AM-879, a PPARy non-agonist and Ser273 phosphorylation blocker, promotes insulin sensitivity without adverse effects in mice.

Obesity is one of the main risk factors for type 2 diabetes, and peroxisome proliferator-activated receptor γ (PPARγ) is considered a promising pathway on insulin sensitivity and adipose tissue metabolism. The search for molecules acting as insulin sensitizers have increased, especially for molecules that block PPARγ-Ser273 phosphorylation, without reaching full agonism. We evaluated the in vivo effects of AM-879, a PPARγ non-agonist, and found that AM-879 exerts different effects in mice depending on the dose. At lower doses, this ligand decreased BAT, increased leptin and Crh expression. However, at a higher dose, it promoted improvement on insulin sensitivity, ameliorates expression of metabolism-related genes, decreased the expression of genes related to liver toxicity, maintaining body weight and adipocyte size. These results present a new lead molecule to ameliorates insulin resistance and confirm AM-879 as a PPARγ non-agonist which blocks Ser273 phosphorylation as a good strategy to modulate insulin sensitivity without developing the adverse effects promoted by PPARγ full agonists.

Harmonized D-dimer levels upon admission for prognosis of COVID-19 severity: Results from a Spanish multicenter registry (BIOCOVID-Spain study).

Coagulopathy is a key feature of COVID-19 and D-dimer has been reported as a predictor of severity. However, because D-dimer test results vary considerably among assays, resolving harmonization issues is fundamental to translate findings into clinical practice. In this retrospective multicenter study (BIOCOVID study), we aimed to analyze the value of harmonized D-dimer levels upon admission for the prediction of in-hospital mortality in COVID-19 patients. All-cause in-hospital mortality was defined as endpoint. For harmonization of D-dimer levels, we designed a model based on the transformation of method-specific regression lines to a reference regression line. The ability of D-dimer for prediction of death was explored by receiver operating characteristic curves analysis and the association with the endpoint by Cox regression analysis. Study population included 2663 patients. In-hospital mortality rate was 14.3%. Harmonized D-dimer upon admission yielded an area under the curve of 0.66, with an optimal cut-off value of 0.945 mg/L FEU. Patients with harmonized D-dimer ≥ 0.945 mg/L FEU had a higher mortality rate (22.4% vs. 9.2%; p < 0.001). D-dimer was an independent predictor of in-hospital mortality, with an adjusted hazard ratio of 1.709. This is the first study in which a harmonization approach was performed to assure comparability of D-dimer levels measured by different assays. Elevated D-dimer levels upon admission were associated with a greater risk of in-hospital mortality among COVID-19 patients, but had limited performance as prognostic test.

Effects of bisphenol A treatment during pregnancy on kidney development in mice: a stereological and histopathological study.

Bisphenol A (BPA) is a chemical found in plastics that resembles oestrogen in organisms. Developmental exposure to endocrine-disrupting chemicals, such as BPA, increases the susceptibility to type 2 diabetes (T2DM) and cardiovascular diseases. Animal studies have reported a nephron deficit in offspring exposed to maternal diabetes. The aim of this study was to investigate the prenatal BPA exposure effects on nephrogenesis in a mouse model that was predisposed to T2DM. This study quantitatively evaluated the renal structural changes using stereology and histomorphometry methods. The OF1 pregnant mice were treated with a vehicle or BPA (10 or 100 µg/kg/day) during days 9-16 of gestation (early nephrogenesis). The 30-day-old offspring were sacrificed, and tissue samples were collected and prepared for histopathological and stereology studies. Glomerular abnormalities and reduced glomerular formation were observed in the BPA offspring. The kidneys of the BPA10 and BPA100 female offspring had a significantly lower glomerular number and density than those of the CONTROL female offspring. The glomerular histomorphometry revealed a significant difference between the female and male CONTROL offspring for the analysed glomerular parameters that disappeared in the BPA10 and BPA100 offspring. In addition, the kidney histopathological examination showed typical male cuboidal epithelial cells of the Bowman capsule in the female BPA offspring. Exposure to environmentally relevant doses of BPA during embryonic development altered nephrogenesis. These structural changes could be associated with an increased risk of developing cardiometabolic diseases later in life.

[Can FT3 levels facilitate the detection of inflammation or catabolism and malnutrition in dialysis patients?]. / ¿Pueden los niveles de T3L facilitar la detección de estados inflamatorios o de catabolismo y desnutrición en enfermos en diálisis?

