[Show abstract][Hide abstract] ABSTRACT: Background
Diabetes has been defined on the basis of different bio-markers, including fasting plasma glucose (FPG), 2-h plasma glucose in an oral glucose tolerance test (2hOGTT), and HbA1c. We assessed the effect of different diagnostic definitions on both the population prevalence of diabetes and the classification of previously undiagnosed individuals as having diabetes versus not having diabetes in a pooled analysis of data from population-based health examination surveys in different regions.
We used data from 96 population-based health examination surveys that had measured at least two of the bio-markers used for defining diabetes. Diabetes was defined using HbA1c (HbA1c ≥6·5% or history of diabetes diagnosis or using insulin or oral hypoglycemic drugs) compared with either FPG only or FPG-or-2hOGTT definitions (FPG ≥7·0 mmol/L or 2hOGTT ≥11·1 mmol/L or history of diabetes or using insulin or oral hypoglycemic drugs). We calculated diabetes prevalence, taking into account complex survey design and survey sample weights. We compared the prevalences of diabetes using different definitions graphically and by regression analyses. We calculated sensitivity and specificity of diabetes diagnosis based on HbA1c compared with diagnosis based on glucose among previously undiagnosed individuals (i.e., excluding those with history of diabetes or using insulin or oral hypoglycemic drugs). We calculated sensitivity and specificity in each survey, and then pooled results using a random-effects model. We assessed the sources of heterogeneity of sensitivity by meta-regressions for study characteristics selected a priori.
Population prevalence of diabetes based on FPG-or-2hOGTT was correlated with prevalence based on FPG alone (r=0·98), but was higher by 2–6 percentage points at different prevalence levels. Prevalence based on HbA1c was lower than prevalence based on FPG in 42·8% of age–sex–survey groups and higher in another 41·6%; in the other 15·6%, the two definitions provided similar prevalence estimates. The variation across studies in the relation between glucose-based and HbA1c-based prevalences was partly related to participants' age, followed by natural logarithm of per person gross domestic product, the year of survey, mean BMI, and whether the survey population was national, sub-national, or from specific communities. Diabetes defined as HbA1c 6·5% or more had a pooled sensitivity of 52·8% (95% CI 51·3–54·3%) and a pooled specificity of 99·74% (99·71–99·78%) compared with FPG 7·0 mmol/L or more for diagnosing previously undiagnosed participants; sensitivity compared with diabetes defined based on FPG-or-2hOGTT was 30·5% (28·7–32·3%). None of the preselected study-level characteristics explained the heterogeneity in the sensitivity of HbA1c versus FPG.
Different biomarkers and definitions for diabetes can provide different estimates of population prevalence of diabetes, and differentially identify people without previous diagnosis as having diabetes. Using an HbA1c-based definition alone in health surveys will not identify a substantial proportion of previously undiagnosed people who would be considered as having diabetes using a glucose-based test.
[Show abstract][Hide abstract] ABSTRACT: In the context of obesity, strong evidences support a distinctive pathological contribution of adipose tissue depending on its anatomical site of accumulation. Therefore, subcutaneous adipose tissue (SAT), has been lately considered metabolically benign compared to visceral fat (VAT) whose location is associated to the risk of developing cardiovascular disease, insulin resistance, and other associated comorbidities. Under the above situation, the chronic local inflammation that characterizes obese adipose tissue, has acquired a major role on the pathogenesis of obesity. In this work, we have analyzed for the first time human obese VAT and SAT secretomes using an improved quantitative proteomic approach for the study of tissue secretomes, comparison of isotope-labeled amino acid incorporation rates (CILAIR). The use of double isotope-labeling-CILAIR approach to analyze VAT and SAT secretomes allowed the identification of location-specific secreted proteins and its differential secretion. Additionally to the very high percentage of identified proteins previously implicated in obesity or in its comorbidities, this approach was revealed as an useful tool for the study of the obese adipose tissue microenvironment including extracellular matrix (ECM) remodeling and inflammatory status. The results herein presented reinforce the fact that VAT and SAT depots have distinct features and contribute differentially to metabolic disease.
[Show abstract][Hide abstract] ABSTRACT: Secondary hypogonadism is common in ageing men; its natural history and predisposing factors are unclear.
1) To identify factors which predispose eugonadal men (T ≥10.5nmol/L) to develop biochemical secondary hypogonadism (T<10.5nmol/L, LH≤9.4U/L) and secondary hypogonadal men to recover to eugonadism. 2) To characterize clinical features associated with these transitions.
Prospective observational general population cohort survey.
Clinical research centres.
