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.

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.

[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.

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.

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.

Protective effects of marein on high glucose-induced glucose metabolic disorder in HepG2 cells.

BACKGROUND: Our previous study has shown that Coreopsis tinctoria increases insulin sensitivity and regulates hepatic metabolism in high-fat diet (HFD)-induced insulin resistance rats. However, it is unclear whether or not marein, a major compound of C. tinctoria, could improve insulin resistance. Here we investigate the effect and mechanism of action of marein on improving insulin resistance in HepG2 cells. METHODS: We investigated the protective effects of marein in high glucose-induced human liver carcinoma cell HepG2. In kinase inhibitor studies, genistein, LY294002, STO-609 and compound C were added to HepG2 cells 1h before the addition of marein. Transfection with siRNA was used to knock down LKB1, and 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2-deoxyglucose (2-NBDG), an effective tracer, was used to detect glucose uptake. RESULTS: The results showed for the first time that marein significantly stimulates the phosphorylation of AMP-activated protein kinase (AMPK) and the Akt substrate of 160kDa (AS160) and enhanced the translocation of glucose transporter 1 (GLUT1) to the plasma membrane. Further study indicated that genistein (an insulin receptor tyrosine kinase inhibitor) altered the effect of marein on glucose uptake, and both LY294002 (a phosphatidylinositol 3-kinase inhibitor) and compound C (an AMP-activated protein kinase inhibitor) significantly decreased marein-stimulated 2-NBDG uptake. Additionally, marein-stimulated glucose uptake was blocked in the presence of STO-609, a CaMKK inhibitor; however, marein-stimulated AMPK phosphorylation was not blocked by LKB1 siRNA in HepG2 cells. Marein also inhibited the phosphorylation of insulin receptor substrate (IRS-1) at Ser 612, but inhibited GSK-3ß phosphorylation and increased glycogen synthesis. Moreover, marein significantly decreased the expression levels of FoxO1, G6Pase and PEPCK. CONCLUSIONS: Consequently, marein improved insulin resistance induced by high glucose in HepG2 cells through CaMKK/AMPK/GLUT1 to promote glucose uptake, through IRS/Akt/GSK-3ß to increase glycogen synthesis, and through Akt/FoxO1 to decrease gluconeogenesis. Marein could be a promising leading compound for the development of hypoglycemic agent or developed as an adjuvant drug for diabetes mellitus.

Recognizing Endocrinopathies Associated With Tyrosine Kinase Inhibitor Therapy in Children With Chronic Myelogenous Leukemia.

Side effects of tyrosine kinase inhibitor (TKI) treatment vary in children and adults with chronic myelogenous leukemia (CML). As children have a much longer life expectancy than adults, TKI therapy may continue for decades and with long-term consequences that differ from adults. Children may develop endocrinopathies related to "off-target" effects of TKIs, such as delayed growth, changes in bone metabolism, thyroid abnormalities, and effects on puberty and fertility. These endocrinopathies present additional challenges for pediatric patients with CML. This review critically evaluates the literature on long-term endocrine side effects of TKIs in the pediatric CML population and provides suggested recommendations.

Drug-induced cerebral glucose metabolism resembling Alzheimer's Disease: a case study.

