RESUMEN
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.
Asunto(s)
Arsénico , Ácido Ascórbico , Dioxigenasas , Trastornos del Metabolismo de la Glucosa , Animales , Ratones , Arsénico/toxicidad , Ácido Ascórbico/uso terapéutico , Dioxigenasas/metabolismo , ADN , Metilación de ADN , Proteínas de Unión al ADN , Glucosa/metabolismo , Trastornos del Metabolismo de la Glucosa/inducido químicamente , Trastornos del Metabolismo de la Glucosa/genética , Trastornos del Metabolismo de la Glucosa/metabolismo , Hígado/metabolismoRESUMEN
Farnesoid X receptors (FXR) are bile acid receptors that play roles in lipid, glucose, and energy homeostasis. Synthetic FXR-specific agonists have been developed for treating nonalcoholic fatty liver disease (NAFLD) patients. However, the detailed mechanism remains unclear. To investigate the effects of FXR on NAFLD and the possible mechanism, FXR-null mice were fed either a normal or a high-fat diet. The FXR-null mice developed hepatomegaly, steatosis, accumulation of lipid droplets in liver cells, glucose metabolism disorder, and elevated serum lipid levels. Transcriptomic results showed increased expression of key lipid synthesis and glucose metabolism-related proteins. We focused on pyruvate dehydrogenase kinase 4 (PDK4), a key enzyme involved in the regulation of glucose and fatty acid (FA) metabolism and homeostasis. Subsequently, we confirmed an increase in PDK4 expression in FXR knockout cells. Moreover, inhibition of PDK4 expression alleviated lipid accumulation in hepatocytes caused by FXR deficiency in vivo and in vitro. Our results identify FXR as a nuclear transcription factor that regulates glucose and lipid metabolism balance through PDK4, providing further insights into the mechanism of FXR agonists in the treatment of metabolic diseases.
Asunto(s)
Trastornos del Metabolismo de la Glucosa/complicaciones , Trastornos del Metabolismo de la Glucosa/metabolismo , Trastornos del Metabolismo de los Lípidos/complicaciones , Trastornos del Metabolismo de los Lípidos/metabolismo , Hepatopatías/complicaciones , Hepatopatías/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal/genética , Animales , Dieta Alta en Grasa , Ácidos Grasos/metabolismo , Técnicas de Inactivación de Genes/métodos , Glucosa/metabolismo , Trastornos del Metabolismo de la Glucosa/genética , Células HEK293 , Hepatocitos/metabolismo , Humanos , Trastornos del Metabolismo de los Lípidos/genética , Hígado/metabolismo , Hepatopatías/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Transfección/métodos , Triglicéridos/metabolismoRESUMEN
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.
Asunto(s)
Clozapina/farmacología , Glucosa/metabolismo , Hígado/efectos de los fármacos , Proteínas de la Membrana/fisiología , Receptores de Progesterona/fisiología , Animales , Antipsicóticos/efectos adversos , Antipsicóticos/farmacología , Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Metabolismo de los Hidratos de Carbono/genética , Clozapina/efectos adversos , Trastornos del Metabolismo de la Glucosa/inducido químicamente , Trastornos del Metabolismo de la Glucosa/genética , Trastornos del Metabolismo de la Glucosa/metabolismo , Hígado/metabolismo , Masculino , Proteínas de la Membrana/genética , Ratas , Ratas Sprague-Dawley , Receptores de Progesterona/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
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.
