choice of a two-step SADI-S without jeopardizing the weight loss outcomes.

The Impact of Early-Stage Chronic Kidney Disease on Weight Loss Outcomes After Gastric Bypass.

PURPOSE: Weight loss achieved through bariatric metabolic surgery was demonstrated to be effective at reversing chronic kidney dysfunction associated with obesity-related glomerulopathy. However, robust data on how pre-operative kidney status impacts on bariatric metabolic surgery weight loss outcomes is still lacking. The aim of this study was to evaluate the impact of kidney dysfunction on weight loss outcomes after bariatric metabolic surgery. METHODS: Patients with obesity to be submitted to gastric bypass surgery underwent a pre-operative evaluation of creatinine clearance, estimated glomerular filtration rate (eGFR), proteinuria, and albuminuria in 24-hour urine. Body mass index (BMI), % total weight loss (%TWL), and % excess BMI loss (%EBMIL) were assessed at 6 and 12 months after surgery. RESULTS: Before surgery, patients (N=127) had a mean BMI of 39.6 ± 3.0 kg/m2, and 56.7% (n=72) had a creatinine clearance > 130 mL/min, 23.6% (n= 30) presented proteinuria > 150 mg/24h, and 15.0% (n= 19) presented albuminuria > 30 mg/24h. After surgery, the mean BMI was 27.7 kg/m2 and 25.0 kg/m2 at 6 and 12 months, respectively (p<0.0001). The %TWL was lower in patients with pre-operative eGFR < percentile 25 (34.4 ± 5.8% vs 39.4 ± 4.9%, p=0.0007, at 12 months). There were no significant correlations between weight loss metrics and pre-operative creatinine clearance rate, proteinuria, or albuminuria. CONCLUSION: Early-stage chronic kidney disease (G2) has a negative impact on short-term weight loss outcomes after bariatric metabolic surgery, albeit in a magnitude inferior to the clinically relevant threshold.

Renal Dysfunction Phenotypes in Patients Undergoing Obesity Surgery.

Obesity surgery candidates are at an increased risk of kidney injury, but pre-operative evaluation usually neglects kidney function assessment. This study aimed to identify renal dysfunction in candidates for bariatric surgery. To reduce the sources of bias, subjects with diabetes, prediabetes under metformin treatment, neoplastic or inflammatory diseases were excluded. Patients' (n = 192) average body mass index was 41.7 ± 5.4 kg/m2. Among these, 51% (n = 94) had creatinine clearance over 140 mL/min, 22.4% (n = 43) had proteinuria over 150 mg/day and 14.6% (n = 28) albuminuria over 30 mg/day. A creatinine clearance higher than 140 mL/min was associated with higher levels of proteinuria and albuminuria. Univariate analysis identified sex, glycated hemoglobin, uric acid, HDL and VLDL cholesterol as being associated with albuminuria, but not with proteinuria. On multivariate analysis, glycated hemoglobin and creatinine clearance as continuous variables were significantly associated with albuminuria. In summary, in our patient population prediabetes, lipid abnormalities and hyperuricemia were associated with albuminuria, but not with proteinuria, suggesting different disease mechanisms might be implicated. Data suggest that in obesity-associated kidney disease, tubulointerstitial injury precedes glomerulopathy. A significant proportion of obesity surgery candidates present clinically relevant albuminuria and proteinuria along with renal hyperfiltration, suggesting that routine pre-operative assessment of these parameters should be considered.

GLP-1 Increases Circulating Leptin Levels in Truncal Vagotomized Rats.

