Interindividual differences in the clinical effectiveness of liraglutide in Type 2 diabetes: a real-world retrospective study conducted in Spain.

AIMS: To study the response of clinical variables (HbA1c , body weight, lipid profile and blood pressure) over 24 months of liraglutide treatment in a real-world clinical setting, and to describe the evolution of HbA1c and body weight reduction in response to liraglutide treatment by employing generalized additive mixed models (GAMMs). METHODS: We included people aged ≥ 18 years with Type 2 diabetes mellitus that initiated liraglutide treatment between November 2011 and May 2015. Demographic and clinical data were retrieved retrospectively over 24 months from electronic medical records with a median duration of observation of 7.0 (IQR 3.0-12.0) months. RESULTS: Individuals that initiated liraglutide therapy were obese (BMI 39.1 kg/m2 ), with inadequate HbA1c (68 mmol/mol [8.4%]), blood pressure and lipid levels. Upon liraglutide treatment, HbA1c , body weight, mean systolic and diastolic blood pressure, and lipid levels decreased gradually. GAMMs demonstrated that longer treatment with liraglutide was a predictor of improved HbA1c response, whereas higher baseline HbA1c , longer Type 2 diabetes duration and treatment with insulin were predictors of worse HbA1c response. Higher baseline weight, longer treatment with liraglutide and the interaction between metformin and time were predictors of improved weight response. CONCLUSIONS: In this real-world study, we showed the effectiveness of liraglutide in improving body weight, HbA1c , mean systolic and diastolic blood pressure, and lipid levels. GAMMs indicated that baseline HbA1c and weight, time of treatment with liraglutide, diabetes duration and the use of metformin or insulin are predictors of clinical response to liraglutide.

Hepatic CD36 downregulation parallels steatosis improvement in morbidly obese undergoing bariatric surgery.

BACKGROUND: The notion that hepatic expression of genes involved in lipid metabolism is altered in obese patients is relatively new and its relationship with hepatic steatosis and cardiometabolic alterations remains unclear. OBJECTIVE: We assessed the impact of Roux-en-Y gastric bypass surgery (RYGB) on the expression profile of genes related to metabolic syndrome in liver biopsies from morbidly obese individuals using a custom-made, focused cDNA microarray, and assessed the relationship between the expression profile and hepatic steatosis regression. MATERIALS AND METHODS: Plasma and liver samples were obtained from patients at baseline and 12 months after surgery. Samples were assayed for chemical and gene expression analyses, as appropriate. Gene expression profiles were assessed using custom-made, focused TaqMan low-density array cards. RESULTS: RYGB-induced weight loss produced a favorable reduction in fat deposits, insulin resistance (estimated by homeostasis model assessment of insulin resistance (HOMA-IR)), and plasma and hepatic lipid levels. Compared with the baseline values, the gene expression levels of key targets of lipid metabolism were significantly altered: CD36 was significantly downregulated (-40%; P=0.001), whereas APOB (+27%; P=0.032) and SCARB1 (+37%; P=0.040) were upregulated in response to surgery-induced weight reduction. We also observed a favorable reduction in the expression of the PAI1 gene (-80%; P=0.007) and a significant increase in the expression of the PPARA (+60%; P=0.014) and PPARGC1 genes (+36%; P=0.015). Notably, the relative fold decrease in the expression of the CD36 gene was directly associated with a concomitant reduction in the cholesterol (Spearman's r=0.92; P=0.001) and phospholipid (Spearman's r=0.76; P=0.04) contents in this tissue. CONCLUSIONS: For the first time, RYGB-induced weight loss was shown to promote a favorable downregulation of CD36 expression, which was proportional to a favorable reduction in the hepatic cholesterol and phospholipid contents in our morbidly obese subjects following surgery.

Sleep biosignature of Type 2 diabetes: a case-control study.

