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1.
Ecotoxicol Environ Saf ; 215: 112130, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33743404

RESUMO

Environmental exposure to arsenic can cause a variety of health problems. Epidemiological and experimental studies have established a diabetogenic role for arsenic, but the mechanisms responsible for arsenic-induced impairment of insulin action are unclear. MicroRNAs (miRNAs) are involved in various metabolic disorders, particularly in the development of insulin resistance. The present study investigated whether arsenite, an active form of arsenic, induces hepatic insulin resistance and the mechanisms underlying it. After male C57BL/6J mice were exposed to arsenite (0 or 20 ppm) in drinking water for 12 months, intraperitoneal glucose tolerance tests (IPGTTs) and insulin tolerance tests (ITTs) revealed an arsenite-induced glucose metabolism disorder. Hepatic glycogen levels were lower in arsenite-exposed mice. Further, for livers of mice exposed to arsenite, miR-191 levels were higher, and protein levels of insulin receptor substrate 1 (IRS1), p-IRS1, and phospho-protein kinase B (p-AKT) were lower. Further, glucose transporter 4 (GLUT4) had lower levels on the plasma membrane. For insulin-treated L-02 cells, arsenite decreased glucose consumption and glycogen levels, increased miR-191 levels, and inhibited the IRS1/AKT pathway and the translocation of GLUT4 from the cytoplasm to the plasma membrane. For insulin-treated L-02 cells, the decreases of glucose consumption, glycogen levels, GLUT4 on the plasma membrane, and p-AKT levels induced by arsenite were reversed by SC79 (agonist of AKT) and an miR-191 inhibitor; these effects caused by miR-191 inhibitor were restored by IRS1 siRNA. In insulin-treated L-02 cells, miR-191, via IRS1, was involved in the arsenite-induced decreases of glucose consumption and glycogen levels and in inhibition of the translocation of GLUT4. Thus, miR-191 blocking the translocation of GLUT4 was involved in arsenite-induced hepatic insulin resistance through inhibiting the IRS1/AKT pathway. Our study reveals a mechanism for arsenite-induced hepatic insulin resistance, which provides clues for discovering biomarkers for the development of type 2 diabetes and for prevention and treatment of arsenic poisoning.


Assuntos
Arsenitos/toxicidade , Transportador de Glucose Tipo 4/metabolismo , Resistência à Insulina/fisiologia , MicroRNAs/metabolismo , Animais , Arsenitos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Glicogênio/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Life Sci ; 270: 119037, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33497738

RESUMO

AIMS: Skeletal muscle insulin resistance (SMIR) contributes to the metabolic syndrome. Mounting evidence has demonstrated that the second generation antipsychotic olanzapine causes SMIR. The present study sought to investigate the molecular mechanisms underlying olanzapine-induced SMIR. MAIN METHODS: Male rats were given olanzapine (5 mg/kg, by a gavage method) for consecutive eight weeks. Plasma glucose and insulin concentrations were determined enzymatically or by ELISA. Gene/protein expression was analyzed by Real-Time PCR, Western blot and/or immunohistochemistry. KEY FINDINGS: Olanzapine increased fasting plasma insulin concentration, and decreased glucose clearance during insulin tolerance test in rats. In skeletal muscle, it decreased protein expression of membrane glucose transporter (GLUT) 4, the ratio of membrane to total GLUT4, and total insulin receptor substrate 1 (IRS1). However, it increased protein phosphorylation of Ser307 in IRS1, Y607 in phosphoinositide 3-kinase p85α and Ser307 in AKT. These results indicate olanzapine-induced impairment of skeletal muscle insulin signaling. Mechanistically, olanzapine upregulated mRNA expression of TNFα, IL6 and IL1ß, and protein phosphorylation of both IκB kinase (IKK)α/ß and nuclear factor (NF)κB p65. Furthermore, it increased protein phosphorylation of Ser485/491 in AMPKα2, whereas it decreased AMPKα2 activity. More importantly, both Western blot and immunohistochemical analyses revealed that olanzapine increased protein phosphorylation of Ser744/748 in protein kinase D1 (PKD1). SIGNIFICANCE: The present results suggest that the PKD1-mediated inflammatory pathway is involved in olanzapine-induced impairment of skeletal muscle insulin signaling in rats. Our findings may go new insight into the mechanisms underlying olanzapine-induced SMIR.


