Intrauterine arsenic exposure induces glucose metabolism disorders in adult offspring by targeting TET2-mediated DNA hydroxymethylation reprogramming of HNF4α in developing livers, an effect alleviated by ascorbic acid.

Exposure to arsenic during gestation has lasting health-related effects on the developing fetus, including an increase in the risk of metabolic disease later in life. Epigenetics is a potential mechanism involved in this process. Ten-eleven translocation 2 (TET2) has been widely considered as a transferase of 5-hydroxymethylcytosine (5hmC). Here, mice were exposed, via drinking water, to arsenic or arsenic combined with ascorbic acid (AA) during gestation. For adult offspring, intrauterine arsenic exposure exhibited disorders of glucose metabolism, which are associated with DNA hydroxymethylation reprogramming of hepatic nuclear factor 4 alpha (HNF4α). Further molecular structure analysis, by SEC-UV-DAD, SEC-ICP-MS, verified that arsenic binds to the cysteine domain of TET2. Mechanistically, arsenic reduces the stability of TET2 by binding to it, resulting in the decrease of 5hmC levels in Hnf4α and subsequently inhibiting its expression. This leads to the disorders of expression of its downstream key glucose metabolism genes. Supplementation with AA blocked the reduction of TET2 and normalized the 5hmC levels of Hnf4α, thus alleviating the glucose metabolism disorders. Our study provides targets and methods for the prevention of offspring glucose metabolism abnormalities caused by intrauterine arsenic exposure.

Former long-term use of combined hormonal contraception and glucose metabolism disorders in perimenopausal women: A prospective, population-based cohort study.

INTRODUCTION: Current use of combined hormonal contraceptives worsens glucose tolerance and increases the risk of type 2 diabetes mellitus at late fertile age, but the impact of their former use on the risk of glucose metabolism disorders is still controversial. MATERIAL AND METHODS: This was a prospective, longitudinal birth cohort study with long-term follow-up consisting of 5889 women. The cohort population has been followed at birth, and at ages of 1, 14, 31 and 46. In total, 3280 (55.7%) women were clinically examined and 2780 also underwent a 2-h oral glucose tolerance test at age 46. Glucose metabolism indices were analyzed in former combined hormonal contraceptive users (n = 1371) and former progestin-only contraceptive users (n = 52) and in women with no history of hormonal contraceptive use (n = 253). RESULTS: Compared with women with no history of hormonal contraceptive use, those who formerly used combined hormonal contraceptives for over 10 years had an increased risk of prediabetes (odds ratio [OR] 3.9, 95% confidence interval [CI]: 1.6-9.2) but not of type 2 diabetes mellitus. Former progestin-only contraceptive use was not associated with any glucose metabolism disorders. The results persisted after adjusting for socioeconomic status, smoking, alcohol consumption, parity, body mass index and use of cholesterol-lowering medication. CONCLUSIONS: Former long-term use of combined hormonal contraceptives was associated with a significantly increased risk of prediabetes in perimenopausal women, which potentially indicates a need of screening for glucose metabolism disorders in these women.

Maternal and fetal metabolomic alterations in maternal lipopolysaccharide exposure-induced male offspring glucose metabolism disorders.

Maternal lipopolysaccharide (LPS) exposure during pregnancy induces metabolic abnormalities in male offspring, but the underlying mechanisms remain unclear. The purpose of this study was to investigate the effects of maternal LPS exposure during pregnancy on metabolic profiling of maternal serum and male fetal liver using Liquid Chromatograph Mass Spectrometer techniques. From day 15 to day 17 of gestation, pregnant mice were administered intraperitoneal LPS (experimental group) (50 µg/kg/d) or saline (control group). On day 18 of gestation, maternal serum and male fetal liver were collected. After LPS exposure, levels of 38 and 75 metabolites, mainly glycerophospholipid and fatty acid metabolites, were altered in maternal serum and male fetal liver, respectively. It was found that in maternal serum and male fetal livers, the glycerophospholipids containing saturated fatty acids (SFAs) and the SFAs were upregulated, while the glycerophospholipids containing polyunsaturated fatty acids (PUFAs) and the PUFAs were downregulated. This concordance between maternal and fetal alterations in glycerophospholipid and fatty acid metabolites may be a metabolomic signature of the early intrauterine period and may provide insight into the mechanisms by which maternal LPS exposure induces disorders of glucose metabolism in male offspring.