GLP-1 is a gastro-intestinal hormone acting within the gut/brain axis for energy balance regulation. We aimed to evaluate the role of the vagus nerve in whole-body energy homeostasis and in mediating GLP-1 effects. For this, rats submitted to truncal vagotomy and sham-operated controls underwent a comprehensive evaluation, including eating behavior, body weight, percentage of white (WAT) and brown adipose tissue (BAT), resting energy expenditure (REE) and acute response to GLP-1. Truncal vagotomized rats had significantly lower food intake, body weight, body weight gain, WAT and BAT, with a higher BAT/WAT ratio, but no significant difference in REE when compared to controls. Vagotomized rats also had significantly higher fasting ghrelin and lower glucose and insulin levels. After GLP-1 administration, vagotomized rats depicted a blunted anorexigenic response and higher plasma leptin levels, as compared to controls. However, in vitro stimulation of VAT explants with GLP-1 resulted in no significant changes in leptin secretion. In conclusion, the vagus nerve influences whole-body energy homeostasis by modifying food intake, body weight and body composition and by mediating the GLP-1 anorectic response. The higher leptin levels in response to acute GLP-1 administration observed after truncal vagotomy suggest the existence of a putative GLP-1-leptin axis that relies on the integrity of gut-brain vagal pathway.

Towards precision medicine in bariatric surgery prescription.

Obesity is a complex, multifactorial and chronic disease. Bariatric surgery is a safe and effective treatment intervention for obesity and obesity-related diseases. However, weight loss after surgery can be highly heterogeneous and is not entirely predictable, particularly in the long-term after intervention. In this review, we present and discuss the available data on patient-related and procedure-related factors that were previously appointed as putative predictors of bariatric surgery outcomes. In addition, we present a critical appraisal of the available evidence on which factors could be taken into account when recommending and deciding which bariatric procedure to perform. Several patient-related features were identified as having a potential impact on weight loss after bariatric surgery, including age, gender, anthropometrics, obesity co-morbidities, eating behavior, genetic background, circulating biomarkers (microRNAs, metabolites and hormones), psychological and socioeconomic factors. However, none of these factors are sufficiently robust to be used as predictive factors. Overall, there is no doubt that before we long for precision medicine, there is the unmet need for a better understanding of the socio-biological drivers of weight gain, weight loss failure and weight-regain after bariatric interventions. Machine learning models targeting preoperative factors and effectiveness measurements of specific bariatric surgery interventions, would enable a more precise identification of the causal links between determinants of weight gain and weight loss. Artificial intelligence algorithms to be used in clinical practice to predict the response to bariatric surgery interventions could then be created, which would ultimately allow to move forward into precision medicine in bariatric surgery prescription.

Accuracy of prediction models for long-term type 2 diabetes remission after gastric bypass.

AIM: To evaluate the accuracy of DiaBetter, DiaRem, Ad-DiaRem and 5y-Ad-DiaRem scores' at predicting T2D remission 10 or more years after surgery. METHODS: Patients with obesity and T2D (n = 126) submitted to RYGB with 10 or more years of follow-up. It was a unicentric trial. Pre-operative anthropometric and clinical data was retrieved to calculate DiaRem, DiaBetter, Ad-DiaRem and 5y-Ad-DiaRem scores, while a hospital visit was conducted to assess current diabetes status. The area under the receiver operating characteristic (AUROC) curve was calculated as estimate of the scores' accuracy to predict long-term T2D remission. RESULTS: Among the entire cohort (n = 126), 70 subjects (55.6%) achieved and maintained T2D remission 10 or more years after RYGB. The 5y-Ad-DiaRem score was the one that depicted the highest discriminative power (AUROC = 0.838) to predict long-term T2D remission when compared to DiaBetter (AUROC = 0.735), DiaRem (AUROC = 0.721) and Ad-DiaRem (AUROC = 0.720). CONCLUSION: The score with highest accuracy to predict long-term T2D remission after RYGB surgery was the 5y-Ad-DiaRem. Yet, the available scores accuracy to predict T2D remission in the long term is still suboptimal, highlighting the unmet need for a better scoring system.

Individuals with type 2 diabetes have higher density of small intestinal neurotensin-expressing cells.