Assuntos
Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Proteína Quinase C/metabolismo , Animais , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Quinase I-kappa B/metabolismo , Inflamação/metabolismo , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , NF-kappa B/metabolismo , Olanzapina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteína Quinase C/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
3.
Food Chem ; 335: 127513, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32745838

RESUMO

Zhenjiang aromatic vinegar is a famous traditional fermented cooking ingredient in China, with multiple nutritional and medicinal applications. Zhenjiang aromatic vinegar extract (100-400 µg/mL) is rich in polyphenols increased the glucose uptake and glucose consumption in high glucose-induced insulin resistant HepG2 (IR-HepG2) cells. Zhenjiang aromatic vinegar extract enhanced glycogen synthesis and attenuated gluconeogenesis by regulating key enzymes in IR-HepG2 cells. In addition, Zhenjiang aromatic vinegar extract ameliorated high glucose-induced IR by inhibiting phosphorylated insulin receptor substrate-1 (IRS-1) expression and activating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in IR-HepG2 cells. Moreover, Zhenjiang aromatic vinegar extract reduced reactive oxygen species generation and phosphorylated c-Jun NH2 terminal kinase (JNK) expression in IR-HepG2 cells. The attenuation of the high glucose is owned to the PI3K/Akt pathway activation, glycogen synthesis induction and gluconeogenesis suppression in IR-HepG2 cells.


Assuntos
Ácido Acético/farmacologia , Glucose/farmacologia , Resistência à Insulina , Polifenóis/análise , Transdução de Sinais/efeitos dos fármacos , Ácido Acético/química , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo
4.
Yakugaku Zasshi ; 140(11): 1351-1363, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132271

RESUMO

Epidemiological studies have shown that coffee consumption may be associated with a lower risk of developing several chronic disorders. To elucidate the molecular mechanism of the effects of coffee, we analyzed molecular response upon exposure to coffee extract using cellular and animal models of these diseases. As obesity is recognized as a major risk factor for these chronic diseases, we investigated the effect of coffee on adipogenesis using mouse preadipocyte 3T3-L1 cells. We found that coffee induced proteasomal degradation of IRS-1, leading to reduction of PPARγ expression, a master transcription factor for adipogenesis. Reduction in weight as well as in IRS-1 expression was detected in the fat tissues of the high fat-diet-fed mice when reared with 60% coffee for 7 weeks. As for Alzheimer's disease, we analyzed the effect of coffee on amyloid ß (Aß) production in human neuronal SH-SY5Y cells. We found a 20% reduction in Aß production when treated with 2.5% coffee for 2 d. This reduction was due to proteasomal degradation of BACE1 (ß-secretase), which was activated by protein kinase A. In addition, coffee ameliorates LPS-induced inflammatory responses in RAW264.7 macrophages by reducing NFκB activity and Nrf2 activation. Roasted coffee prevents selenite-induced cataractogenesis by ameliorating antioxidant loss. Pyrocatechol, a component of roasted coffee, also reduced Aß production and exhibits anti-inflammatory effects by a similar mechanism as coffee. Our results suggest that roasting coffee beans to generate pyrocatechol is necessary for the preventive effects of coffee intake on the chronic diseases.


Assuntos
Doença de Alzheimer/prevenção & controle , Catarata/prevenção & controle , Doença Crônica/prevenção & controle , Café , Ingestão de Líquidos/fisiologia , Adipogenia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Catecóis , Células Cultivadas , Café/química , Modelos Animais de Doenças , Manipulação de Alimentos , Temperatura Alta , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , PPAR gama/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Células RAW 264.7
5.
PLoS Genet ; 16(9): e1009019, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32915782