AIM: To determine whether or not the sleep disturbances associated with Type 2 diabetes affect the structure of sleep. METHODS: We designed a case-control study in 76 patients with Type 2 diabetes and 76 control subjects without Type 2 diabetes, matched by age, gender, BMI and waist and neck circumferences. A subgroup of 32 patients with Type 2 diabetes was also matched with 64 control subjects without Type 2 diabetes according to apnoea-hypopnoea index score. Examination included an overnight full polysomnography. RESULTS: No differences in the percentage of time spent in either rapid eye movement or non-rapid eye movement sleep were observed between groups; however, patients with Type 2 diabetes had more microarousal events during sleep than control subjects [41.4 (total range 4.0-104.4) vs 20.7 (total range 1.3-94.5) events/h; P < 0.001]. These differences were mainly observed during the non-rapid eye movement sleep [7.4 (total range 0-107.2) vs 0.2 (total range 0-65.2) events/h; P < 0.001]. In addition, sleep variables related to oxygen saturation measures, such as the percentage of time spent with oxygen saturation ≤90%, were significantly greater during the rapid eye movement sleep in patients with Type 2 diabetes [20.3 (total range 0-99.2) vs. 10.5 (total range 0-94.0)%; P = 0.047]. This pattern was maintained in the subgroup of patients matched by apnoea-hypopnaea index. Finally, stepwise regression analyses showed that apnoea-hypopnoea index, the presence of Type 2 diabetes and fasting plasma glucose value were independently associated with the number of microarousals (R2 =0.667). CONCLUSIONS: Type 2 diabetes is associated with an altered sleep structure, with different effects according to rapid eye movement (increase in nocturnal hypoxia) or non-rapid eye movement (increase in sleep fragmentation) sleep.

TNF-α system and lung function impairment in obesity.

A potential interaction between pulmonary function, abnormal adipose tissue activity, and systemic inflammation has been suggested. This study explores the relationship between circulating soluble TNF-α receptors (sTNF-R1 and sTNF-R2) and respiratory function parameters in obese subjects. Thirty-one non-diabetic morbidly obese women with a history of non-smoking and without prior cardiovascular or respiratory disease were prospectively recruited in the outpatient Obesity Unit of a referral center. Pulmonary function test included a forced spirometry, static pulmonary volume measurements, non-attended respiratory polygraphy, and arterial gas blood sampling. Circulating levels of sTNFR-R1, sTNF-R2, interleukine 6 and adiponectin were determined using ELISA. Statistical analysis included a multivariate regression analysis taking into account the potential confounders. sTNF-R1 positively correlated with BMI (r=0.571, p=0.001) and arterial carbon dioxide pressure (PaCO(2), r=0.381, p=0.038), but negatively with forced expiratory volume in 1s (FEV(1), r=-0.437, p=0.012), maximum midexpiratory flow (FEF(25-75), r=-0.370, p=0.040) and forced vital capacity (FVC, r=-0.483, p=0.005). However, no correlation between sTNF-R2 and BMI and either pulmonary function tests or arterial blood samples was observed. Multiple linear regression analysis showed that sTNF-R1 independently predicted FEV(1) (beta=-0.437, p=0.012) and FVC (beta=-0.483, p=0.005). Thus, circulating levels of sTNF-R1, but not sTNF-R2, are related to reduced lung volumes and airflow limitation in morbidly obese patients prior to the development of a clinically recognized respiratory disease. Therefore, studies addressed to evaluating the potential beneficial effect of anti-TNF-α agents on pulmonary function tests in obese subjects seem warranted.

Type 2 diabetes impairs pulmonary function in morbidly obese women: a case-control study.

AIMS/HYPOTHESIS: To determine whether the presence of type 2 diabetes and the degree of metabolic control are related to reduced pulmonary function in obese individuals. METHODS: Seventy-five morbidly obese women (25 with type 2 diabetes [cases]--and 50 without diabetes [controls]) with a history of non-smoking and without prior cardiovascular or respiratory disease were prospective recruited for a case-control study in the outpatient obesity unit of a referral centre. Both groups were closely matched by age, BMI and waist circumference. Pulmonary function test included forced spirometry and static pulmonary volume measurements. RESULTS: Type 2 diabetic patients showed lower forced expiratory volume at 1 s (FEV1) (mean difference -11.6% of predicted [95% CI -20.4 to -2.8]; p = 0.011), and FEV1/forced vital capacity (FEV1/FVC) ratio (mean difference -4.4% [95% CI -8.1 to -0.7]; p = 0.049), but a greater residual volume (RV) (mean difference 19.5% of predicted [95% CI 10.8-28.3]; p < 0.001). In addition, an obstructive ventilatory pattern was more frequent in diabetic patients. Significant negative correlations between FEV1 and fasting glucose, HbA1c and HOMA insulin resistance (HOMA-IR) were detected. By contrast, RV was positively correlated with fasting glucose, HbA1c and HOMA-IR. Multiple linear regression analyses showed that fasting glucose and HbA1c independently predicted FEV1 and RV. CONCLUSIONS/INTERPRETATION: The presence of diabetes and the degree of glycaemic control are related to respiratory function impairment in morbidly obese women. Therefore, the impact of type 2 diabetes on pulmonary function should be taken into consideration by those providing care for obese people.

Protein succination as a potential surrogate biomarker of airway obstruction. The ilervas project.