Neurotensin (NT) is a gastro-intestinal hormone involved in several pathways that regulate energy and glucose homeostasis. NT was hypothesized to act in synergy with incretin hormones to potentiate its anti-diabetic effects. Additionally, circulating NT levels were shown to rise after bariatric surgery-induced weight loss. Knowledge of NT-secreting cells distribution along the small intestine and its variation according to diabetes status could provide insights on NT role in mediating type 2 diabetes (T2D) improvement after bariatric surgery. So, our aims were to characterize NT-expressing cell distribution along the human small intestine and to compare the relative density of NT-expressing cells in the small intestine of individuals with and without T2D undergoing bariatric surgery for obesity treatment. Autopsy-derived small intestine fragments (n = 30) were obtained at every 20 cm along the entire intestinal length. Additionally, jejunum biopsies (n = 29) were obtained during elective gastric bypass interventions from patients with (n = 10) or without T2D (n = 18). NT-expressing cells were identified by immunohistochemistry and quantified via computerized morphometric analysis. NT-expressing cell density increased along the human small intestine. NT-expressing cell density was significantly higher from 200 cm distal to the duodenojejunal flexure onward, as well as in subjects with T2D when compared to those without T2D. NT-expressing cell density increases along the human small gut, and a higher density is found in individuals with T2D. This finding suggests a potential role for NT in the mechanisms of disease and T2D improvement observed after bariatric surgery.

Regular Voluntary Running is Associated with Increased Tumor Vascularization and Immune Cell Infiltration and Decreased Tumor Growth in Mice.

Tumors present dysfunctional vasculature that limits blood perfusion and hinders immune cells delivery. We aimed to investigate if regular voluntary running promotes tumor vascular remodelling, improves intratumoral immune cells infiltration and inhibits tumor growth. Tumors were induced in C57BL/6 male mice (n=28) by subcutaneous inoculation in the dorsal region with a suspension of RM1 cells (1.5×105 cells/500 µL PBS) and randomly allocated into two groups: sedentary (n=14) and voluntarily exercised on a wheel (n=14). Seven mice from each group were sacrificed 14 and 28 days after cells' inoculation to evaluate tumor weight, microvessel density, vessels' lumen regularity and the intratumoral quantity of NKG2D receptors, CD4+and CD8+T cells, by immunohistochemistry. The statistical inference was done through a two-way ANOVA. Exercised mice developed smaller tumors at 14 (0.17±0.1 g vs. 0.48±0.2 g, p<0.05) and 28 (0.92±0.7 g vs. 2.09±1.3 g, p<0.05) days, with higher microvessel density (21.20±3.2 vs. 15.86±4.0 vessels/field, p<0.05), more regular vessels' lumen (1.06±0.2 vs. 1.43±0.2, p<0.05), and higher CD8+T cells (464.95±48.0 vs. 364.70±49.4 cells/mm2, p<0.01), after 28 days. NKG2D expression was higher in exercised mice at 14 (263.27±25.8 cells/mm2, p<0.05) and 28 (295.06±56.2 cells/mm2, p<0.001) days. Regular voluntary running modulates tumor vasculature, increases immune cells infiltration and attenuates tumor growth, in mice.

Are SADI-S and BPD/DS bariatric procedures identical twins or distant relatives? - A case report.

Given the common anatomical features and similar short-term weight loss outcomes, Biliopancreatic Diversion with Duodenal Switch (BPD/DS) and Single-Anastomosis Duodenoileal bypass with Sleeve gastrectomy (SADI-S) are considered identical bariatric procedures, apart from technical complexity being lower for SADI-S. In the absence of prospective randomized trials or long-term comparative studies the rationale for choosing between procedures is hampered. Post-bariatric hormonal profiles could contribute to understand the underlying mechanisms and potentially be used as a decision aid when choosing between procedures. The main aim of this study was to compare the outcomes of BPD/DS and SADI-S, in genetically identical individuals exposed to similar environmental factors. Two identical twin (T) female patients, one submitted to BPD/DS (T_BPD/DS) and another to SADIS-S (T_SADI-S) were followed up to one year after surgery. Before surgery and at 3, 6 and 12 months after surgery, both patients underwent mixed meal tolerance tests (MMTT) to evaluate postprandial glucose, glucagon and GLP-1 response. In addition, 3 months after surgery, glucose dynamics were assessed using a Flash Glucose Monitoring (FGM) system for 14 days. The percentage of total weight loss (%TWL) was higher for T_BPD/DS compared to T_SADI-S (34.03 vs 29.03 %). During MMTT, T_BPD/DS presented lower glucose, glucagon, insulin and C-peptide excursions at all timepoints when compared to SADI-S; along with a greater percentage of time within the low glucose range (55.97 vs 39.93 %) and numerically lower glucose variability indexes on FGM (MAG change:0.51 vs 0.63 mmol/l×h-1). In patients with the same genetic background, BPD/DS was shown to result in greater weight loss than SADI-S. The differences in glucose and enteropancreatic hormone profiles observed after BPD/DS and SADI-S suggest that different mechanisms underlie weight loss.