RESUMO

Loci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified in the Metabolic Syndrome in Men (METSIM) study. With GWAS data for 9,262 men, four loci were significantly associated with adiponectin: ADIPOQ, CDH13, IRS1, and PBRM1. We performed stepwise conditional analyses to identify distinct association signals, a subset of which are also nearly independent (lead variant pairwise r2<0.01). Two loci exhibited allelic heterogeneity, ADIPOQ and CDH13. Of seven association signals at the ADIPOQ locus, two signals colocalized with adipose tissue expression quantitative trait loci (eQTLs) for three transcripts: trait-increasing alleles at one signal were associated with increased ADIPOQ and LINC02043, while trait-increasing alleles at the other signal were associated with decreased ADIPOQ-AS1. In reporter assays, adiponectin-increasing alleles at two signals showed corresponding directions of effect on transcriptional activity. Putative mechanisms for the seven ADIPOQ signals include a missense variant (ADIPOQ G90S), a splice variant, a promoter variant, and four enhancer variants. Of two association signals at the CDH13 locus, the first signal consisted of promoter variants, including the lead adipose tissue eQTL variant for CDH13, while a second signal included a distal intron 1 enhancer variant that showed ~2-fold allelic differences in transcriptional reporter activity. Fine-mapping and experimental validation demonstrated that multiple, distinct association signals at these loci can influence multiple transcripts through multiple molecular mechanisms.


Assuntos
Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Alelos , Caderinas/genética , Caderinas/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Frequência do Gene/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Síndrome Metabólica/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
6.
PLoS One ; 15(8): e0235404, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785222

RESUMO

OBJECTIVE: To study the role of selected serum inflammatory cytokines and berberine in the insulin signaling pathway among women with polycystic ovary syndrome (PCOS). METHODS: Selected serum inflammatory cytokines were analyzed in the particle cells, which were interfered by berberine, from 78 infertile women who were to be treated with In Vitro Fertilization (IVF) /Intracytoplasmic Sperm Injection-Embryo Transfer (icsi-et). Among them, 49 patients had PCOS infertility, and 29 were non-PCOS patients whose infertility resulted from fallopian tube and male factors. The elisa method was used to detect the changes in the expression levels of inflammatory factors in the cells. The correlations between the serum inflammatory cytokine expression levels and the corresponding clinical hormones were analyzed. The changes in the expression (mRNA and protein) levels of the serum inflammatory cytokines were studied by real-time quantitative PCR and protein printing. Fluorescence microscope and flow cytometry were used to detect the glucose uptake capacity of ovarian granulosa cells in PCOS patients under the action of insulin after berberine. RESULTS: In the PCOS group, IL-17a (P = 0.001), IL-1Ra (P<0.0001), and IL-6 (P = 0.035) were significantly higher than those in the non-PCOS group. In the non-PCOS group, AMH level was negatively correlated with inflammatory cytokines IL-17a (r = -0.819;P = 0.004), IL-1a (r = -0.716;P = 0.0.02), IL-1b (r = -0.678;P = 0.031), IL-2 (r = -0.765;P = 0.01), and IL-8 (r = -0.705;P = 0.023). However, in the PCOS group, AMH levels were not significantly correlated with the levels of the examined inflammatory cytokines. Berberine significantly reduced the expression level of mTOR mRNA (P = 0.001), and increased the expression level of IRS-1 mRNA (P = 0.009) in the PCOS granule cells. CONCLUSION: In this study, we find that the elevated levels of serum inflammatory factors IL-17a, IL-1Ra, and IL-6 cause women to be in a subclinical inflammatory state for a long time. Abnormal changes in inflammatory factors alter their original negative correlations with AMH levels, thereby weakening the metabolism of glycolipids, promoting insulin resistance, destroying the normal ovulation and fertilization system of women, leading to polycystic ovary syndrome characterized by menstrual thinning and abnormal ovulation. Berberine can improve the sensitivity of insulin by regulating the signal pathway of insulin receptor substrate-1 (IRS-1) and mammalian target of rapamycin (mTOR) in PCOS patients and achieve a therapeutic effect of treating PCOS.