BACKGROUND: With aging of society the absolute number and the proportion of patients with cognitive deficits increase. Multiple disorders and diseases can foster cognitive impairment, e.g., Alzheimer's disease (AD), depressive disorder, or polypharmacy. CASE PRESENTATION: A 74 year old man presented to the Old Age Psychiatry Service with cognitive deficits while being treated for recurrent depressive episodes and essential tremor with Venlafaxine, Lithium, and Primidone. Neuropsychological testing revealed a medio-temporal pattern of deficits with pronounced impairment of episodic memory, particularly delayed recall. Likewise, cognitive flexibility, semantic fluency, and attention were impaired. Positron emission tomography (PET) with fluorodeoxyglucose was performed and revealed a pattern of glucose utilization deficit resembling AD. On cessation of treatment with Lithium and Primidone, cognitive performance improved, particularly episodic memory performance and cognitive flexibility. Likewise, glucose metabolism normalized. Despite normalization of both, clinical symptoms and glucose utilization, the patient remained worried about possible underlying Alzheimer's disease pathology. To rule this out, an amyloid-PET was performed. No cortical amyloid was observed. CONCLUSION: Pharmacological treatment of older subjects may mimic glucose metabolism and clinical symptoms of Alzheimer's disease. In the present case both, imaging and clinical findings, reversed to normal on change of treatment. Amyloid PET is a helpful tool to additionally rule out underlying Alzheimer's disease in situations of clinical doubt even if clinical or other imaging findings are suggestive of Alzheimer's disease.

Rapamycin-induced metabolic defects are reversible in both lean and obese mice.

The inhibition of mTOR (mechanistic target of rapamycin) by the macrolide rapamycin has many beneficial effects in mice, including extension of lifespan and reduction or prevention of several age-related diseases. At the same time, chronic rapamycin treatment causes impairments in glucose metabolism including hyperglycemia, glucose intolerance and insulin resistance. It is unknown whether these metabolic effects of rapamycin are permanent or whether they can be alleviated. Here, we confirmed that rapamycin causes glucose intolerance and insulin resistance in both inbred and genetically heterogeneous mice fed either low fat or high fat diets, suggesting that these effects of rapamycin are independent of genetic background. Importantly, we also found that these effects were almost completely lost within a few weeks of cessation of treatment, showing that chronic rapamycin treatment does not induce permanent impairment of glucose metabolism. Somewhat surprisingly, chronic rapamycin also promoted increased accumulation of adipose tissue in high fat fed mice. However, this effect too was lost when rapamycin treatment was ended suggesting that this effect of rapamycin is also not permanent. The reversible nature of rapamycin's alterations of metabolic function suggests that these potentially detrimental side-effects might be managed through alternative dosing strategies or concurrent treatment options.

Glucometabolic hormones and cardiovascular risk markers in antipsychotic-treated patients.

OBJECTIVE: Treatment with antipsychotic drugs is widely associated with metabolic side effects such as weight gain and disturbed glucose metabolism, but the pathophysiologic mechanisms are unclear. METHOD: Fifty nondiabetic (fasting plasma glucose ≤ 7.0 mmol/L), antipsychotic-treated male patients (ICD-10 diagnosis code F20, F21, F22, F25, F28, or F60; mean ± SD age = 33.0 ± 6.7 years; body mass index [BMI; kg/m²] = 26.0 ± 4.7; waist circumference = 95.9 ± 13.3 cm; glycated hemoglobin A1c [HbA1c] = 5.7% ± 0.3%) and 93 age- and waist circumference-matched healthy male controls (age = 33 ± 7.3 years; BMI = 26.1 ± 3.9; waist circumference = 94.6 ± 11.9 cm; HbA1c = 5.7% ± 0.3%) participated in this cross-sectional study. Blood was sampled in the fasting state and 90 minutes after ingestion of a standardized liquid meal (2,268 kJ). The primary outcomes were glucometabolic hormones and cardiovascular risk markers. Data were collected between March 2008 and February 2010. RESULTS: Compared to healthy controls, patients were characterized by elevated fasting levels of proinsulin, C-peptide, and glucose-dependent insulinotropic polypeptide (GIP) (P < .05) and higher postprandial levels of insulin, proinsulin, C-peptide, and GIP (P ≤ .02). Also, patients exhibited elevated plasma levels of C-reactive protein and signs of dyslipidemia. Fasting plasma levels of insulin, glucagon, glucagon-like peptide-1 (GLP-1), ghrelin, leptin, adiponectin, tumor necrosis factor-α, plasminogen activator inhibitor-1, and interleukin-6 and postprandial levels of glucagon, GLP-1, ghrelin, leptin, and adiponectin did not differ between groups. CONCLUSIONS: Presenting with an insulin resistant-like pattern, including beta cell hypersecretion and elevated GIP levels, nondiabetic antipsychotic-treated patients display emerging signs of dysmetabolism and a compromised cardiovascular risk profile. The appetite-regulating hormones GLP-1 and ghrelin appear not to be influenced by antipsychotic treatment. Our findings provide new clinical insight into the pathophysiology associated with metabolic side effects of antipsychotic treatment and put emphasis on the importance of implementing metabolic screening into psychiatric practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00627757.

