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.

Piperine Attenuates Bmal1-Mediated Glucose Metabolism Disorder in a Trpv1-Dependent Manner in HepG2 Cells.

Piperine (PIP), a pungent alkaloid found in black pepper, has various pharmacological effects by activating the transient receptor potential vanilloid 1 (TRPV1) receptor. In this study, the regulating effect of PIP on glucose metabolism and the underlying mechanism were examined using an insulin-resistant cell model. Results showed that PIP alleviated glucosamine (GlcN)-induced glucose metabolism disorder (from 59.19 ± 1.90 to 88.36 ± 6.57%), restored cellular redox balance (from 148.43 ± 3.52 to 110.47 ± 3.52%), improved mitochondrial function (from 63.76 ± 4.87 to 85.98 ± 5.12%), and mitigated circadian disruption in HepG2 cells via the mediation of circadian clock gene Bmal1. After the knockdown of the Trpv1 gene, the modulating effect of PIP on Bmal1-mediated glucose metabolism was weakened, indicating that PIP alleviated Bmal1-involved insulin resistance and circadian misalignment in a Trpv1-dependent manner in HepG2 cells.

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.

Haloxyfop-P-methyl induces immunotoxicity and glucose metabolism disorders and affects the Nrf2/ARE pathway mediated antioxidant system in Chiromantes dehaani.

Haloxyfop-P-methyl is used extensively in agricultural production, and its metabolites in soil have potentially toxic effects on aquatic ecosystems. In this study, we explored the toxicity of haloxyfop-P-methyl on Chiromantes dehaani. The results of the 21-day toxicity test showed that haloxyfop-P-methyl decreased the weight gain (WG), specific growth rate (SGR) and hepatosomatic index (HSI). In glucose metabolism, haloxyfop-P-methyl reduced pyruvate, lactate, lactate dehydrogenase and succinate dehydrogenase, but enhanced glucose-6-phosphate dehydrogenase and hexokinase. Furthermore, expression of glucose metabolism-related genes was upregulated. We cloned the full-length CdG6PDH gene, which contains a 1587 bp ORF that encoded a 528 amino acid polypeptide. In antioxidant system, haloxyfop-P-methyl increased glutathione, thioredoxin reductase and thioredoxin peroxidase activities and activated the Nrf2/ARE pathway through upregulation of ERK, JNK, PKC and Nrf2. In immunity, low concentrations haloxyfop-P-methyl, or short-term exposure, upregulated the expression of immune-related genes and enhanced immune-related enzymes activity, while high concentrations or long-term exposure inhibited immune function. In summary, haloxyfop-P-methyl inhibited the growth performance, disrupted glucose metabolism, activated the antioxidant system, and led to immunotoxicity. The results deepen our understanding of the toxicity mechanism of haloxyfop-P-methyl and provide basic biological data for the comprehensive assessment of the risk of haloxyfop-P-methyl to the environment and humans.

KLF7 promotes adipocyte inflammation and glucose metabolism disorder by activating the PKCζ/NF-κB pathway.

In the obesity context, inflammatory cytokines secreted by adipocytes lead to insulin resistance and are key to metabolic syndrome development. In our previous study, we found that the transcription factor KLF7 promoted the expression of p-p65 and IL-6 in adipocytes. However, the specific molecular mechanism remained unclear. In the present study, we found that the expression of KLF7, PKCζ, p-IκB, p-p65, and IL-6 in epididymal white adipose tissue (Epi WAT) in mice fed a high-fat diet (HFD) was significantly increased. In contrast, the expression of PKCζ, p-IκB, p-p65, and IL-6 was significantly decreased in Epi WAT of KLF7 fat conditional knockout mice. In 3T3-L1 adipocytes, KLF7 promoted the expression of IL-6 via the PKCζ/NF-κB pathway. In addition, we performed luciferase reporter and chromatin immunoprecipitation assays, which confirmed that KLF7 upregulated the expression of PKCζ transcripts in HEK-293T cells. Collectively, our results show that KLF7 promotes the expression of IL-6 by upregulating PKCζ expression and activating the NF-κB signaling pathway in adipocytes.

Combined Effects of ESRα DNA Methylation and Progesterone on Glucose Metabolic Disorders: The Henan Rural Cohort Study.