Assuntos
Anti-Inflamatórios/uso terapêutico , Berberina/uso terapêutico , Insulina/sangue , Interleucinas/sangue , Síndrome do Ovário Policístico/metabolismo , Adulto , Anti-Inflamatórios/administração & dosagem , Hormônio Antimülleriano/metabolismo , Berberina/administração & dosagem , Células Cultivadas , Feminino , Glicolipídeos/metabolismo , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/tratamento farmacológico , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
7.
J Biomed Sci ; 27(1): 75, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576196

RESUMO

BACKGROUND: ZNF322A is an oncogenic transcription factor that belongs to the Cys2His2-type zinc-finger protein family. Accumulating evidence suggests that ZNF322A may contribute to the tumorigenesis of lung cancer, however, the ZNF322A-mediated downstream signaling pathways remain unknown. METHODS: To uncover ZNF322A-mediated functional network, we applied phosphopeptide enrichment and isobaric labeling strategies with mass spectrometry-based proteomics using A549 lung cancer cells, and analyzed the differentially expressed proteins of phosphoproteomic and proteomic profiles to determine ZNF322A-modulated pathways. RESULTS: ZNF322A highlighted a previously unidentified insulin signaling, heat stress, and signal attenuation at the post-translational level. Consistently, protein-phosphoprotein-kinase interaction network analysis revealed phosphorylation of IRS1 and HSP27 were altered upon ZNF322A-silenced lung cancer cells. Thus, we further investigated the molecular regulation of ZNF322A, and found the inhibitory transcriptional regulation of ZNF322A on PIM3, which was able to phosphorylate IRS1 at serine1101 in order to manipulate glucose uptake via the PI3K/AKT/mTOR signaling pathway. Moreover, ZNF322A also affects the unfolded protein response by phosphorylation of HSP27S82 and eIF2aS51, and triggers autophagosome formation in lung cancer cells. CONCLUSIONS: These findings not only give new information about the molecular regulation of the cellular proteins through ZNF322A at the post-translational level, but also provides a resource for the study of lung cancer therapy.


Assuntos
Autofagossomos/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Neoplasias Pulmonares/genética , Proteínas Oncogênicas/genética , Fatores de Transcrição/genética , Resposta a Proteínas não Dobradas , Células A549 , Proteínas de Choque Térmico/metabolismo , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Proteínas Oncogênicas/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição/metabolismo
8.
Sci Rep ; 10(1): 8509, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444657

RESUMO

Acute aerobic exercise (AE) increases skeletal muscle insulin sensitivity for several hours, caused by acute activation of AMP-activated protein kinase (AMPK). Acute resistance exercise (RE) also activates AMPK, possibly improving insulin-stimulated glucose uptake. However, RE-induced rapamycin-sensitive mechanistic target of rapamycin complex 1 (mTORC1) activation is higher and has a longer duration than after AE. In molecular studies, mTORC1 was shown to be upstream of insulin receptor substrate 1 (IRS-1) Ser phosphorylation residue, inducing insulin resistance. Therefore, we hypothesised that although RE increases insulin sensitivity through AMPK activation, prolonged mTORC1 activation after RE reduces RE-induced insulin sensitising effect. In this study, we used an electrical stimulation-induced RE model in rats, with rapamycin as an inhibitor of mTORC1 activation. Our results showed that RE increased insulin-stimulated glucose uptake following AMPK signal activation. However, mTORC1 activation and IRS-1 Ser632/635 and Ser612 phosphorylation were elevated 6 h after RE, with concomitant impairment of insulin-stimulated Akt signal activation. By contrast, rapamycin inhibited these prior exercise responses. Furthermore, increases in insulin-stimulated skeletal muscle glucose uptake 6 h after RE were higher in rats with rapamycin treatment than with placebo treatment. Our data suggest that mTORC1/IRS-1 signaling inhibition enhances skeletal muscle insulin-sensitising effect of RE.


Assuntos
Glucose/farmacologia , Resistência à Insulina , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Músculo Esquelético/metabolismo , Condicionamento Físico Animal , Sirolimo/farmacologia , Animais , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Músculo Esquelético/efeitos dos fármacos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Edulcorantes/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
9.
Am J Physiol Cell Physiol ; 318(6): C1214-C1225, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32348172

