Phenotype similarities in automatically grouped T2D patients by variation-based clustering of IL-1ß gene expression.

Background: Analyzing longitudinal gene expression data is extremely challenging due to limited prior information, high dimensionality, and heterogeneity. Similar difficulties arise in research of multifactorial diseases such as Type 2 Diabetes. Clustering methods can be applied to automatically group similar observations. Common clinical values within the resulting groups suggest potential associations. However, applying traditional clustering methods to gene expression over time fails to capture variations in the response. Therefore, shape-based clustering could be applied to identify patient groups by gene expression variation in a large time metabolic compensatory intervention. Objectives: To search for clinical grouping patterns between subjects that showed similar structure in the variation of IL-1ß gene expression over time. Methods: A new approach for shape-based clustering by IL-1ß expression behavior was applied to a real longitudinal database of Type 2 Diabetes patients. In order to capture correctly variations in the response, we applied traditional clustering methods to slopes between measurements. Results: In this setting, the application of K-Medoids using the Manhattan distance yielded the best results for the corresponding database. Among the resulting groups, one of the clusters presented significant differences in many key clinical values regarding the metabolic syndrome in comparison to the rest of the data. Conclusions: The proposed method can be used to group patients according to variation patterns in gene expression (or other applications) and thus, provide clinical insights even when there is no previous knowledge on the subject clinical profile and few timepoints for each individual.

Telomere Length Differently Associated to Obesity and Hyperandrogenism in Women With Polycystic Ovary Syndrome.

Background: Polycystic Ovary Syndrome (PCOS) often present metabolic disorders and hyperandrogenism (HA), facts that may influence the telomere length (TL). Aims: To compare the absolute TL (aTL) between women with PCOS and control women, and their association with the presence of obesity and HA parameters. Materials and methods: The PCOS group included 170 unrelated women outpatients and the control group, 64 unrelated donor women. Anthropometric, biochemical-clinical parameters and androgen profile were determined. The PCOS patients were divided accordingly to the presence of obesity and androgenic condition. The aTL was determined from peripheral blood leukocytes by Real Time quantitative PCR. Results: Women with PCOS exhibited a significantly longer aTL than controls after age adjustment (p=0.001). A stepwise multivariate linear regression in PCOS women, showed that WC (waist circumference) contributed negatively (b=-0.17) while testosterone levels contributed positively (b=7.24) to aTL. The non-Obese PCOS (noOB-PCOS) presented the longest aTL when compared to controls (p=0.001). Meanwhile, the aTL was significantly higher in the hyperandrogenic PCOS phenotype (HA-PCOS) than in the controls (p=0.001) and non hyperandrogenic PCOS phenotype (NHA-PCOS) (p=0.04). Interestingly, when considering obesity and HA parameters in PCOS, HA exerts the major effect over the aTL as non-obese HA exhibited the lengthiest aTL (23.9 ± 13.13 Kbp). Conversely, the obese NHA patients showed the shortest aTL (16.5 ± 10.59 Kbp). Conclusions: Whilst a shorter aTL could be related to the presence of obesity, a longer aTL would be associated with HA phenotype. These findings suggest a balance between the effect produced by the different metabolic and hormonal components, in PCOS women.

Relationship between the IL-1ß serum concentration, mRNA levels and rs16944 genotype in the hyperglycemic normalization of T2D patients.

To evaluate Interleukin 1-beta (IL-1ß) serum and mononuclear leucocyte mRNA levels, also rs16944 (-511C/T) genotype, in relation to hyperglycemic normalization in Type 2 diabetes (T2D) patients, we recruited 30 individuals recently T2D diagnosed with hyperglycemia studied at basal time and after 6 and 12 months of the normalization treatment. At basal time, the T polymorphic allele of the rs16944 was associated with lower IL-1ß mRNA expression (p = 0.006); and higher glucose level was positive correlated to IL-1ß protein levels (p = 0.015). After treatment, the individuals showed a significant decrease in glucose level (p = 0.003), but they did not express significant changes in the IL-1ß serum levels. Surprisingly, we observed that the greater decreases in glucose level were associated to increased IL-1ß serum levels (p = 0.040). This is the first follow-up study evaluating IL-1ß mRNA expression and serum levels in hyperglycemic T2D individuals and after glycemic normalization treatment. The current results contribute to the knowledge of the relationship between inflammation and glucose metabolism in T2D.

Inhibition of Osteoblast Function by Brucella abortus is Reversed by Dehydroepiandrosterone and Involves ERK1/2 and Estrogen Receptor.