Asunto(s)
Trastornos del Metabolismo de la Glucosa/genética , Transportador de Glucosa de Tipo 1/metabolismo , Isocitrato Deshidrogenasa/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Mutación/genética , Neoplasias/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Proliferación Celular , Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica , Glucosa/metabolismo , Glutaratos/metabolismo , Glucólisis , Células HCT116 , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Espacio Intracelular/metabolismo , Ácido Láctico/metabolismo , Ratones Endogámicos C57BL , Proteínas Mutantes/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Non-coding RNA 886 (nc886) is coded from a maternally inherited metastable epiallele. We set out to investigate the determinants and dynamics of the methylation pattern at the nc886 epiallele and how this methylation status associates with nc886 RNA expression. Furthermore, we investigated the associations between the nc886 methylation status or the levels of nc886 RNAs and metabolic traits in the YFS and KORA cohorts. The association between nc886 epiallele methylation and RNA expression was also validated in induced pluripotent stem cell (iPSC) lines. RESULTS: We confirm that the methylation status of the nc886 epiallele is mostly binomial, with individuals displaying either a non- or hemi-methylated status, but we also describe intermediately and close to fully methylated individuals. We show that an individual's methylation status is associated with the mother's age and socioeconomic status, but not with the individual's own genetics. Once established, the methylation status of the nc886 epiallele remains stable for at least 25 years. This methylation status is strongly associated with the levels of nc886 non-coding RNAs in serum, blood, and iPSC lines. In addition, nc886 methylation status associates with glucose and insulin levels during adolescence but not with the indicators of glucose metabolism or the incidence of type 2 diabetes in adulthood. However, the nc886-3p RNA levels also associate with glucose metabolism in adulthood. CONCLUSIONS: These results indicate that nc886 metastable epiallele methylation is tuned by the periconceptional conditions and it associates with glucose metabolism through the expression of the ncRNAs coded in the epiallele region.
Asunto(s)
Trastornos del Metabolismo de la Glucosa/genética , ARN no Traducido/análisis , Adulto , Metilación de ADN/genética , Metilación de ADN/fisiología , Epigénesis Genética , HumanosRESUMEN
MicroRNAs (miRNAs) are small (â¼21 nucleotides), endogenous, non-coding RNA molecules implicated in the post-transcriptional gene regulation performed through target mRNA cleavage or translational inhibition. In recent years, several investigations have demonstrated that miRNAs are involved in regulating both carbohydrate and lipid homeostasis in humans and other organisms. Moreover, it has been observed that the dysregulation of these metabolism-related miRNAs leads to the development of several metabolic disorders, such as type 2 diabetes, obesity, nonalcoholic fatty liver, insulin resistance, and hyperlipidemia. Hence, in this current review, with the aim to impulse the research arena of the micro-transcriptome implications in vital metabolic pathways as well as to highlight the remarkable potential of miRNAs as therapeutic targets for metabolic disorders in humans, we provide an overview of the regulatory roles of metabolism-associated miRNAs in humans and murine models.
Asunto(s)
Trastornos del Metabolismo de la Glucosa/metabolismo , Trastornos del Metabolismo de los Lípidos/metabolismo , MicroARNs/biosíntesis , Animales , Modelos Animales de Enfermedad , Trastornos del Metabolismo de la Glucosa/genética , Trastornos del Metabolismo de la Glucosa/patología , Trastornos del Metabolismo de la Glucosa/terapia , Humanos , Trastornos del Metabolismo de los Lípidos/genética , Trastornos del Metabolismo de los Lípidos/patología , Trastornos del Metabolismo de los Lípidos/terapia , Ratones , MicroARNs/genéticaRESUMEN
Glucose and lipids are important nutrients that provide the majority of energy for each organ to maintain homeostasis of the body. With the continuous improvement in living standards, the incidence of metabolic disorder-associated diseases, such as diabetes, hyperlipidemia, and atherosclerosis, is increasing worldwide. Among them, diabetes, which could be induced by both glucose and lipid metabolic disorders, is one of the five diseases with the highest incidence and mortality worldwide. However, the detailed molecular mechanisms underlying glucose and lipid metabolism disorders and target-organ damage are still not fully defined. MicroRNAs (miRNAs) are small, non-coding, single-stranded RNAs, which usually affect their target mRNAs in the cytoplasm by post-transcriptional regulation. Previously, we have found that miR-320 contributed to glucose and lipid metabolism via different signaling pathways. Most importantly, we identified that nuclear miR-320 mediated diabetes-induced cardiac dysfunction by activating the transcription of fatty acid metabolic genes to cause lipotoxicity in the heart. Here, we reviewed the roles of miR-320 in glucose and lipid metabolism and target-organ damage.