RESUMO

Reactive oxygen species such as hydrogen peroxide have been implicated in causing metabolic dysfunction such as insulin resistance. Heme groups, either by themselves or when incorporated into proteins, have been shown to scavenge peroxide and demonstrate protective effects in various cell types. Thus, we hypothesized that a metalloporphyrin similar in structure to heme, Fe(III)tetrakis(4-benzoic acid)porphyrin (FeTBAP), would be a peroxidase mimetic that could defend cells against oxidative stress. After demonstrating that FeTBAP has peroxidase activity with reduced nicotinamide adenine dinucleotide phosphate (NADPH) and NADH as reducing substrates, we determined that FeTBAP partially rescued C2C12 myotubes from peroxide-induced insulin resistance as measured by phosphorylation of AKT (S473) and insulin receptor substrate 1 (IRS-1, Y612). Furthermore, we found that FeTBAP stimulates insulin signaling in myotubes and mouse soleus skeletal muscle to about the same level as insulin for phosphorylation of AKT, IRS-1, and glycogen synthase kinase 3ß (S9). We found that FeTBAP lowers intracellular peroxide levels and protects against carbonyl formation in myotubes exposed to peroxide. Additionally, we found that FeTBAP stimulates glucose transport in myotubes and skeletal muscle to about the same level as insulin. We conclude that a peroxidase mimetic can blunt peroxide-induced insulin resistance and also stimulate insulin signaling and glucose transport, suggesting a possible role of peroxidase activity in regulation of insulin signaling.


Assuntos
Antioxidantes/farmacologia , Mimetismo Biológico , Peróxido de Hidrogênio/toxicidade , Resistência à Insulina , Insulina/farmacologia , Metaloporfirinas/farmacologia , Mioblastos Esqueléticos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peroxidases/farmacologia , Animais , Linhagem Celular , Glicogênio Sintase Quinase 3 beta/metabolismo , Peróxido de Hidrogênio/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Mioblastos Esqueléticos/metabolismo , Mioblastos Esqueléticos/patologia , Fosforilação , Carbonilação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
10.
Biochem Biophys Res Commun ; 525(3): 662-667, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32127173

RESUMO

Insulin resistance (IR) is an important pathological basis of obesity, diabetes and cardiovascular diseases, and emerging evidence demonstrates aerobic exercise as an efficient therapeutical tool in the management of IR and IR-related metabolic disease. Interleukin-4 (IL-4), an important anti-inflammatory cytokine, was recently proved to be involved in regulation of IR, yet the effect of IL-4 on exercise-induced insulin sensitivity and underlying mechanism was less investigated. In this study, using a mouse model of swimming exercise training (60 min/day, 5 days/week for 8 weeks), we found that long-term swimming exercise promoted insulin sensitivity compared with sedentary groups as indexed by the homeostasis model assessment of insulin resistance (HOMA-IR), glucose and insulin tolerance test. Accompanying with increased insulin sensitivity, swimming exercise increased serum IL-4 levels as well as insulin receptor substrate 1 (IRS-1) and protein kinase B (Akt) phosphorylation. Mechanistically, IL-4 treatment increased insulin-stimulated glucose uptake and Akt phosphorylation in skeletal muscle C2C12 cells, and inhibition of IL-4 signaling via ruxolitinib, a Janus kinase (JAK) inhibitor, attenuated IL-4-induced insulin sensitivity. Taken together, our results demonstrated IL-4 as a novel exercise factor contributing to exercise-induced insulin sensitivity, providing a potential therapeutical target of IR and related metabolic disease.


Assuntos
Resistência à Insulina , Interleucina-4/metabolismo , Transdução de Sinais , Regulação para Cima , Animais , Linhagem Celular , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina/genética , Interleucina-4/sangue , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
11.
Am J Physiol Gastrointest Liver Physiol ; 318(4): G736-G747, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32090603