Brucella abortus induces an inflammatory response that stimulates the endocrine system resulting in the secretion of cortisol and dehydroepiandrosterone (DHEA). Osteoarticular brucellosis is the most common presentation of the active disease in humans, and we have previously demonstrated that B. abortus infection inhibits osteoblast function. We aimed to evaluate the role of cortisol and DHEA on osteoblast during B. abortus infection. B. abortus infection induces apoptosis and inhibits osteoblast function. DHEA treatment reversed the effect of B. abortus infection on osteoblast by increasing their proliferation, inhibiting osteoblast apoptosis, and reversing the inhibitory effect of B. abortus on osteoblast differentiation and function. By contrast, cortisol increased the effect of B. abortus infection. Cortisol regulates target genes by binding to the glucocorticoid receptor (GR). B. abortus infection inhibited GRα expression. Cell responses to cortisol not only depend on GR expression but also on its intracellular bioavailability, that is, dependent on the activity of the isoenzymes 11ß-hydroxysteroid dehydrogenase (HSD) type-1, 11ß-HSD2 (which convert cortisone to cortisol and vice versa, respectively). Alterations in the expression of these isoenzymes in bone cells are associated with bone loss. B. abortus infection increased 11ß-HSD1 expression but had no effect on 11ß-HSD2. DHEA reversed the inhibitory effect induced by B. abortus infection on osteoblast matrix deposition in an estrogen receptor- and ERK1/2-dependent manner. We conclude that DHEA intervention improves osteoblast function during B. abortus infection making it a potential candidate to ameliorate the osteoarticular symptoms of brucellosis.

Metabolically healthy obese individuals present similar chronic inflammation level but less insulin-resistance than obese individuals with metabolic syndrome.

The Metabolic Syndrome (MetS) is a cluster of cardiometabolic risk factors, usually accompanied by the presence of insulin resistance (IR) and a systemic subclinical inflammation state. Metabolically healthy obese (MHO) individuals seem to be protected against cardiometabolic complications. The aim of this work was to characterize phenotypically the low-grade inflammation and the IR in MHO individuals in comparison to obese individuals with MetS and control non obese. We studied two different populations: 940 individuals from the general population of Buenos Aires and 518 individuals from the general population of Venado Tuerto; grouped in three groups: metabolically healthy non-obese individuals (MHNO), MHO and obese individuals with MetS (MSO). Inflammation was measured by the levels of hs-CRP (high-sensitivity C reactive protein), and we found that MHO presented an increase in inflammation when compared with MHNO (Buenos Aires: p<0.001; Venado Tuerto: p<0.001), but they did not differ from MSO. To evaluate IR we analyzed the HOMA (Homoeostatic Model Assessment) values, and we found differences between MHO and MSO (Buenos Aires: p<0.001; Venado Tuerto: p<0.001), but not between MHNO and MHO. In conclusion, MHO group would be defined as a subgroup of obese individuals with an intermediate phenotype between MHNO and MSO individuals considering HOMA, hs-CRP and central obesity.

Análisis de la longitud de los telómeros en obesos metabólicamente sanos / Analysis of telomere length in the metabolically healthy obese

La obesidad es el principal componente del síndrome metabólico (SM) y determina la progresión de la enfermedad a las complicaciones metabólicas. Los individuos obesos metabólicamente sanos (OMS) parecen estar protegidos contra esas complicaciones. La longitud de los telómeros (LT) es un nuevo marcador del envejecimiento celular, que tiene una relación compleja con el SM. El objetivo principal de este estudio fue investigar por primera vez la LT en OMS y estudiar la asociación entre LT y el número de componentes del SM. Se estudió a 398 mujeres con una edad media de 46,76 ± 15,47 años (rango: 18-86 años), que se agruparon en: individuos con normopeso sin ningún componente del SM (NP0), obesos sin SM (OMS) y de acuerdo con el número de componentes de SM en los grupos sin ningún componentes de SM (0), con uno o 2 componentes (1 + 2) y con SM por la presencia de 3 o más componentes (SM). La LT de los OMS no se diferenció de la de los NP0, pero fue significativamente mayor que la de los individuos con SM (p = 0,032). Se observó una disminución de la LT con el aumento progresivo del número de componentes del SM (p = 0,004), en donde el grupo 0 presentó una LT significativamente mayor que los grupos 1 + 2 (p = 0,027) y SM (p = 0,003). Demostramos por primera vez que las mujeres OMS presentan una LT similar a las mujeres NP0 y más larga que aquellas mujeres con SM. Además, confirmamos que la LT se acorta con el aumento en el número de alteraciones del SM.

Obesity is the principal component in Metabolic Syndrome (MetS) and determines the progression of metabolic complications. Metabolically healthy obese individuals (MHO) seem to be protected against those complications. Telomere length (TL), as a novel marker of cellular aging, has a complex relationship with MetS. The principal aim of this study was to investigate TL in MHO, and to study the association between TL and the number of MetS components. A study was conducted on 398 women (mean age: 46.76 ± 15.47 years; range: 18 - 86 years), grouped according to the number of MetS components (0, 1 + 2, MetS), a group of normal-weight individuals with 0 MetS components (NW0), and a group of obese without MetS (MHO). No differences were found in the TL of the MHO group compared to the NW0, but it was significantly higher than that of individuals with MetS (P = .032). A decrease in TL was observed with a progressive increase in the number of MetS components (P = .004), whereas the group of individuals without MetS components had significantly longer TL than the groups with 1 and 2 components (P = .027), and MetS (P = .003). Shorter TL is not associated with MHO, but is related to MetS and with an increased number of metabolic abnormalities.