Asunto(s)
Trastornos del Metabolismo de la Glucosa/genética , Trastornos del Metabolismo de los Lípidos/genética , MicroARNs/fisiología , Biomarcadores/metabolismo , HumanosRESUMEN
BACKGROUND Angiopoietinlike protein 5 (ANGPTL5) is an adipocytokine and has an important role in metabolic processes including lipid metabolism, obesity, and type 2 diabetes mellitus. On the basis of these roles, the present study aimed to investigate the level and role of plasma ANGPTL5 in metabolic syndrome (MS) patients. MATERIAL AND METHODS A total of 139 participants was enrolled in this study; 69 of them were diagnosed with MS. Plasma ANGPTL5 levels were measured by enzyme-linked immunosorbent assay. Sex, age, and other laboratory tests were compared statistically. Correlations between ANGPTL5 and biochemical parameters such as lipid levels and insulin resistance were all evaluated statistically. RESULTS In patients with MS, plasma ANGPTL5 levels were higher than in those without MS (P<0.05). Moreover, after adjusting for the glucose profiles, positive correlations were found between plasma ANGPTL5 levels and body mass index (BMI), waist circumference, and waist-hip ratio (WHR); a weak negative correlation was found between ANGPTL5 concentration and high-density lipoprotein cholesterol. After controlling the lipid profiles, positive correlations were found between ANGPTL5 concentration and BMI, WHR, fasting plasma glucose, fasting insulin, glycated hemoglobin, and homeostatic model assessment (HOMA) of insulin resistance; a negative correlation was found between plasma ANGPTL5 concentration and HOMA of ß-cell function. The area under the curve was approximately 0.912 in receiver operating characteristic curve analysis. CONCLUSIONS The findings in the present study showed that plasma ANGPTL5 was more positively correlated with glucose metabolism disorders than with lipid metabolism disorders in patients with MS, which suggested that ANGPTL5 might serve as a potential and useful clinical predictor of MS.
Asunto(s)
Proteínas Similares a la Angiopoyetina/sangre , Proteínas Similares a la Angiopoyetina/genética , Trastornos del Metabolismo de la Glucosa/sangre , Trastornos del Metabolismo de la Glucosa/genética , Síndrome Metabólico/sangre , Síndrome Metabólico/genética , Femenino , Trastornos del Metabolismo de la Glucosa/complicaciones , Humanos , Masculino , Síndrome Metabólico/complicaciones , Persona de Mediana EdadRESUMEN
BACKGROUND: Even though excessive adipose tissue is related to chronic metabolic disturbances, not all subjects with excess weight (EW) display metabolic alterations, and not all normal-weight (NW) subjects have a metabolically healthy (MH) phenotype, probably due to gene-environment interactions. The aim of this study was to investigate the interaction effects of ADIPOQ and PPARG genetic variants in NW and EW individuals with different metabolic phenotypes. METHODS: Data on 345 adults from western Mexico were analyzed. The individuals were classified into NW and EW groups according to body mass index, and were categorized as MH or metabolically unhealthy (MUH), considering homeostatic model assessment insulin resistance (HOMA-IR) and National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) cut-off points for glucose, triglycerides, high-density lipoprotein cholesterol, and blood pressure. Subjects with ≤1 altered parameter were classified as MH. The single nucleotide polymorphisms (SNPs) -11377C>G, -11391G>A, +45T>G, and +276G>T for ADIPOQ and Pro12Ala for PPARG were analyzed by allelic discrimination. High-molecular-weight adiponectin isoform levels were measured by ELISA. RESULTS: Lower serum adiponectin levels were associated with the MUH phenotype in EW subjects. NW subjects with the GG or TG genotype for the +45T>G SNP had reduced odds of the MUH phenotype. Individuals who carried two copies of the GG haplotype at the -11391G>A and -11377C>G SNPs for ADIPOQ had lower serum adiponectin levels than those with zero copies. CONCLUSION: In this population, lower serum adiponectin levels were found in the EW-MUH phenotype, and no differences were observed between the NW-MH and the EW-MH phenotype. In addition, the +45T>G SNP was associated with reduced odds of the MUH phenotype.