3369 community-dwelling men aged 40-79 yr in eight European centres.
Observational follow-up of 4.3 years.
Subjects were categorised according to change/no change in biochemical gonadal status during follow-up into persistent eugonadal (n=1909), incident secondary hypogonadal (n=140), persistent secondary hypogonadal (n=123) and recovered from secondary hypogonadism to eugonadism (n=96). Baseline predictors and changes in clinical features associated with incident secondary hypogonadism and recovery from secondary hypogonadism were analysed by regression models.
The incidence of secondary hypogonadism was 155.9/10,000/year, while 42.9% of men with secondary hypogonadism recovered to eugonadism. Incident secondary hypogonadism was predicted by obesity [BMI≥30kg/m(2): odds ratio (OR)=2.86 (95% confidence interval 1.67;4.90); p<0.0001], weight gain [OR=1.79 (1.15;2.80);p=0.011] and increased waist circumference [OR=1.73 (1.07;2.81); p=0.026 and 2.64 (1.66;4.21);p<0.0001, for waist circumference 94-102 and ≥102 cm, respectively]. Incident secondary hypogonadal men experienced new/worsening sexual symptoms [low libido, erectile dysfunction and infrequent spontaneous erections]. Recovery from secondary hypogonadism was predicted by non-obesity [OR=2.28 (1.21;4.31); p=0.011], weight loss [OR=2.24 (1.04;4.85); p=0.042], normal waist circumference [OR=1.93 (1.01;3.70); p=0.048], younger age [<60yr OR=2.32 (1.12;4.82); p=0.024] and higher education [OR=2.11 (1.05;4.26); p=0.037], but symptoms did not show significant concurrent improvement.
Obesity-related metabolic and lifestyle factors predispose older men to the development of secondary hypogonadism, which is frequently reversible with weight loss.
The Journal of Clinical Endocrinology and Metabolism 05/2015; DOI:10.1210/jc.2015-1571 · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury (TBI) is a growing public health problem worldwide and is a leading cause of death and disability. The causes of TBI include motor vehicle accidents, which are the most common cause, falls, acts of violence, sports-related head traumas and war accidents including blastic brain injuries. Recently, pituitary dysfunction has also been described in boxers and kickboxers. More than 90 years ago, in 1918, neuroendocrine dysfunction due to TBI was describedfor the first time. Only case reports and small case series were reported until 2000, but since then pituitary function in TBI victims has been investigated in more detail. The frequency of hypopituitarism after TBI varies widely among different studies (15-50 of the patients with TBI in most studies). The estimates of persistent hypopituitarism decreaseto 12% if repeated testing is applied. Growth hormone (GH) is the most common hormone lost after TBI, followed by adrenocorticotropic hormone (ACTH), gonadotropins (FSH and LH), and thyroid-stimulating hormone (TSH). The underlying mechanisms responsible for pituitary dysfunction after TBI are not entirely clear; however, recent studies have shown that genetic predisposition and autoimmunity may have a role. Hypopituitarism following TBI may have a negative impact on page or degree of functional recovery and cognition. What is not clear is whether treatment of hypopituitarism has a beneficial effect on specific function. In this review, the current data related to anterior pituitary dysfunction after TBI in adult patients are updated, and guidelines for the diagnosis, follow-up strategies and therapeutic approaches are reported.
[Show abstract][Hide abstract] ABSTRACT: The development of therapeutic strategies for skeletal muscle diseases, such as physical injuries and myopathies, depends on the knowledge of regulatory signals that control the myogenic process. The obestatin/GPR39 system operates as an autocrine signal in the regulation of skeletal myogenesis. Using a mouse model of skeletal muscle regeneration after injury and several cellular strategies, we explored the potential use of obestatin as a therapeutic agent for the treatment of trauma-induced muscle injuries. Our results evidenced that the overexpression of the preproghrelin, and thus obestatin, and GPR39 in skeletal muscle increased regeneration after muscle injury. More importantly, the intramuscular injection of obestatin significantly enhanced muscle regeneration by simulating satellite stem cell expansion as well as myofiber hypertrophy through a kinase hierarchy. Added to the myogenic action, the obestatin administration resulted in an increased expression of VEGF/VEGFR2 and the consequent microvascularization, with no effect on collagen deposition in skeletal muscle. Furthermore, the potential inhibition of myostatin during obestatin treatment might contribute to its myogenic action improving muscle growth and regeneration. Taken together, our data demonstrate successful improvement of muscle regeneration, indicating obestatin is a potential therapeutic agent for skeletal muscle injury and would benefit other myopathies related to muscle regeneration.Molecular Therapy (2015); doi:10.1038/mt.2015.40.