To explore the independent and combined effects of ESRα methylation and progesterone on impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM), a case-control study including 901 subjects was conducted. Generalized linear models were performed to assess the independent and combined effects of ESRα methylation and progesterone on IFG or T2DM. Methylation level of cytosine-phosphoguanine (CpG) 1 in the estrogen receptor α (ESRα) gene was positively related to IFG in both men (odds ratio (OR) (95% confidence interval (CI)): 1.77 (1.05, 3.00)) and postmenopausal women (OR (95% CI): 1.82 (1.09, 3.04)), whereas the association between CpG 1 and T2DM was not significant. Positive associations of progesterone with IFG and T2DM were observed in both men (OR (95% CI): 2.03 (1.18, 3.49) and 3.00 (1.63, 5.52)) and postmenopausal women (OR (95% CI): 2.13 (1.27, 3.56) and 3.30 (1.85, 5.90)). Participants with high CpG 1 methylation plus high progesterone had an increased risk of IFG and T2DM, both in men and postmenopausal women. ESRα methylation and progesterone were positively associated with IFG, and the positive association between progesterone and T2DM was also found. Importantly, we firstly found the combined effects of ESRα methylation and progesterone on IFG and T2DM.

[Electroacupuncture regulates glucose metabolism disorder through PI3K/Akt/GSK3ß signaling pathway in rats with depression].

OBJECTIVE: To explore the mechanism of electroacupuncture (EA) at "Zusanli" (ST36) on improving glucose metabolism disorder in chronic restraint induced depressed rats. METHODS: A total of 30 male SD rats were randomly divided into control, model and EA groups, with 10 rats in each group. The depression model was established by chronic restraint 2.5 h each day for 4 weeks. For rats in the EA group, EA stimulation (1 mA, 2 Hz, 30 min) was applied to bilateral ST36 during the modeling period, once a day for 4 weeks. The body weight of the rats was recorded before and after modeling. The behavior of rats was observed by sugar-water preference and forced swimming after modeling. The contents of glucose and glycosylated albumin in serum were determined by biochemical method. The histopathological morphology and liver glycogen content were observed by HE and PAS staining. The expression levels of phosphatidylinositol 3-kinase (PI3K), phosphorylated (p)-PI3K (p-PI3K), protein kinase B (Akt), p-Akt, glycogen synthase kinase-3ß (GSK3ß) and p-GSK3ß proteins in liver were determined by Western blot. RESULTS: Compared with the control group, the weight increment and sugar-water preference index decreased (P<0.01), the immobile swimming time was prolonged (P<0.01), the glucose and glycosylated albumin contents in serum increased (P<0.05), the expression of p-Akt protein and the ratio of p-Akt/Akt in liver tissues decreased (P<0.001), the expression of p-GSK3ß protein and the ratio of p-GSK3ß/GSK3ß in liver tissues increased (P<0.01,P<0.001) in the model group. Compared with the model group, the weight increment and sugar-water preference index increased (P<0.05), the immobile swimming time was shortened (P<0.05), the glucose and glycosylated albumin contents in serum decreased (P<0.05), the expressions of p-PI3K and p-Akt proteins and the ratio of p-PI3K/PI3K and p-Akt/Akt in liver tissues increased (P<0.05), the expression of p-GSK3ß protein and the ratio of p-GSK3ß/GSK3ß in liver tissues decreased (P<0.01) in the EA group. HE staining showed that the structure of the hepatic lobule was intact, no obvious inflammatory cell infiltration or fibrosis was observed in the lobule and interstitium, and no abnormalities were observed in the small bile duct, portal vein and artery in the portal area. PAS staining showed that the intensity of staining from the center of the hepatic lobule to the periphery of the hepatic lobule was gradually enhanced in the blank group, that is, the glycogen-rich granules in the hepatic cells were gradually increased; most of the hepatocytes were light colored and glycogen was lost significantly in the model group; while the intensity of hepatocyte staining increased, the staining intensity of the perilobular zone was weaker than that in the blank group, and the glycogen particles partially recovered in the EA group. CONCLUSION: EA intervention can regulate glucose metabolism disorder in chronic restraint induced depressed rats through PI3K/Akt/GSK3ß signaling pathway.

Placental mesenchymal stem cells restore glucose and energy homeostasis in obesogenic adipocytes.