Clozapine Induced Disturbances in Hepatic Glucose Metabolism: The Potential Role of PGRMC1 Signaling.

Newly emerging evidence has implicated that progesterone receptor component 1 (PGRMC1) plays a novel role not only in the lipid disturbance induced by atypical antipsychotic drugs (AAPD) but also in the deterioration of glucose homoeostasis induced by clozapine (CLZ) treatment. The present study aimed to investigate the role of PGRMC1 signaling on hepatic gluconeogenesis and glycogenesis in male rats following CLZ treatment (20 mg/kg daily for 4 weeks). Recombinant adeno-associated viruses (AAV) were constructed for the knockdown or overexpression of hepatic PGRMC1. Meanwhile, AG205, the specific inhibitor of PGRMC1 was also used for functional validation of PGRMC1. Hepatic protein expressions were measured by western blotting. Meanwhile, plasma glucose, insulin and glucagon, HbA1c and hepatic glycogen were also determined by assay kits. Additionally, concentrations of progesterone (PROG) in plasma, liver and adrenal gland were measured by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Our study demonstrated that CLZ promoted the process of gluconeogenesis and repressed glycogenesis, respectively mediated by PI3K-Akt-FOXO1 and GSK3ß signaling via inhibition of PGRMC1-EGFR/GLP1R in rat liver, along with an increase in fasting blood glucose, HbA1c levels and a decrease in insulin and hepatic glycogen levels. Furthermore, through PGRMC1-EGFR/GLP1R-PI3K-Akt pathway, knockdown or inhibition (by AG205) of PGRMC1 mimics, whereas its overexpression moderately alleviates CLZ-induced glucose disturbances. Potentially, the PGRMC1 target may be regarded as a novel therapeutic strategy for AAPD-induced hepatic glucose metabolism disorder.

Current use of combined hormonal contraception is associated with glucose metabolism disorders in perimenopausal women.

OBJECTIVE: The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial. DESIGN: The study is a prospective longitudinal population-based cohort study. METHODS: The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n = 153), progestin-only contraceptive (POC, n = 842), and non-hormonal contraceptive users (n = 884). RESULTS: In the entire study population, current CHC use was significantly associated with prediabetes (OR: 2.0, 95% CI: 1.3-3.2) and type 2 diabetes (OR: 3.3, 95% CI: 1.1-9.7) compared to non-hormonal contraceptive use. After 5 years of use, the prediabetes risk increased 2.2-fold (95% CI: 1.3-3.7) and type 2 diabetes risk increased 4.5-fold (95% CI: 1.5-13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR: 1.9, 95% CI: 1.2-3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for BMI and socioeconomic status. CONCLUSIONS: CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.

Link between body weight changes and metabolic parameters in drugs naïve subjects with type 2 diabetes treated with canagliflozin monotherapy.

OBJECTIVES: The aim of this study is to investigate the correlations between the changes of body weight and metabolic parameters during canagliflozin treatment. METHODS: Drug naïve subjects with T2DM (n = 84) received canagliflozin monotherapy for 3 months. The subjects were divided into three groups with equal numbers of subjects (n = 28 each) according to the reductions of BMI levels; highest (group A), intermediate (group B), and lowest (group C) reductions. Changes of the metabolic parameters were compared between group A and group C. These two groups acted as a control of each other. RESULTS: Significant reductions of BMI levels (-4.1%, p < 0.00001) were observed in group A, while, surprisingly, significant increases (+1.5%, p < 0.00001) were seen in group C. In these two groups, similar reductions of HbA1c, FBG, or HOMA-R, and increases of HOMA-B levels were observed. Significant reductions of TG levels (-18.6%) were seen only in group A. At baseline, HbA1c levels were significantly lower in group A versus group C (p < 0.03). In group A, significant correlations between the changes of BMI and those of HbA1c (R = 0.496) were seen. By contrast, in group C, significant negative correlations were observed between these parameters (R = -0.463). CONCLUSIONS: These results suggest that certain populations treated with canagliflozin gained weight, though similar glycemic and beta-cell/insulin sensitivity enhancing properties were observed in comparison to those with efficient weight reductions. Those who lost more weight had better glycemic efficacy in group A. By contrast, those who gained more weight had better glycemic efficacy in group C. Distinct glucose-lowering mechanisms might be operating between these two groups. Involvement of some factors including glucagons and free fatty acids is hypothesized.