BACKGROUND: Airway obstruction (AO) is associated with hypoxemia, systemic inflammation and oxidative stress. These conditions can favor the formation of Advanced Glycation End-products (AGEs) and induce mitochondrial stress. The latter can alter metabolite intermediates in the Krebs cycle leading to the formation of the cysteine-fumarate adduct S-(2-succino) cysteine (2SC) in proteins (protein succination). Protein succination has not been described in airways diseases. RESEARCH QUESTION: To assess differences in levels of AGEs and 2SC between patients with AO and normal spirometry. STUDY DESIGN: and Methods: In this case-control study, we investigated 35 moderate to severe AO patients and 31 subjects with normal spirometry, matched for age, gender, body mass index (BMI), tobacco history, prediabetes and adherence to Mediterranean diet. Plasma 2SC and AGEs concentrations were measured by GS/MS, and AGEs in skin were determined measuring autofluorescence (SAF). Multivariate logistic regression models explored the association between AGEs in the skin, 2SC and the presence of AO. RESULTS: The population was predominantly middle-age (mean of 58.7 years-old), overweight (median of BMI 26.7 kg/m2) and male subjects (69.7%). Patients with AO showed higher values of SAF (p = 0.04) and 2SC (p = 0.047). No differences were observed for plasma AGEs. SAF and 2SC were significantly associated with the presence of AO after adjusting for age, gender, smoking history, BMI and Mediterranean diet score (p = 0.041 and p = 0.038, respectively). INTERPRETATION: Skin AGEs and 2SC are increased in patients with moderate to severe AO and independently associated with its presence. Further studies should confirm these findings and explore their potential role as a biomarker for the disease.

Lipoprotein lipase but not hormone-sensitive lipase activities achieve normality after surgically induced weight loss in morbidly obese patients.

BACKGROUND: Although bariatric surgery is currently the most common practice for inducing weight loss in morbidly obese patients (BMI>40 kg/m2), its effect on the lipid content of adipose tissue and its lipases (lipoprotein lipase [LPL] and hormone-sensitive lipase [HSL]) are controversial. METHODS: We analyzed LPL and HSL activities and lipid content from plasma as well as subcutaneous (SAT) and visceral (VAT) adipose tissue of 34 morbidly obese patients (MO) before and after (6 and 12 months) Roux-en-Y gastric bypass surgery and compare the values with those of normal weight (control) patients. RESULTS: LPL activity was significantly higher in MO (SAT=32.9+/-1.0 vs VAT=36.4+/-3.3 mU/g tissue; p<0.001) than in control subjects (SAT=8.2+/-1.4 vs VAT=6.8+/-1.0 mU/g tissue) in both adipose depots. HSL activity had similar values in both types of tissue (SAT=32.8+/-1.6 and VAT=32.9+/-1.6 mU/g) of MO. In the control group, we found similar results but with lower values (SAT=11.9+/-1.4 vs VAT=12.1+/-1.4 mU/g tissue). Twelve months after surgery, SAT LPL activity diminished (9.8+/-1.4 mU/g tissue, p<0.001 vs morbidly obese), while HSL (46.6+/-3.7 mU/g tissue) remained high. All lipids in tissue and plasma diminished after bariatric surgery except plasma nonesterified fatty acids, which maintained higher levels than controls (16+/-3 vs 9+/-0 mg/dL; p<0.001, respectively). CONCLUSIONS: When obese patients lose weight, they lose not only part of the lipid content of the cells but also the capacity to store triacylglycerides in SAT depots.

A Spanish Society joint SECO and SEEDO approach to the Post-operative management of the patients undergoing surgery for obesity.

PURPOSE: Bariatric surgery is the method of choice for the management or treatment of obesity. Bariatric surgery brings about several physiological changes in the body and is associated with set of complications. The aim of this study is to provide guidelines on post bariatric surgery management based on consensus by the Spanish society for Obesity Surgery (Sociedad Española de Cirugía de la Obesidad) (SECO) and the Spanish Society for the Study of Obesity (Sociedad Española para el Estudio de la Obesidad) (SEEDO). METHOD: The boards proposed seven experts from each society. The experts provided the evidence and a grade of recommendation on the selected topics based on systematic reviews/meta-analysis. A list of clinical practical recommendations levels of evidence and grades of these recommendations was derived from the consensus statements from the members of these societies. RESULTS: Seventeen topics related to post-operative management were reviewed after bariatric surgery. The experts came with 47 recommendations and statements. The mean number of persons voting at each statement was 54 (range 36-76). CONCLUSION: In this consensus, we have designed a set of guidelines to be followed while managing patients after bariatric surgery. Expertise and knowledge of the clinicians are required to convey suitable considerations to the post-bariatric patients. There should also be extensive follow-up plans for the bariatric surgery patients.