Obesity (Ob) depicts a state of energy imbalance(s) being characterized by the accumulation of excessive fat and which predisposes to several metabolic diseases. Mesenchymal stem cells (MSCs) represent a promising option for addressing obesity and its associated metabolic co-morbidities. The present study aims at assessing the beneficial effects of human placental MSCs (P-MSCs) in mitigating Ob-associated insulin resistance (IR) and mitochondrial dysfunction both in vivo and in vitro. Under obesogenic milieu, adipocytes showed a significant reduction in glucose uptake, and impaired insulin signaling with decreased expression of UCP1 and PGC1α, suggestive of dysregulated non-shivering thermogenesis vis-a-vis mitochondrial biogenesis respectively. Furthermore, obesogenic adipocytes demonstrated impaired mitochondrial respiration and energy homeostasis evidenced by reduced oxygen consumption rate (OCR) and blunted ATP/NAD+/NADP+ production respectively. Interestingly, co-culturing adipocytes with P-MSCs activated PI3K-Akt signaling, improved glucose uptake, diminished ROS production, enhanced mitochondrial OCR, improved ATP/NAD+/NADP+ production, and promoted beiging of adipocytes evidenced by upregulated expression of PRDM16, UCP1, and PGC1α expression. In vivo, P-MSCs administration increased the peripheral blood glucose uptake and clearance, and improved insulin sensitivity and lipid profile with a coordinated increase in the ratio of ATP/ADP and NAD+ and NADP+ in the white adipose tissue (WAT), exemplified in WNIN/GR-Ob obese mutant rats. In line with in vitro findings, there was a significant reduction in adipocyte hypertrophy, increased mitochondrial staining, and thermogenesis. Our findings advocate for a therapeutic application of P-MSCs for improving glucose and energy homeostasis, i.e., probably restoring non-shivering thermogenesis towards obesity management.

Periodontitis induced by Porphyromonas gingivalis drives impaired glucose metabolism in mice.

Periodontitis has been demonstrated to be bidirectionally associated with diabetes and has been recognized as a complication of diabetes. As a periodontal pathogen, Porphyromonas gingivalis is a possible pathogen linking periodontal disease and systemic diseases. It has also been found to be involved in the occurrence and development of diabetes. In this study, 6-week-old male C57BL/6 mice were orally administered the P. gingivalis strain ATCC381 for 22 weeks. Histological analysis of the gingival tissue and quantified analysis of alveolar bone loss were performed to evaluate periodontal destruction. Body weight, fasting glucose, glucose tolerance test (GTT), and insulin tolerance test (ITT) were used to evaluate glucose metabolism disorder. We then analyzed the expression profiles of inflammatory cytokines and chemokines in gingival tissue, the liver, and adipose tissue, as well as in serum. The results showed that mice in the P. gingivalis-administered group developed apparent gingival inflammation and more alveolar bone loss compared to the control group. After 22 weeks of P. gingivalis infection, significant differences were observed at 30 and 60 min for the GTT and at 15 min for the ITT. P. gingivalis-administered mice showed an increase in the mRNA expression levels of the pro-inflammatory cytokines (TNF-α, IL-6, IL-17, and IL-23) and chemokines (CCL2, CCL8, and CXCL10) in the gingiva and serum. The expression levels of the glucose metabolism-related genes were also changed in the liver and adipose tissue. Our results indicate that oral administration of P. gingivalis can induce changes in the inflammatory cytokines and chemokines in the gingiva and blood, can lead to alveolar bone loss and to inflammatory changes in the liver and adipose tissues, and can promote glucose metabolism disorder in mice.

Prevalence of Glucose Metabolic Disorders and Associated Inflammatory Markers Among People Living with HIV in Sub-Saharan Africa.

