Ana M. Ramos-Leví

Single-anastomosis duodenoileal bypass with sleeve gastrectomy (SADI-S) for obese diabetic patients

BACKGROUND Bariatric operations achieve a high remission rate of type 2 diabetes in patients with morbid obesity. Malabsorptive operations usually are followed by a higher rate of metabolic improvement, though complications and secondary effects of these operations are usually higher. OBJECTIVES Analyze the results of a simplified duodenal switch, the single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) on patients with obesity and type 2 diabetes mellitus (T2 DM). SETTING University Hospital, Madrid, Spain. METHODS Ninety-seven T2 DM patients with a mean body mass index (BMI) of 44.3 kg/m(2) were included. Mean preoperative glycated hemoglobin was 7.6%, and mean duration of the disease was 8.5 years. Forty patients were under insulin treatment. SADI-S was completed with a sleeve gastrectomy performed over a 54 French bougie and a 200 cm common limb in 28 cases and 250 cm in 69. RESULTS Follow up was possible for 86 patients (95.5%) in the first postoperative year, 74 (92.5%) in the second, 66 (91.6%) in the third, 46 (86.7%) in the fourth and 25 out of 32 (78%) in the fifht postoperative year. Mean glycemia and glycated hemoglobin decreased immediately. Control of the disease, with HbA1c below 6%, was obtained in 70 to 84% in the long term, depending on the initial antidiabetic therapy. Most patients abandoned antidiabetic therapy after the operation. Absolute remission rate was higher for patients under oral therapy than for those under initial insulin therapy, 92.5% versus 47% in the first postoperative year, 96.4% versus 56% in the third and 75% versus 38.4% in the fifth. A short diabetes history and no need for insulin were related to a higher remission rate. Three patients had to be reoperated for recurrent hypoproteinemia. CONCLUSION SADI-S is an effective therapeutic option for obese patients with diabetes mellitus.

Cabergoline treatment in acromegaly: pros

Many options are available for the treatment of acromegaly, including surgery, radiotherapy, and medical treatment. Cabergoline (CAB), a dopamine agonist with high affinity for dopamine receptor type 2, has been used both in monotherapy and in conjunction with somatostatin analogs (SSAs). Although it is administered orally and has a relatively lower-cost in comparison with SSAs, few studies have demonstrated its usefulness, there is a lack of randomized-controlled trials and other drugs (SSAs and pegvisomant) with more data in the literature are available; these issues are the main drawbacks of adopting CAB for the treatment of acromegaly.

Risk Factors for Gestational Diabetes Mellitus in a Large Population of Women Living in Spain: Implications for Preventative Strategies

The aim of this study is to establish a risk appraisal model for GDM by identifying modifiable factors that can help predict the risk of GDM in a large population of 2194 women living in Spain. They were recruited between 2009-2010 when screening for GDM was performed. Participants completed a questionnaire on socio-demographic, anthropomorphic and behavioral characteristics, and reproductive and medical history. A total of 213 (9.7%) women were diagnosed as having GDM. Age, pregestational body weight (BW) and body mass index (BMI), and number of events of medical, obstetric and family history were significantly associated with GDM. After logistic regression model, biscuits and pastries intake <4 times/week, red and processed meats intake <6 servings/week, sugared drinks <4 servings/week, light walking >30 minutes/day, and 30 minutes/day of sports at least 2 days/week, compared with opposite consumption, was associated with less GDM risk. Our study identified several pregestational modifiable lifestyle risk factors associated with an increase in the risk of developing GDM. This may represent a promising approach for the prevention of GDM and subsequent complications. Further intervention studies are needed to evaluate if this appraisal model of risk calculation can be useful for prevention and treatment of GDM.

Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors

Purpose Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors, and their biological behavior is not well known. We studied the presence and potential functional roles of somatostatin receptors (sst1-5), focusing particularly on the truncated variants (sst5TMD4, sst5TMD5) and on their relationships with the angiogenic system (Ang/Tie-2 and VEGF) in human GEP-NETs. Experimental Design We evaluated 42 tumor tissue samples (26 primary/16 metastatic) from 26 patients with GEP-NETs, and 30 non-tumoral tissues (26 from adjacent non-tumor regions and 4 from normal controls) from a single center. Expression of sst1-5, sst5TMD4, sst5TMD5, Ang1-2, Tie-2 and VEGF was analyzed using real-time qPCR, immunofluorescence and immunohistochemistry. Expression levels were associated with tumor characteristics and clinical outcomes. Functional role of sst5TMD4 was analyzed in GEP-NET cell lines. Results sst1 exhibited the highest expression in GEP-NET, whilst sst2 was the most frequently observed sst-subtype (90.2%). Expression levels of sst1, sst2, sst3, sst5TMD4, and sst5TMD5 were significantly higher in tumor tissues compared to their adjacent non-tumoral tissue. Lymph-node metastases expressed higher levels of sst5TMD4 than in its corresponding primary tumor tissue. sst5TMD4 was also significantly higher in intestinal tumor tissues from patients with residual disease of intestinal origin compared to those with non-residual disease. Functional assays demonstrated that the presence of sst5TMD4 was associated to enhanced malignant features in GEP-NET cells. Angiogenic markers correlated positively with sst5TMD4, which was confirmed by immunohistochemical/fluorescence studies. Conclusions sst5TMD4 is overexpressed in GEP-NETs and is associated to enhanced aggressiveness, suggesting its potential value as biomarker and target in GEP-NETs.