Glucose metabolism disorders in children with refractory nephrotic syndrome.

BACKGROUND: Patients with refractory nephrotic syndrome (NS) are at high risk of medication-induced glucose metabolism disorders, because of their long-term use of diabetogenic medications, particularly glucocorticoids and calcineurin inhibitors (CNIs). However, there have been no comprehensive evaluations of glucose metabolism disorders in pediatric patients with refractory NS. Moreover, glucocorticoids and CNIs could not be discontinued in these patients until the effectiveness of rituximab on refractory NS was shown, and therefore, there has been limited opportunity to evaluate glucose metabolism disorders after discontinuation of these medications. METHODS: Consecutive pediatric patients who started rituximab treatment for refractory NS were enrolled. Their glucose metabolism conditions were evaluated using the oral glucose tolerance tests (OGTT) and HbA1c levels at the initiation of rituximab treatment. Patients with glucose metabolism disorders at the first evaluation were reevaluated after approximately 2 years. RESULTS: Overall, 57% (20/35) of study patients had glucose metabolism disorders, and 40% (8/20) of these patients were detected only by their 2-h OGTT blood glucose levels and not by their fasting blood glucose or HbA1c levels. Non-obese/non-overweight patients had significantly more glucose metabolism disorders than obese/overweight patients (p = 0.019). In addition, glucose metabolism disorders in 71% (10/14) of patients persisted after the discontinuation of glucocorticoids and CNIs. CONCLUSIONS: Whether the patient is obese/overweight or not, patients with refractory NS are at high risk of developing glucose metabolism disorders, even in childhood. Non-obese/non-overweight patients who are at high risk of diabetes need extra vigilance.

[The impact of bilberry fruits polyphenols, sorbed on buckwheat flour, on the induced disorders of carbohydrate metabolism of male C57BL/6c mice].

The hypoglycemic properties of polyphenolic compounds of plant origin are confirmed by the results of numerous preclinical and clinical studies. However, the biological effects of these compounds are limited by their low bioavailability. This makes it urgent to develop methods for its increasing due to new methods of entering polyphenols into the organism, for example, by extracting them from natural sources in the form of extracts and concentrating extracts on food polymer matrices for subsequent use as a functional food ingredient (FFI). The aim of this study was to evaluate in vivo the possible effect of consumption of the obtained FFI in the form of a food matrix - buckwheat flour enriched with bilberry polyphenols - on carbohydrate metabolism disorders induced by a high-fat diet with a high content of easily digestible carbohydrates (sucrose) and anxiety level of male C57Bl/6c mice. Material and methods. The food matrix was obtained by sorption of the bilberry fruits polyphenol extract on buckwheat flour. The total polyphenol content in the composition of food matrix was 8.9±0.7 mg-eq gallic acid/g flour. Total anthocyanin content in the composition of food matrix was 4.6±0.1 mg/g flour. The experiment was conducted for 150 days using 48 male C57Bl/6c mice (weaners). The animals were divided into 3 groups: the control group K1 (n=16, the mice received a standard semi-synthetic diet (22.5% protein, 10% fat, 58% carbohydrates as starch, 362 kcal/100 g), the control group K2 (n=14) and the experimental group G3 (n=18). Disorders of carbohydrate and lipid metabolism in animals of groups K2 and G3 were modeled by feeding an iso-nitrogenous high-fat diet with a high content of easily digestible carbohydrates (HFHC-diet: 22.5% protein, 30% fat, 18% carbohydrates in the form of starch, 20% sucrose, 493 kcal/100 g). FFI, a food matrix in the amount of 6.6 g/100 g of feed, was introduced into the diet of animals of the experimental group G3, which corresponded to the amount of polyphenols equal to 58.7 mg-eq gallic acid/100 g of feed and the content of anthocyanins 30.4 mg/100 g of feed. Once every three weeks, the level of glucose in the blood of animals was monitored. On days 60 and 114 of the experiment, animals were tested on an elevated plus maze. Animals were decapitated under light ether anesthesia at the end of experiment. The content of glycated hemoglobin was determined in the blood. Results and discussion. Animals of both groups treated with HFHC-diet consumed significantly less feed compared with animals of the control group K1 (2.91±0.05 g/day per mouse). Moreover, animals of the experimental group G3 consumed significantly more food (2.51±0.04 g/day per mouse) compared with animals of the control group K2 (2.36±0.04 g/day per mouse). In contrast, the energy consumption of animals of both groups fed HFHC-diet was significantly higher compared to the K1 group (10.5±0.2 kcal/ day per mouse). Energy consumption by animals of group G3 (12.3±0.2 kcal/day per mouse) was significantly higher compared to animals of the control group K2 (11.5±0.2 kcal/day per mouse). The data obtained indicate that the consumption of FFI in the form of polyphenols adsorbed on the food matrix can contribute to increased appetite in animals treated with the high-fat diet. The results of the Elevated Plus Maze test indicated the absence of the effect of polyphenols in the composition of the food matrix on the anxiety level of animals. Starting from day 42 until the end of the experiment, the glucose level in animals of group G3 was significantly lower than the corresponding indicator for animals of the control group K2. Conclusion. In accordance with the results obtained, further studies of the safety and clinical efficacy of including the developed FFI in the form of a food matrix with polyphenols into the composition of specialized foods for the prevention of carbohydrate metabolism disorders are advisable.

Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain.

Second-generation antipsychotics (SGAs) are the cornerstone of treatment for schizophrenia because of their high clinical efficacy. However, SGA treatment is associated with severe metabolic alterations and body weight gain, which can increase the risk of type 2 diabetes and cardiovascular disease, and greatly accelerate mortality. Several underlying mechanisms have been proposed for antipsychotic-induced weight gain (AIWG), but some studies suggest that metabolic changes in insulin-sensitive tissues can be triggered before the onset of AIWG. In this review, we give an outlook on current research about the metabolic disturbances provoked by SGAs, with a particular focus on whole-body glucose homeostasis disturbances induced independently of AIWG, lipid dysregulation or adipose tissue disturbances. Specifically, we discuss the mechanistic insights gleamed from cellular and preclinical animal studies that have reported on the impact of SGAs on insulin signaling, endogenous glucose production, glucose uptake and insulin secretion in the liver, skeletal muscle and the endocrine pancreas. Finally, we discuss some of the genetic and epigenetic changes that might explain the different susceptibilities of SGA-treated patients to the metabolic side-effects of antipsychotics.

Samidorphan mitigates olanzapine-induced weight gain and metabolic dysfunction in rats and non-human primates.

BACKGROUND: Olanzapine, regarded as one of the most efficacious antipsychotic medications for the treatment of schizophrenia, is associated with a high risk of weight gain and metabolic dysfunction. ALKS 3831, a clinical candidate for treatment of schizophrenia, is a combination of olanzapine and samidorphan, an opioid receptor antagonist. The addition of samidorphan is intended to mitigate weight gain and the metabolic dysregulation associated with the use of olanzapine. METHODS: Non-clinical studies were conducted to assess the metabolic effects of olanzapine and samidorphan alone and in combination at clinically relevant exposure levels. RESULTS: Chronic olanzapine administration in male and female rats shifted body composition by increasing adipose mass, which was accompanied by an increase in the rate of weight gain in female rats. Co-administration of samidorphan normalized body composition in both sexes and attenuated weight gain in female rats. In hyperinsulinemic euglycemic clamp experiments conducted prior to measurable changes in weight and/or body composition, olanzapine decreased hepatic insulin sensitivity and glucose uptake in muscle while increasing uptake in adipose tissue. Samidorphan appeared to normalize glucose utilization in both tissues, but did not restore hepatic insulin sensitivity. In subsequent studies, samidorphan normalized olanzapine-induced decreases in whole-body glucose clearance following bolus insulin administration. Results from experiments in female monkeys paralleled the effects in rats. CONCLUSIONS: Olanzapine administration increased weight gain and adiposity, both of which were attenuated by samidorphan. Furthermore, the combination of olanzapine and samidorphan prevented olanzapine-induced insulin insensitivity. Collectively, these data indicate that samidorphan mitigates several metabolic abnormalities associated with olanzapine in both the presence and the absence of weight gain.