Background: Glucose metabolic disorder (GMD) is closely related to inflammation among those living with HIV. However, there are extant studies regarding this phenomenon in sub-Saharan Africa (SSA) that bears the burden of HIV infection. Therefore, we assessed the associations between inflammation biomarkers and GMD on a cohort of HIV+ individuals in SSA. Methods: We conducted a cross sectional study at the largest (patient volume) HIV clinic in Tanzania from March to May 2018. Purposive sampling was used to identify 407 HIV+ patients on treatment. Data were collected using the World Health Organization (WHO) STEPwise approach for noncommunicable disease surveillance. Clinical and demographic variables were extracted from the medical chart. Fasting blood glucose and inflammatory markers [C-reactive protein (CRP), interleukin (IL)-6, IL-18, and soluble tumor necrosis factor receptor (sTNFR)-1, sTNFR-2] were measured. Bivariate and multivariate analysis was conducted to examine the association between the biomarkers and GMD. Results: GMD was present in 67.6% (n = 271). Among those with GMD, 44.5%, 38.4%, and 17.1% presented with impaired fasting glucose, impaired glucose tolerance, and diabetes mellitus, respectively. Being older (>55 years) and initiating smoking at an age >28 years was associated with GMD (P = 0.05). Engaging in moderate activity significantly reduced the risk of GMD (P = 0.04). Having a current CD4 count between 351 and 500 reduced the odds of GMD by 66.7% in comparison to clients with CD4 counts ≤350. Comparing the highest to the lowest quartile at the multivariate level, only CRP showed an independent significant association with GMD (adjusted odds ratio: 1.9; 95% confidence interval: 1.03-3.57). Despite a linear relationship, none of the other biomarkers showed a significant association with GMD. Conclusion: Our study shows that high CRP and low CD4 are important contributors to the prevalence of GMD. Even when controlling for confounding variables did not diminish the associations between GMD and CRP. These findings point to the importance of creating awareness, education, and screening for GMD in high-epidemic countries. More rigorous studies are needed to identify the manifestation of inflammation in HIV patients.

Prevalence and predictors of glucose metabolism disorders among People Living with HIV on combination antiretroviral therapy.

OBJECTIVE: We investigated prevalence and predictors of glucose metabolism disorders (GMDs) among People Living with HIV (PLWH) on efavirenz- and atazanavir/ritonavir-based combination antiretroviral therapy (cART). METHODS: This cross-sectional study involved adult PLWH on efavirenz- (n = 240) and atazanavir/ritonavir-based (n = 111) cART. The prevalence of GMDs was determined by fasting serum glucose, insulin, and homeostasis model assessment. A logistic regression model was used to determine predictors. RESULTS: The overall prevalence of GMDs for all regimens was 27.6% (97/351) [95% CI 23.0-32.6%] s, with 31.1% (75/240) [95% CI 25.4-37.5%] for efavirenz-based and 19.8% (22/111) [95% CI 12.9-28.5%)] for atazanavir/ritonavir-based cART group. The prevalence of impaired fasting glycemia was significantly higher (p = 0.026) in the efavirenz- [(15.4%) (37/240); 95%CI (11.1-20.6%)] than atazanavir/ritonavir-based [(7.2%) (8/111), (95%CI (3.2-13.7%)] cART. However, no significant difference was observed in the prevalence of diabetes mellitus and insulin resistance between the two regimens. Age ≥46 years old and specific type of ARV contained in cART, such as TDF, were independent predictors of GMD in both groups. Whereas the male gender and BMI category were predictors of GMDs among EFV-based cART group, AZT- and ABC- containing regimens and triglyceride levels were predictors in the ATV/r-based group. CONCLUSIONS: GMDs were highly prevalent among adults on EFV- than ATV/r-based cARTs. Age ≥46 years and TDF-containing cARTs are common predictors in both regimens. Close monitoring for impaired fasting glucose during long-term EFV-based cART is recommended for early diagnosis of type-2 diabetes and management.

Nutritional factors and metabolic biomarkers: impact in risk and survival of women with breast cancer / Fatores nutricionais e biomarcadores metabólicos: impacto no risco e sobrevida de mulheres com câncer de mama