Metabolic surgery: Quo Vadis?

The impact of bariatric surgery beyond its effect on weight loss has entailed a change in the way of regarding it. The term metabolic surgery has become more popular to designate those interventions that aim at resolving diseases that have been traditionally considered as of exclusive medical management, such as type 2 diabetes mellitus (T2D). Recommendations for metabolic surgery have been largely addressed and discussed in worldwide meetings, but no definitive consensus has been reached yet. Rates of diabetes remission after metabolic surgery have been one of the most debated hot topics, with heterogeneity being a current concern. This review aims to identify and clarify controversies regarding metabolic surgery, by focusing on a critical analysis of T2D remission rates achieved with different bariatric procedures, and using different criteria for its definition. Indications for metabolic surgery for patients with T2D who are not morbidly obese are also discussed.

Levels of regulatory T cells CD69+NKG2D+IL-10+ are increased in patients with autoimmune thyroid disorders

Abstract Regulatory T (Treg) cells play an important role in the pathogenesis of autoimmune thyroid disorders (AITD). New subsets of CD4+CD69+ and CD4+NKG2D+ T lymphocytes that behave as regulatory cells have been recently reported. The role of these immunoregulatory lymphocytes has not been previously explored in AITD. We analyzed by multi-parametric flow cytometry different Treg cell subsets in peripheral blood from 32 patients with AITD and 19 controls, and in thyroid tissue from seven patients. The suppressive activity was measured by an assay of inhibition of lymphocyte activation. We found a significant increased percentage of CD4+CD69+IL-10+, CD4+CD69+NKG2D+, and CD4+CD69+IL-10+NKG2D+ cells, in peripheral blood from GD patients compared to controls. The increase in CD4+CD69+IL-10+ and CD4+CD69+IL-10+NKG2D+ T cells was especially remarkable in patients with active Graves’ ophthalmopathy (GO), and a significant positive correlation between GO activity and CD4+CD69+IL-10+ or CD4+CD69+IL-10+NKG2D+ cells was also found. In addition, these cells were increased in patients with a more severe and/or prolonged disease. Thyroid from AITD patients showed an increased proportion of CD69+ regulatory T cells subpopulations compared to autologous peripheral blood. The presence of CD69+, NKG2D+, and IL-10+ cells was confirmed by immunofluorescence microscopy. In vitro functional assays showed that CD69+ Treg cells exerted an important suppressive effect on the activation of T effector cells in controls, but not in AITD patients. Our findings suggest that the levels of CD69+ regulatory lymphocytes are increased in AITD patients, but they are apparently unable to down-modulate the autoimmune response and tissue damage.

C-peptide levels predict type 2 diabetes remission after bariatric surgery

BACKGROUND C-peptide (Cp) serves as a surrogate of pancreatic beta-cell reserve. This study evaluates the clinical significance of basal Cp as a predictor of type 2 diabetes (T2D) remission after bariatric surgery (BS). RESEARCH DESIGN AND METHODS Retrospective study of 22 patients with BMI > 35 kg/m² and T2D who underwent BS. Evaluation of anthropometric and glucose metabolism parameters before BS and at one-year follow-up. Analysis of patients with T2D remission (HbA1c < 6%, fasting glucose (FG) < 100 mg/dl, absence of pharmacologic treatment) and preoperative characteristics associated (logistic binary regression model). ROC curve to estimate an optimal Cp value to predict T2D remission. RESULTS Preoperativeley (mean ± SD): age 53.3 ± 9.4 years, BMI 42.9 ± 6.8 kg/m², T2D duration 6.9 ± 5.2 years, FG 159.6 ± 56.6 mg/dL, HbA1c 7.5 ± 1.1%, Cp 4.0 ± 2.0 (median 3.8, range 0.1-8.9) ng/mL. At one year follow-up, remission of T2D in 12 cases (54.5%). Preoperative Cp correlated with 12-month HbA1c (r = -0.519, p = 0.013). Preoperative Cp was higher in those who achieved remission: 5.0 ± 1.7 vs 3.0 ± 1.7 ng/ml, p = 0,013. A Cp concentration > 3.75 ng/mL provided a clinically useful cut-off for prediction of T2D remission. T2D remission rates were different according to median preoperative Cp: 27.3% if Cp < 3.8 ng/mL and 81.7% if Cp > 3.8 ng/mL (p = 0.010). CONCLUSIONS Patients with elevated preoperative Cp levels achieve higher rates of T2D remission one year after BS. A Cp concentration > 3.75 ng/mL seems clinically useful.