INTRODUCTION: Low serum free triiodothyronine (FT3) levels have been reported in a high percentage of chronic renal failure (CRF) patients and have been considered as independent predictors of mortality in both hemodialysis (HD) and peritoneal dialysis (PD). A reduction in thyroid function in dialysis patients could be a marker of malnutrition and/or inflammation. OBJECTIVE: Our aim has been to evaluate the incidence of low T3 syndrome in a group of dialysis patients and analyze its relationship with different parameters of malnutrition and inflammation. PATIENTS AND METHODS We included 32 stable dialysis patients (24 HD and 8 DP); mean age +/- SD 71.2 +/- 11.7 years; 46.9% males; 15.6% diabetics; mean time on dialysis 47 +/- 43 months. The following parameters were measured in every patient: thyrothropin (TSH), Free T4 (FT4) and Free T3 (FT3); biochemical data related to nutritional status; anthropometric measurements, bioelectrical impedance vector analysis (BIVA), and dietary survey of three consecutive days. Statistical analysis was performed by using SPSS 11.0. RESULTS: Mean hormonal values of thyroid function were: TSH 2,2 +/- 1.5 U/ml (range: 0,4-5.0); FT4 14.7 +/- 2.3 pmol/l (range: 11.0-23.0) and FT3 4,0 +/- 0.71 pmol/l (range: 3.95-6.80). Only 2 patients (6.3%) showed low FT4 levels and another 2 patients increased TSH levels, whereas 17 patients (53.1%) presented with low FT3 levels. We did not found any correlation between serum FT3, FT4 and TSH levels. We found a correlation between FT3 and inflammation/nutritional parameters: prealbumin (r = 0,36; p = 0,04); transferrin (r = 0,40; p = 0,025); PCR (r = -0.38; p = 0,039); and IGF-I (r = 0,38; p = 0,03); body mass index (BMI) (r = 0,51; p = 0,002); arm circumference (AC) (r = 0,65; p = 0,000), and arm muscle circumference (AMC) (r = 0,72; p = 0,000). FT3 levels were also correlated with BIVA parameters: phase angle (r = 0,54; p = 0,002); muscle mass percentage (r = 0,49; p = 0,005); and cell mass percentage (r = 0,53; p = 0,02), but not with any data of fat mass. AMC was the only variable that independently correlated with FT3 levels in the multivariate regression analysis (r = 0,69; r2: 0,48; p = 0,000) CONCLUSION: Half of our dialysis patients have decreased levels of serum FT3 without alteration on FT4 or TSH. Low FT3 levels are correlated bioquimical and anthropometric parameters indicators of malnutrition and inflammation. Periodical measurement of FT3 levels could be used by clinicians as an accesible and reproducible method to detect such states.

Can FT3 levels facilitate the detection of inflammation or catabolism and malnutrition in dialysis patients?

Introduction: Low serum free triiodothyronine (FT3) levels have been reported in a high percentage of chronic renal failure (CRF) patients and have been considered as independent predictors of mortality in both haemodialysis (HD) and peritoneal dialysis (PD). A reduction in thyroid function in dialysis patients could be a marker of malnutrition and/or inflammation. Objective: Our aim has been to evaluate the incidence of low T3 syndrome in a group of dialysis patients and analyze its relationship with different parameters of malnutrition and inflammation. Patients and Methods: We included 32 stable dialysis patients (24 HD and 8 DP); mean age ± SD 71.2 ± 11.7 years; 46.9% males; 15.6% diabetics; mean time on dialysis 47 ± 43 months. The following parameters were measured in every patient: thyrothropin (TSH), Free T4 (FT4) and Free T3 (FT3); biochemical data related to nutritional status; anthropometric measurements, bioelectrical impedance vector analysis (BIVA), and dietary survey of three consecutive days. Statistical analysis was performed by using SPSS 11.0. Results: Mean hormonal values of thyroid function were: TSH 2,2 ± 1.5 U/ml (range: 0,4-5.0); FT4 14.7 ± 2.3 pmol/l (range: 11.0-23.0) and FT3 4,0±0.71 pmol/l (range: 3.95-6.80). Only 2 patients (6.3%) showed low FT4 levels and another 2 patients increased TSH levels, whereas 17 patients (53.1%) presented with low FT3 levels. We did not found any correlation between serum FT3, FT4 and TSH levels. We found a correlation between FT3 and inflammation/nutritional parameters: prealbumin (r = 0,36; p = 0,04); transferrin (r = 0,40; p = 0,025); PCR (r = -0.38; p = 0,039); and IGF-I (r = 0,38; p = 0,03); body mass index (BMI) (r = 0,51; p = 0,002); arm circumference (AC) (r = 0,65; p = 0,000), and arm muscle circumference (AMC) (r = 0,72; p = 0,000). FT3 levels were also correlated with BIVA parameters: phase angle (r = 0,54; p = 0,002); muscle mass percentage (r = 0,49; p = 0,005); and cell mass percentage (r = 0,53; p = 0,02), but not with any data of fat mass. AMC was the only variable that independently correlated with FT3 levels in the multivariate regression analysis (r = 0,69; r2: 0,48; p = 0,000). Conclusion: Half of our dialysis patientshave decreased levels of serum FT3 without alteration on FT4 or TSH. Low FT3 levels are correlated bioquimical and anthropometric parameters indicators of malnutrition and inflammation. Periodical measurement of FT3 levels could be used by clinicians as an accessible and reproducible method to detect such states (AU)