Asunto(s)
Adiponectina/sangre , Trastornos del Metabolismo de la Glucosa/genética , Trastornos del Metabolismo de los Lípidos/genética , Fenotipo , Adiponectina/genética , Adulto , Alelos , Antropometría , Glucemia/análisis , Estudios Transversales , Ensayo de Inmunoadsorción Enzimática , Femenino , Haplotipos , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , PPAR gamma/genética , Polimorfismo de Nucleótido SimpleRESUMEN
PURPOSE: We aimed to explore the associations of serum cortisone and glucocorticoid receptor (GR) polymorphism with glucose metabolism and type 2 diabetes mellitus (T2DM) among Chinese adults. METHODS: A total of 2315 participants were included in the present study. Serum cortisone was measured by liquid chromatography-tandem mass spectrometry. Multivariable logistic regression and linear regression were employed to assess the associations between serum cortisone and different glucose metabolism status. RESULTS: Serum cortisone was positively associated with impaired fasting glucose (IFG) and T2DM ((Quartile 4 vs Quartile 1, odds ratio (OR) = 1.36, 95% confidence interval (CI) 1.01, 1.84, and OR = 2.08, 95% CI 1.50, 2.89, respectively)). A 100% increase in cortisone was associated with a 0.015 (95% CI 0.005, 0.025) mg/dl higher fasting plasma glucose (FPG), a 0.007 (95% CI 0.001, 0.013) higher glycosylated hemoglobin (HbA1c), a 0.4% (95% CI - 0.007, 0.000) lower HOMA2-IR, and a 58.1% (95% CI - 0.788, - 0.373) lower HOMA2-ß. After stratification by genotype, the association between serum cortisone and T2DM was not significant in TT genotype carriers. In addition, at the higher concentrations of cortisone, TT genotype carriers had a lower FPG, HbA1c, and HOMA2-IR and a higher HOMA2-ß than GG and GT carriers. CONCLUSIONS: Elevated serum cortisone was associated with an increased risk of IFG and T2DM, and the associations may be modified by rs9324924 polymorphism.
Asunto(s)
Glucemia/metabolismo , Cortisona/sangre , Trastornos del Metabolismo de la Glucosa/sangre , Trastornos del Metabolismo de la Glucosa/genética , Hemoglobina Glucada/metabolismo , Resistencia a la Insulina/genética , Receptores de Glucocorticoides/genética , Adulto , China , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo GenéticoRESUMEN
PURPOSE OF REVIEW: This review summarizes our current knowledge on type 2 diabetes mellitus (T2DM) and glucose metabolism alterations in Prader-Willi syndrome (PWS), the most common syndromic cause of obesity, and serves as a guide for future research and current best practice. RECENT FINDINGS: Diabetes occurs in 10-25% of PWS patients, usually in adulthood. Severe obesity is a significant risk factor for developing of T2DM in PWS. Paradoxically, despite severe obesity, a relative hypoinsulinemia, without the expected insulin resistance, is frequently observed in PWS. The majority of PWS subjects with T2DM are asymptomatic and diabetes-related complications are infrequent. Long-term growth hormone therapy does not adversely influence glucose homeostasis in all ages, if weight gain does not occur. Early intervention to prevent obesity and the regular monitoring of glucose levels are recommended in PWS subjects. However, further studies are required to better understand the physiopathological mechanisms of T2DM in these patients.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Trastornos del Metabolismo de la Glucosa/metabolismo , Insulina/metabolismo , Obesidad/metabolismo , Síndrome de Prader-Willi/metabolismo , Glucemia/análisis , Metabolismo de los Hidratos de Carbono , Comorbilidad , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Glucosa/metabolismo , Trastornos del Metabolismo de la Glucosa/etiología , Trastornos del Metabolismo de la Glucosa/genética , Trastornos del Metabolismo de la Glucosa/terapia , Hormona del Crecimiento/uso terapéutico , Hormonas/uso terapéutico , Humanos , Hiperfagia/etiología , Insulina/deficiencia , Obesidad/etiología , Obesidad/genética , Obesidad/terapia , Síndrome de Prader-Willi/complicaciones , Síndrome de Prader-Willi/genéticaRESUMEN