Low intake of digestible carbohydrates ameliorates duodenal absorption of carbohydrates in mice with glucose metabolism disorders induced by artificial sweeteners.

BACKGROUND: Long-term artificial sweetener consumption has been reported to induce glucose intolerance, and the intestinal microbiota seems as an important target. While the impacts of artificial sweeteners on energy balance remain controversial, this work aimed to evaluate the protective effects in mice of a low digestible carbohydrate (LDC) diet on plasma glucose, plasma fasting insulin, sweet taste receptors, glucose transporters, and absorption of carbohydrates, together with consumption of acesulfame potassium (AK) or saccharin (SAC). RESULTS: Artificial sweetener was administered to mice for 12 weeks to induce glucose metabolism disorders; mice were treated with an LDC diet for the final 6 weeks. The experimental groups were treated with an LDC diet that had the same energy as the normal-diet group. Prolonged administration of artificial sweeteners led to metabolic dysfunction, characterized by significantly increased plasma glucose, insulin resistance, sweet taste receptors, glucose transporters, and absorption of carbohydrates. Treatment with an LDC diet positively modulated these altered parameters, suggesting overall beneficial effects of an LDC diet on detrimental changes associated with artificial sweeteners. CONCLUSIONS: Reducing digestible carbohydrates in the diet can significantly reduce the absorption of carbohydrates and improve glucose metabolism disorders caused by dietary factors. These effects may be due to the fact that reducing the amount of digestible carbohydrates in the feed can reduce the number of intestinal sweet receptors induced by exposure to artificial sweeteners. © 2019 Society of Chemical Industry.

The influence of polymorphisms in the drug transporter, ABCB1 on the toxicity of glucocorticoids in Saudi children with acute lymphoblastic leukaemia.

BACKGROUND: Glucocorticoids play essential roles in the treatment of childhood acute lymphoblastic leukaemia (ALL); however, treatment with these agents can result in severe side-effects. This study, the first of its kind in a Saudi population, investigates associations of ABCB1 gene polymorphisms (pharmacodynamics and pharmacokinetic) with the development of toxicity and side effects (glucose abnormality, liver toxicity and infection) in a small population of Saudi children with ALL. METHODS: Three single nucleotide polymorphisms (SNPs) of the ABCB1 gene (rs 3213619 T129C, rs 2032582 G2677T and rs1045642 C3435T) were analysed in 70 Saudi children with ALL and 60 control subjects. Participants were treated according to the ALL 2000 study protocol. Toxicities were assessed and associations with genotypes were evaluated according to Common Toxicity Criteria (NCI-CTC). RESULTS: Significant associations were observed among carriers and the mutated genotype C3435T (ABCB1), which had an incidence of infection (p = 0.05). Although no correlations were found between liver toxicity and glucose abnormalities for patients carrying ABCB1 SNPs, risk factors for liver toxicity were elevated by a factor of three for patients carrying the SNP G2677T, OR 3.00 (1.034-8.702). The risk factor of glucose abnormality toxicity for the patients carring T129C were increased three times OR 3.06 (0.486-19.198). CONCLUSIONS: In terms of infection incidence, polymorphism C3435T may contribute to potential life-threatening infections during paediatric ALL therapy, through glucocorticoid usage.

Metabolic Effects of a Chronic Dietary Exposure to a Low-Dose Pesticide Cocktail in Mice: Sexual Dimorphism and Role of the Constitutive Androstane Receptor.