Introducción: Un alto porcentaje de pacientes en diálisis presenta niveles séricos disminuidos de triiodotironina libre (T3L), y algunos autores han mostrado su relación con marcadores de inflamación. Niveles bajos de T3L también se han mostrado como predictores independientes de mortalidad en diálisis. Objetivo: Evaluar la incidencia de síndrome T3L baja en un grupo de pacientes en diálisis y analizar su relación con diferentes parámetros de malnutrición e inflamación. Pacientes y métodos: Se estudiaron 32 pacientes estables en diálisis (24 hemodiálisis y 8 diálisis peritoneal), edad (media ± DS) 71,2 ± 11,7 años; 46,9% varones; 15,6% diabéticos; media de tiempo en diálisis 47 ± 43 meses. En cada paciente se cuantificó: tirotropina, T4 Libre y T3L; parámetros bioquímicos relacionados con nutrición e inflamación; parámetros antropométricos, composición corporal mediante bioimpedancia eléctrica con análisis vectorial e ingesta de nutrientes. El análisis estadístico se hizo usando un SPSS 11.0. Resultados: La media de los valores de las hormonas tiroideas fue: TSH 2,2 ± 1,5 U/ml (rango 0,4-5,0), T4L 14,7 ± 2,3 pmol/l (rango: 11,0-23,0) y T3L 4,0 ± 0,71 pmol/l (rango: 3,95-6,80). Sólo dos pacientes (6,3%) mostraron niveles de T4L bajos, y otros dos pacientes aumento de TSH, mientras que 17 pacientes (53,1%) presentaron niveles bajos de T3L. No encontramos ninguna correlación entre los niveles de T3L, T4L y TSH. Los niveles de T3L se correlacionaron con parámetros de inflamación/ nutrición: prealbúmina (r = 0,36; p = 0,04); transferrina (r = 0,40; p = 0,025); proteína C reactiva (r = - 0,38; p = 0,039); y factor de crecimiento similar a la insulina (r = 0,38; p = 0,03); índice de masa corporal (r = 0,51; p = 0,002); circunferencia de brazo (r = 0,65; p = 0,000); perímetro muscular de brazo (r = 0,72; p = 0,000), ángulo de fase (r = 0,57; p = 0,001); porcentaje de masa muscular (r = 0,49; p = 0,005) y porcentaje de masa celular (r = 0,54; p = 0,002). En el análisis de regresión lineal múltiple, el perímetro muscular del brazo fue la única variable que mostró asociación independiente con los niveles de T3L (r = 0,69; p = 0,000). Conclusión: Alrededor del 50% de los pacientes en diálisis tienen niveles séricos disminuidos de T3L sin alteración de TSH o T4L. Estos niveles se correlacionan con parámetros de malnutrición e inflamación. Su determinación periódica podría facilitar al clínico un método accesible y reproducible de detección de estos estados (AU)

Induction and reversibility of insulin resistance in rats exposed to exogenous D-fructose.

Long-term exposure of normal rats to a fructose-enriched diet or drinking water is currently used as an animal model for experimental insulin resistance. The present study deals with a comparison between rats given access to either a fructose-enriched diet or fructose-enriched drinking water. In both situations, a decrease in food intake and body weight gain, and the induction of insulin resistance with intolerance to D-glucose despite increased secretory response to the aldohexose of insulin-producing cells were documented. Moreover, the rats exposed to exogenous D-fructose displayed a lesser sensitivity to overnight fasting than control animals, in terms of the alteration of glucose homeostasis and reduction of the ratio between plasma insulin and D-glucose concentration. It is also shown that the fructose-induced insulin resistance, as assessed in a hyperinsulinemic-euglycemic clamp, represents a phenomenon reversed within 15-30 days after removal of the keto-hexose from the drinking water.