Breast cancer (BC) is the most common cause of cancer and the leading cause of death in women. BC is a complex disease and distributes in distinct molecular subtypes regarding the expression of estrogen receptor (ER), progesterone receptor (PR), receptor tyrosine-protein kinase erbB-2 (HER2), and Ki67 protein status. Although BC is multifactorial evidence indicates that nutritional factors are relevant during steps of carcinogenesis, recurrence, and survival. We aim to assess the role of nutrition status and metabolic biomarkers in women with BC. This is a case-control study between May 2011 and August 2012. In the case group, there was a follow-up until April 2019, characterizing a cohort study. From these groups, different manuscripts were structured with different study designs according to each hypothesis. Manuscript 1 - cohort based on the follow-up of the BC group, Manuscript 2 - a cross-sectional study with women with Luminal A BC (ER positive, PR positive/negative, HER2 negative, Ki67 low) and Manuscript 3 - a cross-sectional case-control study. Data were obtained by medical records, interviews and anthropometric parameters with electrical impedance. Blood samples were collected after 12-hour fasting to analyze serum glucose, glycated hemoglobin, insulin growth factor 1 (IGF-1), insulin growth factor binding protein (IGFBP-3), insulin and adipokines, thiobarbituric acid reactive substances (TBARS), non-esterified fatty acids (NEFA), DNA oxidative damage (8-OH-dG) and lipoproteins (total cholesterol - TC, Low-density lipoprotein cholesterol - LDL-c, high-density lipoprotein cholesterol - HDL-c and triacylglycerols) and fatty acid profile of erythrocyte membrane. All statistical tests were performed using Statistical Package for Social Sciences® (SPSS), version 21.0. Statistical significance was set at p < 0.050. The main results of the study showed that premenopausal women with BC and clinical staging (CS) between II and III had a more atherogenic lipid profile characterized by the decrease in HDL-c, increase in LDL-c, non-HDL-C and apolipoprotein B (Apo B). We highlight that women with BC and high LDL-c and non-HDL-c had increase odd of having larger tumor size whereas HDL-c was associated with a decreased risk. Premenopausal women with BC had an increased level of TBARS and NEFA at diagnosis and had a lower survival probability. Additionally, women with Luminal A BC had higher serum levels of glucose, IGF-1, IGFBP-3, IL1ß, IL6, and lower IL10 compared to its matching controls. Also, women with increased serum levels of TBARS, glucose, and insulin increased risk of Luminal A BC, and higher levels of adiponectin decrease the risk of developing Luminal A BC when controlled by menopause status and BMI. Women with BC presented impaired IGF-1/insulin axis, sustained by overweight/obesity and higher central adiposity. Increased levels of serum glucose, insulin, and IGF-1 showed higher odds to developing BC. In conclusion, our results demonstrate the relevant impact of metabolic biomarkers on risk of developing BC and in survival outcomes. This study reinforces the relevance to increase prevention strategies regarding lifestyle and nutrition to decrease incidence and improve outcome of BC.

Câncer de mama (CM) é a causa mais comum de câncer no mundo e a principal causa de morte em mulheres. O CM é uma doença complexa e é classificada em tipos moleculares de acordo com a expressão do receptor de estrogênio (RE), receptor de progesterona (RP), receptor tyrosine-protein kinase erbB-2 (HER2) e proteína Ki67. Embora o CM seja multifatorial, há evidências científicas que indicam que componentes nutricionais podem ser relevantes durante as diversas etapas da carcinogênese, recidiva e sobrevivência. O objetivo deste estudo foi avaliar o papel do estado nutricional e marcadores metabólicos em mulheres com CM. Trata-se de um estudo caso-controle realizado entre maio 2011 e agosto 2012. O grupo caso foi acompanhado até abril 2019, caracterizando um estudo de coorte. A partir destes grupos foram estruturados diversos manuscritos com delineamentos diferentes, segundo cada hipótese levantada, a saber: Manuscrito 1 - Coorte baseada no seguimento do grupo CM, Manuscrito 2 - Estudo transversal baseado em mulheres com CM Luminal A (RE positivo, RP positivo/negativo, HER2 negativo, Ki67 baixo) e; Manuscrito 3 - estudo transversal do tipo caso-controle. Os dados foram obtidos através de prontuários médicos, entrevista e avaliação antropométrica com uso de bioimpedância elétrica. As amostras de sangue foram coletadas após jejum de 12 horas e a partir dessas foram analisadas glicemia, hemoglobina glicada (HbA1c), insulina, fator de crescimento semelhante à insulina 1 (IGF-1), proteína 3 de ligação ao fator de crescimento semelhante a insulina (IGFBP-3), substâncias reativas ao ácido tiobarbitúrico (TBARS), ácidos graxos não esterificados (NEFA), dano oxidativo ao DNA (8-OH-dG), perfil lipídico (colesterol total - CT, colesterol associado à lipoproteína de baixa densidade - LDL-c, colesterol associado à lipoproteína de alta densidade - HDL-c e triacilgliceróis) e perfil de ácidos graxos incorporados às membranas eritrocitárias. Todos os testes estatísticos foram realizados no programa Statistical Package for Social Sciences® (SPSS), versão 21.0. Significância estatística foi considerada em p < 0,050. Os principais resultados do estudo mostram que mulheres com CM na pré-menopausa e com estadiamento clínico II e III tiveram um perfil lipídico mais aterogênico caracterizado pela diminuição do HDL-c, aumento do LDL-c, nãoHDL-c e apolipoproteína B (Apo B). Destaca-se que mulheres com CM e LDL-c e nãoHDL-c aumentados apresentaram maior chance de tumores maiores, enquanto mulheres com CM com maior HDL-c apresentaram menor risco. Mulheres com CM na pré-menopausa que apresentaram maior conteúdo de TBARS e NEFA no momento do diagnóstico tiveram menor sobrevida. Adicionalmente, mulheres com CM e tumores do tipo Luminal A tiveram maiores concentrações de glicose, IGF-1, IGFBP-3, IL1ß, IL6 e menores de IL10 comparadas com o grupo controle. Mulheres com com concentrações mais elevadas de TBARS, glicose e insulina apresentaram maior risco de CM Luminal A, enquanto aquelas com concentrações mais elevadas de adiponectina apresentaram menor risco de desenvolver CM Luminal A, mesmo quando controlados pelo estado de menopausa e IMC. Mulheres com CM apresentaram alterações no eixo IGF-1/insulina que foi sustentada no sobrepeso/obesidade e no aumento da adiposidade central. Observou-se que mulheres com concentrações mais elevadas de glicose, insulina e IGF-1 tiveram maior chance de desenvolver CM. Em conclusão, os resultados demonstram o relevante impacto dos marcadores metabólicos no risco de desenvolver CM e o seu impacto na sobrevida. Este estudo reforça a relevância das estratégias de prevenção relacionadas ao estilo de vida e nutrição a fim de diminuir incidência e melhorar a sobrevida de mulheres com CM.