BACKGROUND: Epidemiological evidence suggests a link between pesticide exposure and the development of metabolic diseases. However, most experimental studies have evaluated the metabolic effects of pesticides using individual molecules, often at nonrelevant doses or in combination with other risk factors such as high-fat diets. OBJECTIVES: We aimed to evaluate, in mice, the metabolic consequences of chronic dietary exposure to a pesticide mixture at nontoxic doses, relevant to consumers' risk assessment. METHODS: A mixture of six pesticides commonly used in France, i.e., boscalid, captan, chlorpyrifos, thiofanate, thiacloprid, and ziram, was incorporated in a standard chow at doses exposing mice to the tolerable daily intake (TDI) of each pesticide. Wild-type (WT) and constitutive androstane receptor-deficient (CAR-/-) male and female mice were exposed for 52 wk. We assessed metabolic parameters [body weight (BW), food and water consumption, glucose tolerance, urinary metabolome] throughout the experiment. At the end of the experiment, we evaluated liver metabolism (histology, transcriptomics, metabolomics, lipidomics) and pesticide detoxification using liquid chromatography-mass spectrometry (LC-MS). RESULTS: Compared to those fed control chow, WT male mice fed pesticide chow had greater BW gain and more adiposity. Moreover, these WT males fed pesticide chow exhibited characteristics of hepatic steatosis and glucose intolerance, which were not observed in those fed control chow. WT exposed female mice exhibited fasting hyperglycemia, higher reduced glutathione (GSH):oxidized glutathione (GSSG) liver ratio and perturbations of gut microbiota-related urinary metabolites compared to WT mice fed control chow. When we performed these experiments on CAR-/- mice, pesticide-exposed CAR-/- males did not exhibit BW gain or changes in glucose metabolism compared to the CAR-/- males fed control chow. Moreover, CAR-/- females fed pesticide chow exhibited pesticide toxicity with higher BWs and mortality rate compared to the CAR-/- females fed control chow. CONCLUSIONS: To our knowledge, we are the first to demonstrate a sexually dimorphic obesogenic and diabetogenic effect of chronic dietary exposure to a common mixture of pesticides at TDI levels, and to provide evidence for a partial role for CAR in an in vivo mouse model. This raises questions about the relevance of TDI for individual pesticides when present in a mixture. https://doi.org/10.1289/EHP2877.

Efficacy and safety of aripiprazole for the treatment of schizophrenia: an overview of systematic reviews.

PURPOSE: To conduct an overview to summarize the efficacy and safety of aripiprazole for the treatment of schizophrenia. METHODS: A literature search was performed in PubMed, the Cochrane Library, LILACS, and the Centre for Reviews and Dissemination, for articles published until March 31, 2017. We included systematic reviews with meta-analyses of randomized controlled trials assessing the efficacy, and/or the safety of aripiprazole, for patients with schizophrenia. Two authors independently performed the study selection, data extraction, and quality assessment. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach and the Risk of Bias in Systematic Review (ROBIS) tool were used to appraise the quality of evidence and the risk of bias in the reviews, respectively. RESULTS: Fourteen studies fulfilled the inclusion criteria. Aripiprazole showed efficacy similar to that of both typical and atypical antipsychotic drugs (except olanzapine and amisulpride). Aripiprazole caused significantly lower weight gain and alterations in glucose and cholesterol levels, as compared to clozapine, risperidone, and olanzapine. In addition, aripiprazole caused significantly fewer general extrapyramidal side effects, less use of antiparkinsonian drugs, and akathisia, compared with typical antipsychotic drugs and risperidone. The overall quality of evidence in the reviews ranged from "very low" to "moderate," principally because of the risk of bias of original trials, inconsistency, and imprecision in the outcomes. According to the ROBIS tool, there are four reviews with "high" risk of bias and five with "unclear" risk of bias. CONCLUSIONS: Aripiprazole exhibited efficacy similar to that of other antipsychotic drugs and a better safety profile than that of typical (i.e., less some extrapyramidal side effects) and atypical (i.e., less metabolic changes) antipsychotic drugs.

Di-(2-ethylhexyl)-phthalate induces glucose metabolic disorder in adolescent rats.