[Show abstract][Hide abstract] ABSTRACT: Uroguanylin (UGN) is a 16 amino acid peptide produced mainly by intestinal epithelial cells. Nutrients intake increases circulating levels of prouroguanylin that is processed and converted to UGN to activate the guanylyl cyclase 2C receptor (GUCY2C). Given that the UGN-GUCY2C system has been proposed as a novel gut-brain endocrine axis regulating energy balance, the aim of the present study was to investigate the regulation of UGN protein levels in duodenum and circulating levels in lean and obese mice under different nutritional conditions and its potential interaction with leptin.
Swiss, C57BL/6 wild-type and ob/ob male adult mice under different nutritional conditions were used: fed ad libitum standard diet (control); 48 h fasting (fasted); 48 h fasting followed by 24 h of feeding (refed); and fed high-fat diet (45 %) during 10 weeks. In addition, peripheral leptin administration was performed. Intestinal uroguanylin expression was studied by Western blot analysis; plasma levels were measured by ELISA.
Food deprivation significantly reduced plasma UGN levels, which were correlated with the lower protein levels of UGN in duodenum. These effects were reverted after refeeding and leptin challenge. Consistently, in ob/ob mice UGN expression was decreased, whereas leptin treatment up-regulated UGN levels in duodenum in these genetically modified mice compared to WT. Diet-induced obese mice displayed increased UGN levels in intestine and plasma in comparison with lean mice.
Our findings suggest that UGN levels are correlated with energy balance status and that the regulation of UGN by nutritional status is leptin-dependent.
European Journal of Nutrition 03/2015; DOI:10.1007/s00394-015-0869-2 · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism.
[Show abstract][Hide abstract] ABSTRACT: The fact that gastric surgery is at the moment the most effective treatment to fight against obesity highlights the relevance of gastric derived proteins as potential targets to treat this pathology. Taking advantage of a previously established gastric explant model for endocrine studies, the proteomic analysis of gastric secretome was performed. To validate this gastric explant system for proteomic analysis, the identification of ghrelin, a classical gastric derived peptide, was performed by MS. In addition, the differential analysis of gastric secretomes under differential nutritional status (control feeding vs fasting vs re-feeding) was performed. The MS identified proteins are showed in the present manuscript. The data supplied in this article is related to the research article entitled “Comparative secretome analysis of rat stomach under different nutritional status”
[Show abstract][Hide abstract] ABSTRACT: Context: Low testosterone (T) has been associated with incident metabolic syndrome (MetS), but it remains unclear if this association is independent of sex hormone binding globulin (SHBG). Estradiol (E2) may also be associated with MetS, but few studies have investigated this. Objective: To study the association between baseline sex steroids and the development of incident MetS and to investigate the influence of SHBG, BMI and insulin resistance on this risk. Methods: 3369 community-dwelling men aged 40-79 years were recruited for participation in EMAS. MetS was defined by the updated NCEP ATP III criteria. Testosterone and E2 levels were measured by liquid and gas chromatography/mass spectrometry respectively. Logistic regression was used to assess the association between sex steroids and incident MetS. Results: 1651 men without MetS at baseline were identified. During follow-up 289 men developed incident MetS, while 1362 men did not develop MetS. Men with lower baseline total T levels were at higher risk for developing MetS (Odds ratio (OR)=1.72, p<0.001), even after adjustment for SHBG (OR=1.43, p=0.001), BMI (OR=1.44, p<0.001) or HOMA-IR (OR=1.64, p<0.001). E2 was not associated with development of MetS (OR=1.04; p=0.56). However, a lower E2/T ratio was associated with a lower risk of incident MetS (OR=0.38; p<0.001), even after adjustment for SHBG (OR=0.48; p<0.001), BMI (OR=0.60; p=0.001) or HOMA-IR (OR=0.41; p<0.001). Conclusions: In men, lower T levels, but not E2, are linked with an increased risk of developing MetS, independent of SHBG, BMI or insulin resistance. A lower E2/T ratio may be protective against developing MetS.