BACKGROUND AND AIMS: Plasma apolipoprotein C3 (ApoC3) is associated with higher plasma triglyceride and type 2 diabetes incidence. We evaluated whether body mass index (BMI) or glucose metabolism were associated with ApoC3 in healthy monozygotic (MZ) twins. METHODS AND RESULTS: Forty-seven MZ twin-pairs (20 man, 27 women), aged 23-42 years, were divided in subgroups according to discordance or concordance for (a) BMI (within-pair difference (Δ) in BMI≥3.0 or<3.0 kg/m2), or (b) 2-h glucose iAUC, during oral glucose tolerance test (ΔGlucose iAUC ≥97.5 or<97.5 mmol × 120 minutes). Within these discordant or concordant subgroups, we tested (Wilcoxon signed-rank test) co-twin differences in ApoC3, adiposity measures, insulin-resistance and beta-cell function indices, and plasma and lipoprotein lipids. In BMI-Discordant (p = 0.92) or BMI-Concordant (p = 0.99) subgroups, ApoC3 did not differ between leaner and heavier co-twins. In the Glucose-Discordant subgroup, ApoC3 was significantly higher in twins with higher Glucose iAUC than in their co-twins with the lower Glucose iAUC (10.03 ± 0.78 vs. 8.48 ± 0.52 mg/dl; M ± SE; p = 0.032). Co-twins with higher Glucose iAUC also had higher waist circumference, body fat percentage, liver fat content, worse insulin-sensitivity and beta-cell function and higher cholesterol and triglyceride in plasma VLDL, IDL, and LDL. In Glucose-Concordant twin-pairs, no significant differences were observed in the explored variables. In all twin-pairs, ΔApoC3 correlated with Δ in lipids and glucose metabolism variables, the closest relationship being between ΔApoC3 and ΔVLDL triglyceride (r = 0.74, p < 0.0001). CONCLUSIONS: While ApoC3 was not related to acquired differences in BMI, it associated with early dysregulation of glucose metabolism independently of obesity and genetic background.
Asunto(s)
Apolipoproteína C-III/sangre , Glucemia/metabolismo , Índice de Masa Corporal , Trastornos del Metabolismo de la Glucosa/sangre , Prueba de Tolerancia a la Glucosa , Obesidad/sangre , Adiposidad , Adulto , Biomarcadores/sangre , Femenino , Finlandia , Trastornos del Metabolismo de la Glucosa/diagnóstico , Trastornos del Metabolismo de la Glucosa/genética , Trastornos del Metabolismo de la Glucosa/fisiopatología , Voluntarios Sanos , Humanos , Masculino , Obesidad/diagnóstico , Obesidad/genética , Obesidad/fisiopatología , Factores de Riesgo , Factores de Tiempo , Triglicéridos/sangre , Gemelos Monocigóticos/genética , Adulto JovenRESUMEN
Kisspeptin has well-established critical roles in the control of reproduction and fertility. Recently, evidence has emerged that suggests kisspeptin may have additional roles in the regulation of glucose homeostasis. Conflicting reports on the effects of kisspeptin on insulin secretion in animal models have been published, which cannot be fully accounted for by the different kisspeptin isoforms and range of kisspeptin doses used in these studies. Human studies have demonstrated associations between circulating kisspeptin levels and measures of insulin secretion and insulin resistance; and the only published interventional study has confirmed kisspeptin enhances glucose-stimulated insulin secretion in humans. Further studies are required to elucidate the mechanisms underlying the effects of kisspeptin on the pancreatic ß-cell and to determine the therapeutic potential of kisspeptin receptor agonist in the treatment of disorders of glucose homeostasis.
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Trastornos del Metabolismo de la Glucosa/etiología , Glucosa/metabolismo , Kisspeptinas/fisiología , Animales , Fertilidad/efectos de los fármacos , Fertilidad/genética , Trastornos del Metabolismo de la Glucosa/tratamiento farmacológico , Trastornos del Metabolismo de la Glucosa/genética , Homeostasis/efectos de los fármacos , Homeostasis/genética , Humanos , Insulina/metabolismo , Secreción de Insulina/efectos de los fármacos , Secreción de Insulina/genética , Kisspeptinas/farmacología , Kisspeptinas/uso terapéutico , Receptores de Kisspeptina-1/agonistas , Reproducción/efectos de los fármacos , Reproducción/genéticaRESUMEN
Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.