As a plasticizer, di-(2-ethylhexyl)-phthalate (DEHP) is widely added in various commercial products. Some researchers had suggested that DEHP has adverse effects on the glucose metabolism, but the mechanisms remain unclear. Adolescent Wistar rats were divided into four groups and administered DEHP by gavage at 0, 5, 50, and 500 mg kg-1 d-1 for 28 days. ELISA was used to quantify the serum insulin and leptin levels; RT-PCR, immunohistochemistry, and Western blot were used to detect the mRNA and protein expressions of Janus-activated kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling 3 (SOCS3), leptin receptor (Ob-R), and insulin receptor (IR) in liver and pancreas In comparison to the control group, the DEHP-treated rats showed the following: (1) higher organ coefficient of liver; (2) higher fasting blood glucose levels, higher fasting serum insulin and leptin levels, higher insulin resistance index homeostasis model assessment; (3) lower protein levels of Ob-R and IR in the liver and pancreas; (4) higher protein levels of JAK2 and STAT3 in the liver; and (5) higher protein and mRNA levels of SOCS3 in the liver and pancreas. Exposure to DEHP induced glucose metabolic disorder in the adolescent rats, and the mechanism is that DEHP may interfere with the JAK2/STAT3/SOCS3 pathway, regulated the sensitivity of the insulin receptor and leptin receptor.

Inactivation of TNF/LT locus alters mouse metabolic response to concentrated ambient PM2.5.

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with increased cardiometabolic morbidity and mortality. This is widely believed to be attributable to PM2.5 exposure-induced pulmonary and subsequent systemic inflammation. Tumor necrosis factor alpha (TNFα), lymphotoxin α (LTα), and lymphotoxin ß (LTß) are three homologous pro-inflammatory cytokines, each with both unique and redundant activities in inflammation. Their role in PM2.5 exposure-induced inflammation and adverse cardiometabolic effects has to be determined. METHODS AND RESULTS: LTα/TNFα/LTß triple-knockout (TNF/LT KO) and wildtype (WT) mice were exposed to concentrated ambient PM2.5 (CAP) for 5 months. Lung pathological analysis revealed that TNF/LT deficiency reduced CAP exposure-induced pulmonary inflammation. However, glucose homeostasis assessments showed that TNF/LT deficiency significantly aggravated CAP exposure-induced glucose intolerance and insulin resistance. Consistent with glucose homeostasis assessments, CAP exposure significantly increased the body weight and adiposity of TNF/LT KO but not WT mice. In contrast to its body weight effects, CAP exposure reduced food intake of WT but not TNF/LT KO mice. On the other hand, CAP exposure induced marked fat droplet accumulation in brown adipose tissues of WT mice and significantly decreased their uncoupling protein 1 (UCP1) expression, and these effects were markedly exacerbated in TNF/LT KO mice. CONCLUSION: The present study suggests that TNF/LT deficiency influences PM2.5 exposure-induced response of energy metabolism through alterations in both food intake and energy expenditure.

Steroid-induced impairment of glucose tolerance: Prevalence among pediatric patients on long-term steroid use in Nigeria.

INTRODUCTION: Glucocorticoid (referred to from here on as simply steroid) is used for effective treatment of various inflammatory disorders since its discovery in 1940s. However, these useful drugs cause important side effects, such as impairment of glucose tolerance. We sought to determine the prevalence of steroid-induced impairment of glucose tolerance in pediatric patients on long-term steroid use. MATERIALS AND METHODS: A cross-sectional, descriptive and hospital-based study. Consenting subjects who met the inclusion criteria were screened with random glucometer measurements repeated twice. An average of both readings obtained from the initial measurement of their random blood glucose (RBG) and a repeat during the next clinic visit was taken as the RBG. RESULTS: Hundred patients were studied, 66 males/34 females. Subjects with nephrotic syndrome were 61 while 39 had asthma. Mean age of 10.13 years (range: 0.5-18 years); mean body mass index (BMI): 18.2 kg/m2 (range: 6.6 to 26.30 kg/m2 ). The subjects with nephrotic syndrome were on oral prednisolone while the asthmatics were on inhaled fluticasone, budesonide and oral methylprednisolone. Mean (range) duration of steroid use was 9.74 (0.5-72) months. Mean (range) RBG was 3.49 (3.3-7.5) mmol/L. None of the subjects showed abnormal RBG. However, the RBG was further categorized into low, moderate and high normal RBG. A positive correlation between longer duration of steroid use as well as high doses of both oral and inhaled steroids, and high normal RBG existed (P = .015). No statistically significant relationship existed between body mass index (BMI) percentile and RBG (P = .437). CONCLUSION: Low to moderate doses of oral and inhaled steroids should be used when indicated as they are associated with lesser risk of impairment of glucose tolerance in the pediatric population.