Factors accounting for high ferritin levels in obesity.

UNLABELLED: Ferritin is a widely used marker of iron status. A relationship between iron stores, obesity and metabolic syndrome (METs) has been proposed. OBJECTIVE: To compare serum ferritin between obese women with and without METs, and to evaluate the main factors accounting for ferritin levels. DESIGN: Prospective study. SUBJECTS: A total of 239 consecutive postmenopausal women with body mass index (BMI) > or =30 kg/m(2) were included. Exclusion criteria were conditions that could influence body iron stores. In addition to ferritin, serum iron, transferrin, transferrin saturation index and the soluble transferrin receptor were measured. METs was defined according to the International Diabetes Federation guidelines. Multiple regression analyses were performed taking into account ferritin as the dependent variable. RESULTS: Serum ferritin levels were significantly higher in obese women with METs (n=169) in comparison with obese women without METs (n=70): 81.00 (17-648) vs 48.50 (11-149) ng ml(-1), P<0.001. No differences in the other markers of iron status were observed. Diabetic patients (n=82) had higher ferritin levels than non-diabetic patients (P<0.001). Non-diabetic patients with METs (n=95) also showed higher ferritin levels than non-diabetic patients without METs (P=0.001). Among the components of METs only diabetes was independently associated with serum ferritin levels in both the whole group (P=0.02) and in patients with METs (P=0.005). CONCLUSION: Metabolic syndrome and in particular type 2 diabetes is the main contributor to the high ferritin levels reported in obesity. Our findings suggest that ferritin should not be used as a reliable index of iron overload in obese patients with diabetes.

Peculiarities of the obese patient with cancer: a national consensus statement by the Spanish Society for the Study of Obesity and the Spanish Society of Medical Oncology.

The relationship between obesity and cancer is clear and is present at all times during course of the disease. The importance of obesity in increasing the risk of developing cancer is well known, and some of the most prevalent tumours (breast, colorectal, and prostate) are directly related to this risk increase. However, there is less information available on the role that obesity plays when the patient has already been diagnosed with cancer. Certain data demonstrate that in some types of cancer, obese patients tolerate the treatments more poorly. Obesity is also known to have an impact on the prognosis, favouring lower survival rates or the appearance of secondary tumours. In this consensus statement, we will analyse the scientific evidence on the role that obesity plays in patients already diagnosed with cancer, and the available data on how obesity control can improve the quality of daily life for the cancer patient.

Obesity as a risk factor in cancer: A national consensus of the Spanish Society for the Study of Obesity and the Spanish Society of Medical Oncology.

In the last few years, many prospective studies have demonstrated a clear association between obesity and cancers of the colon and rectum, breast in post-menopausal women, endometrium, kidney, oesophagus and pancreas. Obesity is also associated with a high risk of recurrence and cancer-related death. The pathophysiology of obesity involves various changes that may be implicated in the relationship between obesity and cancer, such as excess inflammatory cytokines and chronic inflammation, hyperinsulinaemia, insulin resistance, and raised leptin and oestrogens. The Spanish Society for the Study of Obesity and the Spanish Society of Medical Oncology have signed a cooperation agreement to work together towards reducing the impact of obesity in cancer. Preventing obesity prevents cancer.

[Pheochromocytoma associated with multiple endocrine neoplasia 2A and sporadic: differential characteristics]. / Feocromocitoma asociado a neoplasia endocrina múltiple 2A y esporádico: características diferenciales.

BACKGROUND: To study distinctive clinical features of pheochromocytoma in the setting of multiple endocrine neoplasia type 2A (MEN 2A) in comparison with sporadic pheochromocytoma. PATIENTS AND METHOD: All patients diagnosed of sporadic pheochromocytoma (n = 29) and in the setting of MEN 2A (n = 16) between 1976 and 1998 in a tertiary hospital were included in the study. The following variables were compared: age at diagnosis, symptoms, presence and characteristics of hypertension, size of the tumor, localization and malignancy. The accuracy of diagnostic tests was also evaluated. RESULTS: The pheochromocytoma associated to MEN 2A had a higher prevalence in our study (35.5%) and the diagnosis was performed earlier than for sporadic pheochromocytoma (29.1 [7.8] vs. 47,5 [10. 9] years; p < 0.001). Other distinctive features in comparison with sporadic pheochromocytoma were: bilaterality (81.25 vs. 3.44%; p < 0. 001), absence of symptoms (44 vs 11%; p < 0.05) and paroxysmal hypertension. Concerning the diagnostic tests, it must be noted the low sensitivity (60%) of vanillylmandelic acid in MEN 2A. CONCLUSIONS: The pheochromocytoma in the setting of MEN 2A is diagnosed at younger age and frequently asymptomatic and bilateral. In view of the high prevalence of MEN 2A in our country, a genetic analysis should be performed in all patients with pheochromocytoma, especially when it is bilateral.