Blood glucose related adverse drug reaction of antitumor monoclonal antibodies: a retrospective analysis using Vigibase

Abstract On the increasing prevalence of using mAbs (monoclonal antibodies) in cancer therapy and the severe risk of hyperglycemia, we aimed to analyze the main clinical ADRs of mAbs, with a focus on adverse hyperglycemic events associated with currently clinically used mAbs. mAbs as well as target information were selected from Martinadale book and published articles. Drug approving information was collected from each government website, and ADR statistic data were collected from VigibaseR, comparing with Adverse Event Reporting System of US FDA. Top 10 mAbs were classified within listing in total ADR records, ADRs per year, hyperglycemic ADR records. Vigibase data were updated onto 15 Feb 2019. 20 mAbs were analyzed with 263217 ADR reports, wherein 16751 records on Metabolism and nutrition disorders and 1444 records on Glucose metabolism disorders. The geographic, age, gender distributions and annual ADR report numbers were listed respectively. Of the top 10, Rituximab, Bevacizumab and Nivolumab were on the top 3 in total ADR record and hyperglycemic record. Top 3 record results were similar in Vigibase and FDA database. It is of increasing importance for clinicians to be aware of early detection, patient management, or drug selection strategies when using mAbs, particularly within the high glycemic risk-reported mAbs, to improve the efficacy and tolerability of mAbs regiment and optimize patient outcomes.

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.

Glucose Metabolism Disorder Induces Spermatogenic Dysfunction in Northern Pig-Tailed Macaques (Macaca leonina) With Long-Term SIVmac239 Infection.

Although spermatogenic dysfunction is widely found in patients with human immunodeficiency virus (HIV), the underlying reasons remain unclear. Thus far, potential hypotheses involving viral reservoirs, testicular inflammation, hormone imbalance, and cachexia show inconsistent correlation with spermatogenic dysfunction. Here, northern pig-tailed macaques (NPMs) exhibited marked spermatogenic dysfunction after long-term infection with simian immunodeficiency virus (SIVmac239), with significant decreases in Johnsen scores, differentiated spermatogonial stem cells, and testicular proliferating cells. The above hypotheses were also evaluated. Results showed no differences between SIV- and SIV+ NPMs, except for an increase in follicle stimulating hormone (FSH) during SIV infection, which had no direct effect on the testes. However, long-term SIVmac239 infection undermined pancreatic islet ß cell function, partly represented by significant reductions in cellular counts and autophagy levels. Pancreatic islet ß cell dysfunction led to glucose metabolism disorder at the whole-body level, which inhibited lactate production by Sertoli cells in testicular tissue. As lactate is the main energy substrate for developing germ cells, its decrease was strongly correlated with spermatogenic dysfunction. Therefore, glucose metabolism disorder appears to be a primary cause of spermatogenic dysfunction in NPMs with long-term SIVmac239 infection.