Baseline glucose homeostasis predicts the new onset of diabetes during statin therapy: A retrospective study in real life.

OBJECTIVE: We evaluated the risk of altered glucose levels and new-onset diabetes (NOD) associated with statins according to glucose levels at baseline in a population treated for dyslipidemia on primary prevention for >5 years. DESIGN: The retrospective study included 308 subjects (265 on statins and 43 controls on diet) with a follow-up of 5-15 years. The cohort was classified according to glucose tolerance at both baseline and follow-up. RESULTS: The cumulative incidence of NOD was 13.6% (9.3% in controls and 13.5% in treated patients). NOD was diagnosed after 3.4±1.8 years. In the group with normal glucose levels at baseline, a family history of diabetes (OR: 3.4, 95% CI 1.3-8.9), BMI >30 kg/m2 (OR: 8.5, 95% CI 2.0-35.8), treatment with thiazide (OR: 21.9, 95% CI 1.2-384.2) and no alcohol consumption (OR: 0.3, 95% CI 0.1-0.8) reduced the risk of developing altered glucose levels or NOD. No effects of statins were seen. In the group with altered glucose levels at baseline, hypertension (OR: 5.0, 95% CI 1.0-25.3) and hypertriglyceridemia (OR: 3.5, 95% CI 1.0-11.8) increased the risk of remaining with altered glucose levels or developing NOD. Treatment with statins (OR: 7.5, 95% CI 1.5-37.4), in particular atorvastatin, was associated with an increased risk. In the whole population, statin therapy (OR: 4.0, 95% CI 1.1-14.1, p<0.020), and in particular simvastatin and atorvastatin, was associated with increased risk of altered glucose levels or NOD. Patients who developed or maintained altered glucose levels or NOD had a poor metabolic phenotype at baseline. CONCLUSIONS: Statins were associated with an increased risk of NOD or altered glucose levels, mainly in subjects with altered glucose levels before the beginning of therapy. Poor metabolic phenotype and unhealthy behaviors or family history of diabetes contributed to that risk.

Low-Level Environmental Lead Exposure and Dysglycemia in Adult Individuals: Results from the Canadian Health and Measure Survey 2007-2011.

We aimed to evaluate the association of exposure to lead with glycated hemoglobin (HbA1c), fasting glucose levels (FGLs), and the likelihood for dysglycemia. We accessed data from Canada Health and Measures Survey. General linear models were used to estimate the association between blood lead concentrations (BPb) and both HbA1c and FGLs, while controlling for confounders. Multivariate logistic regression was used for assessing the relation between BPb and the likelihood for dysglycemia. FGLs in participants with moderate BPb (2.5-5.0 µg/dL) were 1.03 (95 % CI 1.00-1.06) times higher compared with participants with BPb < 2.5 µg/dL. Equivalent figures for those with BPb ≥ 5.0 µg/dL were 1.10 (95 % CI 1.01-1.20) times, relative to the lowest stratum. This association was attenuated using HbA1c to define dysglycemia. Lead exposure was associated with the likelihood for neither FGLs ≥ 1.10 g/L nor HbA1c ≥ 5.7 %. The association between lead exposure and dysglycemia, if any, is likely to be very modest, at least at the population level.

The influence of phthalates and bisphenol A on the obesity development and glucose metabolism disorders.

The prevalence of obesity and type 2 diabetes mellitus epidemics presents a great health problem worldwide. Beside the changes in diet and decreased physical activity, there is growing interest in endocrine disrupting chemicals that may have effects on these conditions. Among them, the role of certain phthalates and bisphenol A is confirmed. We have summarized the existing literature on this issue including cross-sectional, follow up epidemiological studies and in vivo and in vitro studies. Most data support the effects of bisphenol A and some phthalates, such as di-2-ethyl-hexyl phthalate, diethyl phthalate, dibuthyl phthalate, dimethyl phthalate, dibenzyl phthalate, diisononyl phthalate and others on the development obesity and type 2 diabetes mellitus. These endocrine disrupting chemicals interfere with different cell signaling pathways involved in weight and glucose homeostasis. Since the data are rather inconsistent, there is a need for new, well-designed prospective studies.