[Show abstract][Hide abstract] ABSTRACT: Objective: A number of factors can influence the reported outcomes of transsphenoidal surgery (TSS) for Cushing's disease - including different remission and recurrence criteria, for which there is no consensus. Therefore, a comparative analysis of the best treatment options and patient management strategies is difficult. In this review, we investigated the clinical outcomes of initial TSS in patients with Cushing's disease based on definitions of and assessments for remission and recurrence. Methods: We systematically searched PubMed and identified 44 studies with clear definitions of remission and recurrence. When data were available, additional analyses by time of remission, tumour size, duration of follow-up, surgical experience, year of study publication, and adverse events related to surgery were performed. Results: Of the 44 articles selected, only one reported endoscopic TSS. Data from a total of 6,400 patients who received microscopic TSS were extracted and analysed. A variety of definitions of remission and recurrence of Cushing's disease after initial microscopic TSS was used, giving broad ranges of remission (42.0-96.6%; median, 77.9%) and recurrence (3.1-47.4%; median, 11.5%). Better remission and recurrence outcomes were achieved for micro- versus macroadenomas; however, no correlations were found with other parameters, other than improved safety with longer surgical experience. Conclusions: The variety of methodologies used in clinical evaluation of TSS for Cushing's disease strongly support the call for standardization and optimization of studies to inform clinical practice and maximize patient outcomes. Clinically significant rates of failure of initial TSS highlight the need for effective second-line treatments.
European Journal of Endocrinology 01/2015; 172(6). DOI:10.1530/EJE-14-0883 · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity is a major public health threat for many industrialised countries. Bariatric surgery is the most effective treatment against obesity, suggesting that gut derived signals are crucial for energy balance regulation. Several descriptive studies have proven the presence of gastric endogenous systems that modulate energy homeostasis; however, these systems and the interactions between them are still not well known. In the present study, we show for the first time the comparative 2-DE gastric secretome analysis under different nutritional status. We have identified 38 differently secreted proteins by comparing stomach secretomes from tissue explant cultures of rats under feeding, fasting and re-feeding conditions. Among the proteins identified, glyceraldehyde-3-phosphate dehydrogenase was found to be more abundant in gastric secretome and plasma after re-feeding, and downregulated in obesity. Additionally, two calponin-1 species were decreased in feeding state, and other were modulated by nutritional and metabolic conditions. These and other secreted proteins identified in this work may be considered as potential gastrokines implicated in food intake regulation.
Journal of Proteomics 01/2015; DOI:10.1016/j.jprot.2015.01.001 · 3.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity is nowadays a public health problem both in the industrialized world and developing countries. The different treatments to fight against obesity are not very successful with the exception of gastric surgery. The mechanism behind the achievement of this procedure remains unclear although the modifications in the pattern of gastrointestinal hormones production appear to be responsible for the beneficial effect. The gastrointestinal tract has emerged in the last time as an endocrine organ in charge of response to the different stimulus related to nutritional status by the modulation of more than 30 signals acting at central level to modulate food intake and body weight. The production of some of these gastric derived signals has been proved to be altered in obesity (ghrelin, CCK, and GLP-1). In fact, bariatric surgery modifies the production of both gastrointestinal and adipose tissue peripheral signals beyond the gut microbiota composition. Through this paper the main peripheral signals altered in obesity will be reviewed together with their modifications after bariatric surgery.
Gastroenterology Research and Practice 01/2015; 2015:1-12. DOI:10.1155/2015/560938 · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prefrontal (PFC) and orbitofrontal cortex (OFC) appear to be associated with both executive functions and olfaction. However, there is little data relating olfactory processing and executive functions in humans. The present study aimed at exploring the role of olfaction on executive functioning, making a distinction between primary and more cognitive aspects of olfaction. Three executive tasks of similar difficulty were used. One was used to assess hot executive functions (Iowa Gambling Task-IGT), and two as a measure of cold executive functioning (Stroop Colour and Word Test-SCWT and Wisconsin Card Sorting Test-WCST). Sixty two healthy participants were included: 31 with normosmia and 31 with hyposmia. Olfactory abilities were assessed using the ''Sniffin' Sticks'' test and the olfactory threshold, odour discrimination and odour identification measures were obtained. All participants were female, aged between 18 and 60. Results showed that participants with hyposmia displayed worse performance in decision making (IGT; Cohen's-d = 0.91) and cognitive flexibility (WCST; Cohen's-d between 0.54 and 0.68) compared to those with normosmia. Multiple regression adjusted by the covariates participants' age and education level showed a positive association between odour identification and the cognitive inhibition response (SCWT-interference; Beta = 0.29; p = .034). The odour discrimination capacity was not a predictor of the cognitive executive performance. Our results suggest that both hot and cold executive functions seem to be associated with higher-order olfactory functioning in humans. These results robustly support the hypothesis that olfaction and executive measures have a common neural substrate in PFC and OFC, and suggest that olfaction might be a reliable cognitive marker in psychiatric and neurologic disorders.
PLoS ONE 01/2015; 10(6):e0130319. DOI:10.1371/journal.pone.0130319 · 3.53 Impact Factor