Associations between vitamin D levels and glucose metabolism markers among pregnant women and their infants in Puerto Rico.

INTRODUCTION: Objectives: low vitamin D during pregnancy is common and could adversely affect health outcomes. This study evaluated vitamin D status during pregnancy and early in life, and its association with glucose metabolism. Methods: maternal serum 25(OH)D, glucose, and insulin levels were measured longitudinally during pregnancy in Hispanic women with overweight/obesity (n = 31) and their infants at birth and 4 months. Results: insulin and HOMA-IR levels were higher among women with vitamin D below adequate levels compared to those with adequate levels in pregnancy (p < 0.05). Late in pregnancy, as vitamin D increased by one unit (ng/mL), insulin decreased by 0.44 units and HOMA-IR by 0.09 units. Maternal vitamin D late in pregnancy was correlated with infant vitamin D levels at birth (r = 0.89; p < 0.01) and 4 months (r = 0.9; p = 0.04), and with glucose (r = 0.79; p = 0.03) and insulin (r = 0.83; p = 0.04) at 4 months. Conclusion: maternal vitamin D status was associated with maternal and infant glucose metabolism in this sample.

INTRODUCCIÓN: Objetivos: un bajo nivel de vitamina D durante el embarazo es común y puede tener consecuencias adversas en la salud. Este estudio evaluó el nivel de vitamina D en mujeres embarazadas y sus bebés, así como su asociación con los marcadores de glucosa. Métodos: los niveles séricos de 25(OH)D, glucosa e insulina se midieron longitudinalmente en mujeres embarazadas hispanoamericanas con sobrepeso/obesidad (n = 31) y en sus bebés, desde el nacimiento hasta los 4 meses de edad, en Puerto Rico. Resultados: los niveles maternos de insulina y HOMA-IR eran mayores en las mujeres con niveles de vitamina D por debajo de lo considerado adecuado, comparado con aquellas con niveles adecuados durante todo el embarazo (p < 0,05). Al final del embarazo, a medida que los niveles de vitamina D aumentaron, por cada unidad (ng/mL) de aumento, la insulina disminuyo en 0,44 unidades y el HOMA-IR en 0,09 unidades. El nivel de vitamina D al final del embarazo se correlacionó con los niveles del bebé al nacer (r = 0,89; p < 0,01) y a los 4 meses (r = 0,9; p = 0,04), y con los niveles de glucosa (r = 0,79; p = 0,03) e insulina (r = 0,83; p = 0,04) a los 4 meses. Conclusión: el nivel materno de vitamina D se asoció con los marcadores maternos e infantiles de glucosa en esta muestra.

A sex-specific propensity-adjusted analysis of colonic adenoma detection rates in a screening cohort.

The prevalence of colorectal adenoma and advanced adenoma (AA) differs between sexes. Also, the optimal age for the first screening colonoscopy is under debate. We, therefore, performed a sex-specific and age-adjusted comparison of adenoma, AA and advanced neoplasia (AN) rates in a real-world screening cohort. In total, 2824 asymptomatic participants between 45- and 60-years undergoing screening colonoscopy at a single-centre in Austria were evaluated. 46% were females and mean age was 53 ± 4 years. A propensity score for being female was calculated, and adenoma, AA and AN detection rates evaluated using uni- and multivariable logistic regression. Sensitivity analyses for three age groups (group 1: 45 to 49 years, n = 521, 41% females, mean age 47 ± 1 years; group 2: 50 to 54 years, n = 1164, 47% females, mean age 52 ± 1 years; group 3: 55 to 60 years, n = 1139, 46% females, mean age 57 ± 2 years) were performed. The prevalence of any adenoma was lower in females (17% vs. 30%; OR 0.46, 95% CI 0.38-0.55; p < 0.001) and remained so after propensity score adjustment for baseline characteristics and lifestyle factors (aOR 0.52, 95% CI 0.41-0.66; p < 0.001). The same trend was seen for AA with a significantly lower prevalence in females (3% vs. 7%; OR 0.38, 95% CI 0.26-0.55; p < 0.001) that persisted after propensity score adjustment (aOR 0.54, 95% CI 0.34-0.86; p = 0.01). Also, all age-group sensitivity analyses showed lower adenoma, AA and AN rates in females. Similar numbers needed to screen to detect an adenoma, an AA or AN were found in female age group 3 and male age group 1. Colorectal adenoma, AA and AN were consistently lower in females even after propensity score adjustment and in all age-adjusted sensitivity analyses. Our study may add to the discussion of the optimal age for initial screening colonoscopy which may differ between the sexes.