Proteomic analysis of cerebrospinal fluid from obese women with idiopathic intracranial hypertension: a new approach for identifying new candidates in the pathogenesis of obesity.

Body weight control is tightly regulated in the hypothalamus. The inaccessibility of human brain tissue can be partially solved by using cerebrospinal fluid (CSF) as a tool for assessing the central nervous system's production of orexigen and anorexigen factors. Using proteomic analysis, the present study investigated the differentially displayed proteins in human CSF from obese and non-obese subjects. We designed a case-control study conducted in a reference hospital where eight obese (cases) and eight non-obese (controls) women with idiopathic intracranial hypertension were included. Intracranial hypertension was normalised through the placement of a ventriculo- or lumboperitoneal shunt in the 12 months before their inclusion in the study. Isotope-coded protein label (for proteins > 10 kDa) and label-free liquid chromatography (for proteins < 10 kDa) associated with mass spectrometry analysis were used. Eighteen differentially expressed proteins were identified. Many of them fall into three main groups: inflammation (osteopontin, fibrinogen γ and ß chain, α1 acid glycoprotein 2 and haptoglobin), neuroendocrine mediators (neurosecretory protein VGF, neuroendocrine protein 7B2, chromogranin-A and chromogranin B), and brain plasticity (testican-1, isoform 10 of fibronectin, galectin-3 binding protein and metalloproteinase inhibitor type 2). The differential production of osteopontin, neurosecretory protein VGF, chromogranin-A and fibrinogen γ chain was further confirmed by either enzyme-linked immunosorbent assay or western blotting. In conclusion, we have identified potential candidates that could be involved in the pathogenesis of obesity. Further studies aiming to investigating the precise role of these proteins in the pathogenesis of obesity and their potential therapeutic implications are needed.

Iron in obesity. An ancient micronutrient for a modern disease.

Iron is a necessary constituent of several macromolecules involved in cell metabolism, but, at the same time, it could be a potentially dangerous element. For this reason iron balance must be finely regulated. At present, obesity has been recognized as a worldwide public health problem. Excess body fat is associated with increased all-cause mortality and increased risk for several medical morbidities. Many studies have shown that obesity might increase the risk of iron deficiency but, at the same time, obese subjects exhibit high serum ferritin levels. Recent studies seem to indicate that obesity is associated with iron deficiency although the aetiology appears to be multifactorial and includes (i) A decrease in iron food intake; (ii) An impairment of intestinal iron uptake and iron release from stores because of an overexpression of hepcidin and (iii) Inadequate iron bioavailability because of inflammation. In addition, abnormal ferritin concentrations can be explained by chronic inflammation rather than by iron overload. The aim of the present article is to review current knowledge of iron and obesity.

Ghrelin and apolipoprotein AIV levels show opposite trends to leptin levels during weight loss in morbidly obese patients.

BACKGROUND: Although bariatric surgery is the most common procedure used to induce weight loss in morbidly obese patients, its effect on plasma satiety factors (leptin, ghrelin, and apolipoprotein (apo)-AIV) is controversial. The aim of this work was to analyze these parameters before and at different times after surgery. METHODS: Plasma was obtained from 34 patients before undergoing Roux-en-Y gastric bypass and during weight loss in the 12 months following surgery. RESULTS: Morbidly obese patients had significantly higher values (147%) of leptin than normal-weight (NW) persons, while their ghrelin levels were 46% less than NW. Apo-AIV levels had approximately the same value in both groups (obese and NW). During weight loss, leptin decreased by 75% and ghrelin increased by 78%. Both parameters reached values less than or near NW, respectively, at 1 year after surgery. During the first month after surgery, apo-AIV plasma levels decreased (47%) but later increased and finally returned to preoperative values. Apo-AIV levels were correlated negatively with leptin and positively with ghrelin. High-density lipoprotein (HDL) levels were positively correlated with those of ghrelin and apo-AIV. CONCLUSIONS: During weight loss, plasma leptin and ghrelin could be good markers of total fat decrease. Ghrelin could also indicate gastric mucous improvement, whereas apo-AIV could indicate the recovery of intestinal function. Changes produced in the HDL levels of morbidly obese patients during weight loss suggest a decreased risk of coronary disease.