Visceral Adipose Tissue Bioenergetics Varies According to Individuals' Obesity Class.

Obesity is associated with complex adipose tissue energy metabolism remodeling. Whether AT metabolic reprogramming differs according to body mass index (BMI) and across different obesity classes is unknown. This study's purpose was to evaluate and compare bioenergetics and energy substrate preference of visceral adipose tissue (VAT) pertaining to individuals with obesity class 2 and class 3. VAT obtained from patients with obesity (n = 15) class 2 (n = 7; BMI 37.53 ± 0.58 kg/m2) or class 3 (n = 8; BMI 47.79 ± 1.52 kg/m2) was used to assess oxygen consumption rate (OCR) bioenergetics and mitochondrial substrate preferences. VAT of patients with obesity class 3 presented significantly higher non-mitochondrial oxygen consumption (p < 0.05). In VAT of patients with obesity class 2, inhibition of pyruvate and glutamine metabolism significantly decreased maximal respiration and spare respiratory capacity (p < 0.05), while pyruvate and fatty acid metabolism inhibition, which renders glutamine the only available substrate, increased the proton leak with a protective role against oxidative stress (p < 0.05). In conclusion, VAT bioenergetics of patients with obesity class 2 depicts a greater dependence on glucose/pyruvate and glutamine metabolism, suggesting that patients within this BMI range are more likely to be responsive to interventions based on energetic substrate modulation for obesity treatment.

Prolonged Fasting Induces Histological and Ultrastructural Changes in the Intestinal Mucosa That May Reduce Absorption and Revert after Enteral Refeeding.

Background: Malnutrition is usual in patients referred for endoscopic gastrostomy (PEG). Refeeding syndrome is rarely observed in PEG-fed patients, which could possibly be associated with reduced absorption induced by prolonged starvation. Objective: In patients submitted to PEG after a significant period of fasting, the present study aims to: 1. evaluate the histological/ultrastructural initial changes in the intestinal mucosa, potentially associated with reduced absorption, and 2. assess if these changes could reverse with enteral refeeding. Methods: The present study is an observational, prospective, controlled study. Adult patients with ingestion below 50% of daily needs for at least one month and/or diagnosis of malnutrition were enrolled. Duodenal biopsies were taken at baseline and after 3-6 months of PEG feeding, which then underwent histological/ultrastructural analysis. Random healthy individuals were used as controls. Results: A total of 30 patients (16 men/14 women) aged 67.1 ± 13.5 years were included. Malnutrition was found in 40% of patients. Approximately 14 patients completed follow-up during both periods (46.7%). At baseline: duodenal mucosal atrophy was evident in three patients (10%); the median villi length (MVL) was 0.4 mm (0.25-0.6 mm), with it being shorter than the controls, which was 0.6 mm (0.4-0.7 mm) (p = 0.006); ultrastructural changes included focal shortening, bending, and disruption of enterocyte microvilli, the presence of citoplasmatic autophagic vacuoles, dilation and vesiculation of the smooth endoplasmic reticulum, and the presence of dilated intercellular spaces with basement membrane detachment. After refeeding, most patients displayed normal histology (92.9%) and increase MVL (p < 0.001), ultrastructural changes disappeared, and enterocytes resumed a normal appearance, although retaining scarce, small, dense bodies in apical regions from the evolution of previous autophagy. Conclusions: Prolonged fasting induces histological and ultrastructural changes in the intestinal mucosa that may reflect impaired absorption in the early post-PEG period. These changes were reverted after refeeding with enteral nutrition.

Colon tumor CD31 expression is associated with higher disease-free survival in patients with metabolic syndrome.