Asunto(s)
Trastornos del Metabolismo de la Glucosa/genética , Habénula/metabolismo , Transducción de Señal , Tabaquismo/complicaciones , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Animales , AMP Cíclico/metabolismo , Glucosa/metabolismo , Trastornos del Metabolismo de la Glucosa/metabolismo , Humanos , Ratones , Mutagénesis , Nicotina/metabolismo , Células PC12 , Páncreas/metabolismo , Ratas , Receptores Nicotínicos/metabolismo , Tabaquismo/genética , Tabaquismo/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/genéticaRESUMEN
Circadian rhythms are closely associated with metabolic homeostasis. Metabolic disorders can be alleviated by many bioactive components through controlling of clock gene expressions. Capsaicin has been demonstrated with many beneficial effects including anti-obesity and anti-insulin resistance activities, yet whether the rhythmic expression of circadian clock genes are involved in the regulation of redox imbalance and glucose metabolism disorder by capsaicin remains unclear. In this work, the insulin resistance was induced in HepG2 cells by treatment of glucosamine. Glucose uptake levels, reactive oxygen species, H2O2 production, and mitochondrial membrane potential (MMP) were measured with/without capsaicin cotreatment. The mRNA and protein expressions of core circadian clock genes were evaluated by RT-qPCR and western blot analysis. Our study revealed that circadian misalignment could be ameliorated by capsaicin. The glucosamine-induced cellular redox imbalance and glucose metabolism disorder were ameliorated by capsaicin in a Bmal1-dependent manner.
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Capsaicina/administración & dosificación , Relojes Circadianos/efectos de los fármacos , Trastornos del Metabolismo de la Glucosa/tratamiento farmacológico , Resistencia a la Insulina , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Animales , Péptidos y Proteínas de Señalización del Ritmo Circadiano/genética , Péptidos y Proteínas de Señalización del Ritmo Circadiano/metabolismo , Glucosa/metabolismo , Trastornos del Metabolismo de la Glucosa/genética , Trastornos del Metabolismo de la Glucosa/metabolismo , Trastornos del Metabolismo de la Glucosa/fisiopatología , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Insulinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidación-Reducción/efectos de los fármacosRESUMEN
Proopiomelanocortin (POMC) is a key mediator of satiety. Epigenetic marks such as DNA methylation may modulate POMC expression and provide a biological link between early life exposures and later phenotype. Animal studies suggest epigenetic marks at POMC are influenced by maternal energy excess and restriction, prenatal stress and Triclosan exposure. Postnatal factors including energy excess, folate, vitamin A, conjugated linoleic acid and leptin may also affect POMC methylation. Recent human studies suggest POMC DNA methylation is influenced by maternal nutrition in early pregnancy and associated with childhood and adult obesity. Studies in children propose a link between POMC DNA methylation and elevated lipids and insulin, independent of body habitus. This review brings together evidence from animal and human studies and suggests that POMC is sensitive to nutritional programming and is associated with a wide range of weight-related and metabolic outcomes.
Asunto(s)
Metilación de ADN , Epigénesis Genética , Trastornos del Metabolismo de la Glucosa/metabolismo , Fenómenos Fisiológicos de la Nutrición , Obesidad/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Proopiomelanocortina/metabolismo , Animales , Femenino , Trastornos del Metabolismo de la Glucosa/etiología , Trastornos del Metabolismo de la Glucosa/genética , Humanos , Obesidad/etiología , Obesidad/genética , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Proopiomelanocortina/genéticaRESUMEN
The solute carrier (SLC) group of membrane transport proteins is crucial for cells via their control of import and export of vital molecules across the cellular membrane. Defects in these transporters with narrow substrate specificities cause monogenic disorders, giving us essential clues of their precise roles in cellular functioning. The SLC5 family in particular has been linked to various human diseases, of mild and severe phenotype as well as high and low prevalence. In this review, we describe the effects on health of SLC5 dysfunction and dysregulation by summarizing findings in patients with transporter gene defects. Patients display a plethora of pathologies which include glucose/galactose malabsorption, familiar renal glycosuria, thyroid dyshormonogenesis, and distal hereditary motor neuronopathies. In addition, the therapeutic potential of intervening in transporter activities for treating common diseases such as diabetes and cancer is explored.