Cancer-associated IDH mutations induce Glut1 expression and glucose metabolic disorders through a PI3K/Akt/mTORC1-Hif1α axis.

Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations and their key effector 2-hydroxyglutarate (2-HG) have been reported to promote oncogenesis in various human cancers. To elucidate molecular mechanism(s) associated with IDH1/2 mutations, we established mouse embryonic fibroblasts (MEF) cells and human colorectal cancer cells stably expressing cancer-associated IDH1R132C or IDH2R172S, and analyzed the change in metabolic characteristics of the these cells. We found that IDH1/2 mutants induced intracellular 2-HG accumulation and inhibited cell proliferation. Expression profile analysis by RNA-seq unveiled that glucose transporter 1 (Glut1) was induced by the IDH1/2 mutants or treatment with 2-HG in the MEF cells. Consistently, glucose uptake and lactate production were increased by the mutants, suggesting the deregulation of glucose metabolism. Furthermore, PI3K/Akt/mTOR pathway and Hif1α expression were involved in the up-regulation of Glut1. Together, these results suggest that Glut1 is a potential target regulated by cancer-associated IDH1/2 mutations.

Reversal of Insulin Resistance in Overweight and Obese Subjects by trans-Resveratrol and Hesperetin Combination-Link to Dysglycemia, Blood Pressure, Dyslipidemia, and Low-Grade Inflammation.

The dietary supplement, trans-resveratrol and hesperetin combination (tRES-HESP), induces expression of glyoxalase 1, countering the accumulation of reactive dicarbonyl glycating agent, methylglyoxal (MG), in overweight and obese subjects. tRES-HESP produced reversal of insulin resistance, improving dysglycemia and low-grade inflammation in a randomized, double-blind, placebo-controlled crossover study. Herein, we report further analysis of study variables. MG metabolism-related variables correlated with BMI, dysglycemia, vascular inflammation, blood pressure, and dyslipidemia. With tRES-HESP treatment, plasma MG correlated negatively with endothelial independent arterial dilatation (r = -0.48, p < 0.05) and negatively with peripheral blood mononuclear cell (PBMC) quinone reductase activity (r = -0.68, p < 0.05)-a marker of the activation status of transcription factor Nrf2. For change from baseline of PBMC gene expression with tRES-HESP treatment, Glo1 expression correlated negatively with change in the oral glucose tolerance test area-under-the-curve plasma glucose (ΔAUGg) (r = -0.56, p < 0.05) and thioredoxin interacting protein (TXNIP) correlated positively with ΔAUGg (r = 0.59, p < 0.05). Tumor necrosis factor-α (TNFα) correlated positively with change in fasting plasma glucose (r = 0.70, p < 0.001) and negatively with change in insulin sensitivity (r = -0.68, p < 0.01). These correlations were not present with placebo. tRES-HESP decreased low-grade inflammation, characterized by decreased expression of CCL2, COX-2, IL-8, and RAGE. Changes in CCL2, IL-8, and RAGE were intercorrelated and all correlated positively with changes in MLXIP, MAFF, MAFG, NCF1, and FTH1, and negatively with changes in HMOX1 and TKT; changes in IL-8 also correlated positively with change in COX-2. Total urinary excretion of tRES and HESP metabolites were strongly correlated. These findings suggest tRES-HESP counters MG accumulation and protein glycation, decreasing activation of the unfolded protein response and expression of TXNIP and TNFα, producing reversal of insulin resistance. tRES-HESP is suitable for further evaluation for treatment of insulin resistance and related disorders.