Cryptotanshinone reverses ovarian insulin resistance in mice through activation of insulin signaling and the regulation of glucose transporters and hormone synthesizing enzymes.

OBJECTIVE: To investigate the effects of cryptotanshinone (CRY), an active component of Chinese medicine, on ovarian androgen production, insulin resistance (IR), and glucose metabolism in mice. DESIGN: Animal model and in vitro tissue model. SETTING: University-affiliated laboratory. ANIMAL(S): Mice. INTERVENTION(S): Ovarian IR was induced by dexamethasone (DEX) in vivo. Animals were randomized to receive CRY treatment for 3 days or not. Ovulation rates, serum steroid levels, and glucose uptake in ovaries were quantified, and proteins in the phosphatidylinositol 3-hydroxy kinase pathway were measured. In vitro ovarian IR was also induced by DEX for 3 days. Ovarian steroid hormone secretion and glucose uptake were measured, and the hormone-synthesizing enzymes were determined by semiquantitative reverse transcription-polymerase chain reaction. MAIN OUTCOME MEASURE(S): Ovarian glucose uptake, in vivo ovulation rate, serum and culture medium steroid level, and molecular expression of phosphatidylinositol 3-hydroxy kinase and steroidogenic enzymes. RESULT(S): Dexamethasone significantly increased ovulation rates in vivo and increased T and E2 production and decreased ovarian glucose uptake in vivo and in vitro. Cryptotanshinone significantly reduced ovulation rates in vivo and decreased T and estrogen production in vitro. Cryptotanshinone attenuated the inhibition of DEX on AKT2 and suppressed the up-regulation of CYP11 and CYP17 expression by DEX. CONCLUSION(S): Cryptotanshinone reversed DEX-induced androgen excess and ovarian IR in mice through activation of insulin signaling and the regulation of glucose transporters and hormone-synthesizing enzymes. This suggests a potential role for CRY in treating the ovulatory dysfunction associated with PCOS.

Neurocognitive, mental health, and glucose disorders in farmers exposed to organophosphorus pesticides.

About 25 million agricultural workers in the developing world suffer from at least one episode of poisoning each year, mainly by anticholinesterase-like organophosphates (OPs). The objective of this cross-sectional study was to establish the OP toxicity in 187 occupationally exposed farmers in terms of neurocognitive impairment, mental health status, clinical symptoms, diabetes, and haematological factors. The exposed group was compared to 187 healthy age-, sex-, and education-matching controls. Neurocognitive impairment was measured using the Subjective Neurocognition Inventory (SNI) and mental health status using the General Health Questionnaire-28 (GHQ-28). The subjects were also tested for fasting blood glucose (FBG), blood urea nitrogen (BUN), cholesterol (CL), triglycerides (TG), creatinine, oral glucose tolerance test (GTT), high-density lipoprotein (HDL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). The exposed farmers showed higher FBG (p<0.001), BUN (p=0.007), CL (p<0.001), oral GTT (p<0.001), and lower AST (p<0.001), ALP (p<0.001), and creatinine (p=0.004) than controls. The rates of anxiety/ insomnia and severe depression were also significantly higher in the farmers than in controls (p=0.015 and p<0.001, respectively). Meanwhile, the rate of social dysfunction was significantly lower than in controls (p<0.001). Disorders affecting psychomotor speed, selective attention, divided attention, verbal memory, nonverbal memory, prospective memory, spatial functioning, and initiative/energy were all lower in the farmers (p<0.001). Farmers showed clinical symptoms eczema, saliva secretion, fatigue, headache, sweating, abdominal pain, nausea, superior distal muscle weakness, inferior distal muscle weakness, inferior proximal muscle weakness, breath muscle weakness, hand tingling, foot tingling, epiphoria, polyuria, miosis, dyspnoea, bradycardia, and rhinorrhoea, which all significantly correlated with the number of working years. These findings indicate that farmers who work with OPs are prone to neuropsychological disorders and diabetes.