Metabolic syndrome (MS) is recognized as a risk factor for colon cancer (CC). However, how does the interplay between metabolic dysfunction caused by MS and its individual components affect CC microenvironment and prognosis remains unexplored. Angiogenesis and lymphangiogenesis are fundamental processes for tumor progression and dissemination, ensuring oxygen and nutrient delivery and supporting one of the most important pathways of tumor dissemination, contributing to metastasis. Thus, our aim was to evaluate whether the expression of molecular biomarkers involved in angiogenic and lymphangiogenic processes influenced CC clinicopathological features and prognosis in patients with MS. Clinical and pathological data of 300 patients submitted to CC surgical resection at a single tertiary hospital were retrospectively retrieved from hospital records. Tumor tissue microarrays of archived paraffin-embedded blocks were used to assess CD31, VEGF-A and D2-40 tissue expression by immunohistochemistry. The percentage of stained area was quantified by computerized morphometric analysis. No association between tissue expression of angiogenesis and lymphangiogenesis biomarkers and tumor clinical and pathological characteristics was found. However, in subgroup analysis of patients with MS, dysglycemia was associated with lower D2-40 expression (p = 0.007) and high waist-circumference was associated with higher D2-40 (p = 0.0029) and VEGF-A expression (p = 0.026). In an adjusted Cox proportional hazard model CD31 expression was significantly associated with greater disease-free survival (HR=0.62; 95% CI: 0.41-0.95, p = 0.028). No association was found between D2-40 and VEGF-A expression and CC prognosis. Our data reinforces previous reports that suggest the potential use of CD31 as a CC prognostic biomarker. Additionally, our data further supports the evidence for an interplay between metabolic dysfunction, tumor microenvironment, and vascularization pathways.

Modulation of Autophagy in Adrenal Tumors.

Adrenal masses are one of the most common tumors in humans. The majority are benign and non-functioning and therefore do not require immediate treatment. In contrast, the rare adrenal malignant tumors are often highly aggressive and with poor prognosis. Besides usually being detected in advanced stages, often already with metastases, one of the reasons of the unfavorable outcome of the patients with adrenal cancer is the absence of effective treatments. Autophagy is one of the intracellular pathways targeted by several classes of chemotherapeutics. Mitotane, the most commonly used drug for the treatment of adrenocortical carcinoma, was recently shown to also modulate autophagy. Autophagy is a continuous programmed cellular process which culminates with the degradation of cellular organelles and proteins. However, being a dynamic mechanism, understanding the autophagic flux can be highly complex. The role of autophagy in cancer has been described paradoxically: initially described as a tumor pro-survival mechanism, different studies have been showing that it may result in other outcomes, namely in tumor cell death. In adrenal tumors, this dual role of autophagy has also been addressed in recent years. Studies reported both induction and inhibition of autophagy as a treatment strategy of adrenal malignancies. Importantly, most of these studies were performed using cell lines. Consequently clinical studies are still required. In this review, we describe what is known about the role of autophagy modulation in treatment of adrenal tumors. We will also highlight the aspects that need further evaluation to understand the paradoxical role of autophagy in adrenal tumors.

Ang-Tie Angiogenic Pathway Is Distinctively Expressed in Benign and Malignant Adrenocortical Tumors.

The differential diagnosis between adrenocortical adenomas (ACAs) and adrenocortical carcinomas (ACCs) relies on unspecific clinical, imaging and histological features, and, so far, no single molecular biomarker has proved to improve diagnostic accuracy. Similarly, prognostic factors have an insufficient capacity to predict the heterogeneity of ACC clinical outcomes, which consequently lead to inadequate treatment strategies. Angiogenesis is a biological process regulated by multiple signaling pathways, including VEGF and the Ang-Tie pathway. Many studies have stressed the importance of angiogenesis in cancer development and metastasis. In the present study, we evaluated the expression of VEGF and Ang-Tie pathway mediators in adrenocortical tumors (ACTs), with the ultimate goal of assessing whether these molecules could be useful biomarkers to improve diagnostic accuracy and/or prognosis prediction in ACC. The expression of the proteins involved in angiogenesis, namely CD34, VEGF, VEGF-R2, Ang1, Ang2, Tie1 and Tie2, was assessed by immunohistochemistry in ACC (n = 22), ACA with Cushing syndrome (n = 8) and non-functioning ACA (n = 13). ACC presented a significantly higher Ang1 and Ang2 expression when compared to ACA. Tie1 expression was higher in ACC with venous invasion and in patients with shorter overall survival. In conclusion, although none of these biomarkers showed to be useful for ACT diagnosis, the Ang-Tie pathway is active in ACT and may play a role in regulating ACT angiogenesis.