RESUMO

Aging is a risk factor in the development of many diseases, including liver-related diseases. The two aims of the present study were 1) to determine how aging affects liver health in mice in the absence of any interventions and 2) if degenerations observed in relation to blood endotoxin levels are critical in aging-associated liver degeneration. Endotoxin levels and markers of liver damage, mitochondrial dysfunction, insulin resistance, and apoptosis as well as the Toll-like receptor 4 (Tlr-4) signaling cascade were studied in liver tissue and blood, respectively, of 3- and 24-mo-old male C57BL/6J mice. In a second set of experiments, 3- to 4-mo-old and 14-mo-old female lipopolysaccharide-binding protein (LBP)-/- mice and littermates fed standard chow, markers of liver damage, insulin resistance, and mitochondrial dysfunction were assessed. Plasma activity of aspartate aminotransferase and histological signs of hepatic inflammation and fibrosis were significantly higher in old C57BL/6J mice than in young animals. The number of neutrophils, CD8α-positive cells, and mRNA expression of markers of apoptosis were also significantly higher in livers of old C57BL/6J mice compared with young animals, being also associated with a significant induction of hepatic Tlr-4 and LBP expression as well as higher endotoxin levels in peripheral blood. Compared with age-matched littermates, LBP-/- mice display less signs of senescence in liver. Taken together, our data suggest that, despite being fed standard chow, old mice developed liver inflammation and beginning fibrosis and that bacterial endotoxin may play a critical role herein.NEW & NOTEWORTHY Old age in mice is associated with marked signs of liver degeneration, hepatic inflammation, and fibrosis. Aging-associated liver degeneration is associated with elevated bacterial endotoxin levels and an induction of lipopolysaccharide-binding protein (LBP) and Toll-like receptor 4-dependent signaling cascades in liver tissue. Furthermore, in old aged LBP-/- mice, markers of senescence seem to be lessened, supporting the hypothesis that bacterial endotoxin levels might be critical in aging-associated decline of liver.


Assuntos
Proteínas da Fase Aguda/metabolismo , Envelhecimento , Proteínas de Transporte/metabolismo , Endotoxinas/sangue , Cirrose Hepática/patologia , Fígado/patologia , Glicoproteínas de Membrana/metabolismo , Proteínas da Fase Aguda/genética , Animais , Apoptose , Biomarcadores , Proteínas de Transporte/genética , Feminino , Regulação da Expressão Gênica , Glucose/metabolismo , Inflamação/patologia , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Fígado/metabolismo , Malato Desidrogenase/genética , Malato Desidrogenase/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
12.
Artigo em Inglês | MEDLINE | ID: mdl-32045698

RESUMO

The exact role of VD deficiency in the development of non-alcoholic fatty liver disease (NAFLD) remains unknown. In this study, we induced VD deficiency by feeding Female Sprague-Dawley rats a VD deficient (VDD) Diet and studied the hepatic changes associated with VD deficiency. Simultaneously, we provided the VDD rats with VD or 8-methoxy psoralen (8-MOP), a suggested vitamin D receptor agonist, to test the reversibility of the hepatic changes. VDD Rats developed borderline non-alcoholic steatohepatitis (NASH) with considerable elevation in hepatic triglycerides, total cholesterol, and malondialdehyde. Furthermore, VD deficiency induced the expression of crucial enzymes and transcription factors involved in denovo lipogenesis, which justified the hepatic lipid accumulation. Insulin receptor signaling was affected by VD deficiency, demonstrated by the elevation in insulin substrate-1 (IRS1) and reduction in insulin substrate-2 (IRS2) signaling. Treatment with VD or 8-MOP attenuated IRS1 signaling and its downstream targets, leading to a decline in de novo lipogenesis, while the elevation in IRS2 expression resulted in the nuclear exclusion of forkhead box O1 (FoxO1) and diminished gluconeogenesis, a vital source of acetyl-CoA for de novo lipogenesis. Moreover, 8-MOP and Calcipotriol modulated insulin signaling in human hepatocyte cell line L02, which highlighted the crucial role of VD in the regulation of hepatic lipid contents in rats and humans. Silencing of the vitamin D receptor expression in L02 diminished the inhibitory effect of Calcipotriol and 8-MOP on fatty acid synthase and acetyl- CoA carboxylase 1 and provided the evidence that 8-MOP actions mediated via vitamin D receptor.