The role of estrogens in control of energy balance and glucose homeostasis.

Estrogens play a fundamental role in the physiology of the reproductive, cardiovascular, skeletal, and central nervous systems. In this report, we review the literature in both rodents and humans on the role of estrogens and their receptors in the control of energy homeostasis and glucose metabolism in health and metabolic diseases. Estrogen actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution. Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation and inflammation. Estrogen actions in pancreatic islet ß-cells also regulate insulin secretion, nutrient homeostasis, and survival. Estrogen deficiency promotes metabolic dysfunction predisposing to obesity, the metabolic syndrome, and type 2 diabetes. We also discuss the effect of selective estrogen receptor modulators on metabolic disorders.

Economic grand rounds: economic costs of failure to monitor adverse effects of second-generation antipsychotics: an underestimated factor.

Since 2003, the U.S. Food and Drug Administration as well as the American Diabetes Association, the American Psychiatric Association, and others have called for routine monitoring of cardiometabolic risk factors for patients of all ages prescribed second-generation antipsychotic medications. This survey of major public and private mental health treatment systems in 2010 found that adherence to such guidelines was limited. The authors describe some of the impediments to widespread monitoring of cardiometabolic risk factors among psychiatric patients taking second-generation antipsychotics and advocate for a nationwide commitment to providing the organizational and financial supports necessary to ensure systematic screening of cardiometabolic health among such patients.

Weight gain and metabolic risks associated with antipsychotic medications in children and adolescents.

BACKGROUND: Antipsychotic-related weight gain and metabolic adverse effects have become a major focus, especially in youth. METHODS: Review of randomized, cohort, and pharmacoepidemiologic studies of antipsychotic-related weight gain and metabolic adverse effects and of interventions for their reduction in youth. RESULTS: Across 34 published head-to-head and placebo-controlled studies in youth with psychotic and bipolar disorders, weight gain ranged from 3.8 to 16.2 kg with olanzapine (n=353), 0.9-9.5 kg with clozapine (n=97), 1.9-7.2 kg with risperidone (n=571), 2.3-6.1 kg with quetiapine (n=133), and 0-4.4 kg with aripiprazole (n=451). In 24 placebo-controlled trials, the numbers-needed-to-harm for weight gain ≥7% in youth with bipolar disorder and schizophrenia were 39 (confidence interval [CI]: -1 to +6, not significant) for aripiprazole, 36 (CI: -1 to +7, not significant) for ziprasidone, 9 (CI: 7-14) for quetiapine, 6 (CI: 5-8) for risperidone, and 3 (CI: 3-4) for olanzapine. Data in youth with autism and disruptive behavior disorders, available only for some antipsychotics, suggest greater weight gain, possibly due to less prior antipsychotic exposure. Three-month results from a large cohort study in antipsychotic-naïve youth indicated that metabolic effects differ among second-generation antipsychotics, despite significant weight gain with all studied agents, suggesting additional, weight-independent effects. Further, pharmacoepidemiologic work indicates that antipsychotic polypharmacy increases the risk for obesity (odds ratio [OR]: 2.28 [CI: 1.49-3.65]) or any cardiovascular, cerebrovascular, or hypertensive adverse event (OR: 1.72 [CI: 1.10-2.69]). However, despite marked weight gain and its greater impact on youth, monitoring rates are low and studies of pharmacologic and behavioral interventions are extremely limited. CONCLUSIONS: More research is needed to develop strategies to minimize antipsychotic-related weight gain and metabolic effects in youth and to discover treatments with lower risk potential.