Metabolomic signatures after bariatric surgery - a systematic review.

Metabolomics emerged as an important tool to gain insights on how the body responds to therapeutic interventions. Bariatric surgery is the most effective treatment for severe obesity and obesity-related co-morbidities. Our aim was to conduct a systematic review of the available data on metabolomics profiles that characterize patients submitted to different bariatric surgery procedures, which could be useful to predict clinical outcomes including weight loss and type 2 diabetes remission. For that, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses - PRISMA guidelines were followed. Data from forty-seven original study reports addressing metabolomics profiles induced by bariatric surgery that met eligibility criteria were compiled and summarized. Amino acids, lipids, energy-related and gut microbiota-related were the metabolite classes most influenced by bariatric surgery. Among these, higher pre-operative levels of specific lipids including phospholipids, long-chain fatty acids and bile acids were associated with post-operative T2D remission. As conclusion, metabolite profiling could become a useful tool to predict long term response to different bariatric surgery procedures, allowing more personalized interventions and improved healthcare resources allocation.

High-intensity infrasound effects on glucose metabolism in rats.

Recent focus has been given on the effects of high-intensity infrasound (HII) exposure, and whether it induces changes in pancreatic morphology and glucose metabolism is still unknown. As such, we have studied the impact of HII exposure on glucose tolerance, insulin sensitivity, pancreatic islet morphology, muscle GLUT4 and plasma insulin and corticosterone levels. Normal and glucose intolerant wild-type Wistar rats were randomly divided in two groups: one group not exposed to HII and the other continuously exposed to HII. Animals were sacrificed at three timepoints of exposure (1, 6 or 12 weeks). An intraperitoneal glucose tolerance test was performed, blood samples were collected and the pancreas and the quadriceps femoris muscle were excised. Circulating insulin and corticosterone levels were determined and pancreatic and muscular tissue were routinely processed for histochemistry and immunohistochemistry with an anti-GLUT4 antibody. Animals exposed to HII had higher corticosterone levels than animals not exposed. No differences were found on insulin concerning HII exposure or glucose intolerance. Glucose intolerant animals had pancreatic islet fibrosis and no differences were found in GLUT4 ratio concerning HII exposure. In conclusion, we found that continuous exposure to HII increases stress hormone levels without inducing glucose intolerance in rats.

Bariatric Surgery Outcomes in Patients with Latent Autoimmune Diabetes of the Adult.

Bariatric surgery is a very effective treatment for obesity-associated type 2 diabetes. However, the benefits of bariatric surgery in patients with obesity and autoimmune diabetes, such as type 1 diabetes and latent autoimmune diabetes in adults (LADA), are controversial. We report 3 female patients with obesity and LADA who underwent laparoscopic Roux-en-Y gastric bypass >10 years ago. The patients were diagnosed with LADA both 1 and 9 years before (n = 2) or 11 years after the surgery (n = 1). Patients preoperative body mass index ranged from 36 to 47 kg/m2 and improved to 23-37 kg/m2 in the last follow-up visit, 10-15 years after surgery. Daily insulin dose also decreased from an average of 0.68 to 0.45 IU/kg in those patients treated with insulin before bariatric surgery. Only one patient developed diabetes-related target organ damage. This study shows that patients with LADA depict remarkable reduction of body weight and insulin requirements over long-term after bariatric surgery. So, LADA should not be considered a contraindication for bariatric surgery yet should only be recommended for patients with concomitant obesity with the primary aim of achieving sustained weight loss.