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Diabetes Mellitus/genética , Trastornos del Metabolismo de la Glucosa/genética , Neoplasias/genética , Proteínas Transportadoras de Solutos/genética , Diabetes Mellitus/metabolismo , Trastornos del Metabolismo de la Glucosa/metabolismo , Humanos , Neoplasias/metabolismo , Proteínas de Transporte de Sodio-GlucosaRESUMEN
Ion channels and transporters play essential roles in excitable cells including cardiac, skeletal and smooth muscle cells, neurons, and endocrine cells. In pancreatic beta-cells, for example, potassium KATP channels link the metabolic signals generated inside the cell to changes in the beta-cell membrane potential, and ultimately regulate insulin secretion. Mutations in the genes encoding some ion transporter and channel proteins lead to disorders of glucose homeostasis (hyperinsulinaemic hypoglycaemia and different forms of diabetes mellitus). Pancreatic KATP, Non-KATP, and some calcium channelopathies and MCT1 transporter defects can lead to various forms of hyperinsulinaemic hypoglycaemia (HH). Mutations in the genes encoding the pancreatic KATP channels can also lead to different types of diabetes (including neonatal diabetes mellitus (NDM) and Maturity Onset Diabetes of the Young, MODY), and defects in the solute carrier family 2 member 2 (SLC2A2) leads to diabetes mellitus as part of the Fanconi-Bickel syndrome. Variants or polymorphisms in some ion channel genes and transporters have been reported in association with type 2 diabetes mellitus.
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Canalopatías/metabolismo , Trastornos del Metabolismo de la Glucosa/metabolismo , Canales Iónicos/metabolismo , Bombas Iónicas/metabolismo , Animales , Canalopatías/genética , Trastornos del Metabolismo de la Glucosa/genética , Humanos , Canales Iónicos/genética , Bombas Iónicas/genéticaRESUMEN
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.
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Antineoplásicos/efectos adversos , Enfermedades Transmisibles/genética , Glucocorticoides/efectos adversos , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adolescente , Factores de Edad , Antineoplásicos/farmacocinética , Estudios de Casos y Controles , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Niño , Enfermedades Transmisibles/inducido químicamente , Enfermedades Transmisibles/diagnóstico , Enfermedades Transmisibles/epidemiología , Femenino , Frecuencia de los Genes , Glucocorticoides/farmacocinética , Trastornos del Metabolismo de la Glucosa/inducido químicamente , Trastornos del Metabolismo de la Glucosa/epidemiología , Trastornos del Metabolismo de la Glucosa/genética , Humanos , Incidencia , Masculino , Farmacogenética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Factores de Riesgo , Arabia Saudita/epidemiología , Resultado del Tratamiento , Adulto JovenRESUMEN
Variation in blood flow mediated by the posterior communicating collateral arteries (PComs) contributes to variation in the severity of tissue injury in obstructive disease. Evidence in animals and humans indicates that differences in the extent of PComs, i.e., their anatomic lumen diameter and whether they are present bilaterally, unilaterally, or absent, are a major factor. These differences arise during development since they are present at birth. However, the causal mechanisms are unknown. We used angiography after maximal dilation to examine involvement of genetic, environmental, and stochastic factors. The extent of PComs varied widely among seven genetically diverse strains of mice. Like pial collaterals in the microcirculation, aging and hypertension reduced PCom diameter, while in contrast, obesity, hyperlipidemia, metabolic syndrome, and diabetes mellitus had no effect. Naturally occurring intrauterine growth restriction had no effect on extent of PCom or pial collaterals in the adult. The number and diameter of PComs evidenced much larger apparent stochastic-dependent variation than pial collaterals. In addition, both PComs underwent flow-mediated outward remodeling after unilateral permanent MCA occlusion that varied with genetic background and was greater on the ipsilesional side. These findings indicate that variation in the number and diameter of PCom collateral arteries arises from stochastic factors and naturally occurring genetic variants that differ from those that cause variation in pial collateral arterioles. Environmental factors also contribute: aging and hypertension reduce PCom diameter. Our results suggest possible sources of variation of PComs in humans and provide information relevant when studying mouse models of occlusive cerebrovascular disease.