Epigallocatechin-3-O-gallate (EGCG) protects the insulin sensitivity in rat L6 muscle cells exposed to dexamethasone condition.

The tea polyphenol epigallocatechin-3-O-gallate (EGCG) displays some antidiabetic effects; however the mechanisms are incompletely understood. In the present study, the investigation of the effects of EGCG on insulin resistance was performed in rat L6 cells treated with dexamethasone. We found that dexamethasone increased Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1) and reduced phosphorylation of AMPK and Akt. Furthermore, glucose uptake and glucose transporter (GLUT4) translocation were inhibited by dexamethasone. However, the treatment of EGCG improved insulin-stimulated glucose uptake by increasing GLUT4 translocation to plasma membrane. Furthermore, we also demonstrated these EGCG effects essentially depended on the AMPK and Akt activation. Together, our data suggested that EGCG inhibited dexamethasone-induced insulin resistance through AMPK and PI3K/Akt pathway.

Hormonal contraception and metabolic outcomes in women with or at risk for HIV infection.

OBJECTIVE: The use of hormonal contraception (HC) is increasing in HIV-infected women. Both HC and HIV infection have been associated with adverse metabolic outcomes. We investigated the association of progestin-only and combined (estrogen/progestin) HC with disorders of glucose and lipid metabolism in HIV-infected and uninfected women. METHODS: Linear mixed models evaluated the association of HC type with fasting high density lipoprotein, low density lipoprotein, triglycerides, the homeostasis model assessment estimate of insulin resistance (HOMA-IR), and glucose in 885 HIV-infected and 408 HIV-uninfected women from the Women's Interagency HIV Study seen between October 2000 and September 2005. RESULTS: Compared with non-HC users, progestin-only HC was independently associated with lower HDL [-3 mg/dL; 95% confidence interval (CI) -5, -1 in HIV-infected and -6 mg/dL; 95% CI: -9, -3 in HIV-uninfected women] and greater HOMA-IR (+0.86; 95% CI: 0.51-1.22 and +0.56; 95% CI: 0.12-1.01). Combined HC was associated with higher HDL (+5 mg/dL; 95% CI: 2-7 and +5 mg/dL; 95% CI: 3-7). CONCLUSIONS: HIV-infected women using progestin-only HC have lower HDL and greater HOMA-IR than HIV-infected non-HC users. Combined HC may be preferred in HIV-infected women of reproductive age at risk for cardiovascular disease, but interactions with antiretroviral therapy that may impair contraceptive efficacy have been reported. Alternative HC methods that minimize adverse outcomes but maintain efficacy require further study.

Oral glucose tolerance tests in treated patients with schizophrenia. Data to support an adaptation of the proposed guidelines for monitoring of patients on second generation antipsychotics?

OBJECTIVE: A recent consensus conference has proposed guidelines for the monitoring for diabetes in patients with schizophrenia and also identifies the need of long-term prospective studies. METHOD: A large scale prospective study on metabolic risks of antipsychotic medication is currently ongoing. At baseline, patients get a full laboratory screening, ECG and an oral glucose tolerance test (OGTT). Baseline data on 100 non-diabetic patients at study inclusion and stable on medication for at least 6 months are presented. RESULTS: Glucose abnormalities are found in 22% of patients at baseline. A monitoring protocol based only on fasting glucose would not have detected 63.6% of these patients with classifiable glucose abnormalities in our sample. Fasting insulin and measures for insulin resistance have a high predictive value for abnormalities late in the OGTT. CONCLUSION: Already at baseline, metabolic problems are frequently present in patients with schizophrenia treated with antipsychotics. Adding assessment of fasting insulin in a monitoring protocol improves detection of glucose abnormalities late in an OGTT.