Circulating Microvesicles Regulate Treg and Th17 Differentiation in Human Autoimmune Thyroid Disorders

BACKGROUND Microvesicles (MVs) are emerging as important contributors to the development of inflammatory and autoimmune diseases. MVs can mediate immune modulation carrying genetic information, including microRNAs that can be transferred between cells. DESIGN We determined the plasma levels of annexin-V+ MVs derived from different immune cells and platelets in patients with autoimmune thyroid diseases (AITDs) and in healthy controls. T lymphocyte polarization assays were performed in the presence of MVs to evaluate their effect in T regulatory and T helper 17 cells differentiation. microRNA content into plasma MVs and their corresponding mRNA targets were evaluated by RT-PCR. RESULTS The percentage of platelet-derived MVs (CD41a+) was significantly increased in plasma samples from AITD patients compared with healthy controls. In contrast, patients with AITD showed a lower percentage of leukocyte and endothelial cell-derived MVs compared with controls. In addition, functional assays showed that MVs from AITD patients inhibited the in vitro differentiation of Foxp3+ T regulatory cells (11.35% vs 4.40%, P = .01) and induced the expression of interferon-γ by CD4+ lymphocytes (10.91% vs 13.99%, P = .01) as well as the differentiation of T helper 17 pathogenic (IL-17+interferon-γ+) cells (1.98% vs 5.13%, P = .03). Furthermore, in AITD patients, whereas miR-146a and miR-155 were increased in circulating MVs, their targets IL-8 and SMAD4 were decreased in peripheral blood mononuclear cells. CONCLUSIONS Our data indicate that circulating MVs seem to have a relevant role in the modulation of the inflammatory response observed in AITD.

Update on pharmacology of obesity: Benefts and risks

The prevalence of obesity in Western countries has increased at a much greater pace than the development of new efficient and safe drugs, beyond mere lifestyle changes, for the treatment of overweight. Numerous different types of drugs which had been used in the past for the treatment of obesity have currently been withdrawn due to undesirable long-term side effects. The only available drug in Europe is orlistat, which serves only as an aid for the treatment of obesity. In the USA, however, a few central adrenergic-mediators, for instance, diethylpropion and phentermine, have been available for decades to treat obesity during a short-term period (less than 12 weeks). The Food and Drug Administration (FDA) has recently approved lorcaserin and the combination phentermine/ topiramate for the treatment of obesity. The first one is a selective serotonin 2C receptor agonist that works by decreasing food intake with few side effects. Its outcomes on weight are modest, but may be helpful in certain selected patients. The phentermine/topiramate combination has proved to be highly effective, achieving a 10% reduction in weight in the majority of patients, although attention must be drawn to the possible development of side effects in both the short and the long-term follow-up. Further investigation regarding the mechanisms involved in weight balance will anticipate the development of new expectations for the treatment of obesity in the near future.

Graves’ Disease Is Associated with a Defective Expression of the Immune Regulatory Molecule Galectin-9 in Antigen-Presenting Dendritic Cells

Introduction Patients with autoimmune thyroid disease (AITD) show defects in their immune-regulatory mechanisms. Herein we assessed the expression and function of galectin-1 and galectin-9 (Gal-1, Gal-9) in dendritic cells (DCs) from patients with AITD. Materials and Methods Peripheral blood samples from 25 patients with Graves’ disease (GD), 11 Hashimoto’s thyroiditis (HT), and 24 healthy subjects were studied. Thyroid tissue samples from 44 patients with AITD and 22 patients with goiter were also analyzed. Expression and function of Gal-1 and Gal-9 was assessed by quantitative RT-PCR, immunofluorescence and flow cytometry. Results A diminished expression of Gal-9, but not of Gal-1, by peripheral blood DCs was observed in GD patients, mainly in those with Graves´ ophthalmopathy, and a significant negative association between disease severity and Gal-9 expression was detected. In addition, the mRNA levels of Gal-9 and its ligand TIM-3 were increased in thyroid tissue from AITD patients and its expression was associated with the levels of Th1/Th12/Th17 cytokines. Immunofluorescence studies proved that intrathyroidal Gal-9 expression was confined to DCs and macrophages. Finally, in vitro functional assays showed that exogenous Gal-9 had a suppressive effect on the release of Th1/Th2/Th17 cytokines by DC/lymphocyte autologous co-cultures from both AITD patients and healthy controls. Conclusions The altered pattern of expression of Gal-9 in peripheral blood DCs from GD patients, its correlation with disease severity as well as its ability to suppress cytokine release suggest that Gal-9 could be involved in the pathogenesis of AITD.