Assuntos
Proteínas Substratos do Receptor de Insulina/metabolismo , Metoxaleno/farmacologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Deficiência de Vitamina D/complicações , Ração Animal , Animais , Calcitriol/administração & dosagem , Calcitriol/análogos & derivados , Linhagem Celular , Feminino , Técnicas de Silenciamento de Genes , Gluconeogênese , Humanos , Insulina/metabolismo , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Metoxaleno/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Vitamina D/administração & dosagem , Vitamina D/metabolismo , Deficiência de Vitamina D/metabolismo
13.
Cancer Res ; 80(7): 1428-1437, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32015092

RESUMO

Genomic rearrangements leading to the aberrant expression of ERG are the most common early events in prostate cancer and are significantly enriched for the concomitant loss of PTEN. Genetically engineered mouse models reveal that ERG overexpression alone is not sufficient to induce tumorigenesis, but combined loss of PTEN results in an aggressive invasive phenotype. Here, we show that oncogenic ERG repressed PI3K signaling through direct transcriptional suppression of IRS2, leading to reduced RTK levels and activity. In accordance with this finding, ERG-positive human prostate cancers had a repressed AKT gene signature and transcriptional downregulation of IRS2. Although overexpression of IRS2 activated PI3K signaling, promoting cell migration in a PI3K-dependent manner, this did not fully recapitulate the phenotype seen with loss of PTEN as PI3K signaling is not as robust as observed in the setting of loss of PTEN. Importantly, deletions of the PTEN locus, which promotes active PI3K signaling, were among the most significant copy-number alterations that co-occurred with ERG genomic rearrangements. This work provides insight on how initiating oncogenic events may directly influence the selection of secondary concomitant alterations to promote oncogenic signaling during tumor evolution. SIGNIFICANCE: This work provides insight on how initiating oncogenic events may directly influence the selection of secondary concomitant alterations to promote tumorigenesis.


Assuntos
Proteínas Substratos do Receptor de Insulina/genética , Proteínas Oncogênicas/metabolismo , Neoplasias da Próstata/genética , Regulador Transcricional ERG/metabolismo , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Rearranjo Gênico , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , Proteínas Oncogênicas/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Cultura Primária de Células , Regiões Promotoras Genéticas/genética , Próstata/patologia , Neoplasias da Próstata/patologia , RNA-Seq , Transdução de Sinais/genética , Regulador Transcricional ERG/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Am J Physiol Endocrinol Metab ; 318(5): E625-E635, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32101031

RESUMO

Cellular mechanisms causing insulin resistance (IR) in chronic kidney disease (CKD) are poorly understood. One potential mechanism is that CKD-induced inflammation activates the signal transducer and activator of transcription 3 (Stat3) in muscle. We uncovered increased p-Stat3 in muscles of mice with CKD or mice fed high-fat diet (HFD). Activated Stat3 stimulates the expression of Fbxo40, a muscle-specific E3 ubiquitin ligase that stimulates ubiquitin conjugation leading to degradation of insulin receptor substrate 1 (IRS1). Evidence that Stat3 activates Fbxo40 includes 1) potential Stat3 binding sites in Fbxo40 promoters; 2) Stat3 binding to the Fbxo40 promoter; and 3) constitutively active Stat3 stimulating both Fbxo40 expression and its promoter activity. We found that IL-6 activates Stat3 in myotubes, increasing Fbxo40 expression with reduced IRS1 and p-Akt. Knockdown Fbxo40 using siRNA from myotubes results in higher levels of IRS1 and p-Akt despite the presence of IL-6. We treated mice with a small-molecule inhibitor of Stat3 (TTI-101) and found improved glucose tolerance and insulin signaling in skeletal muscles of mice with CKD or fed an HFD. Finally, we uncovered improved glucose tolerance in mice with muscle-specific Stat3 KO versus results in Stat3f/f mice in response to the HFD. Thus Stat3 activation in muscle increases IR in mice. Inhibition of Stat3 by TTI-101 could be developed into clinical strategies to improve muscle insulin signaling in inflammation and other catabolic diseases.


Assuntos
Proteínas F-Box/metabolismo , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Insuficiência Renal Crônica/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Dieta Hiperlipídica , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Camundongos Knockout , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais/fisiologia
15.
Eur J Pharmacol ; 872: 172959, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-32004528

RESUMO

Infliximab (IFX), a monoclonal antibody for tumor necrosis factor-alpha (TNF-α), is known to restore blood glucose homeostasis. However, its effects on improving renal insulin resistance (IR) are not yet studied. So we investigate the impact of infliximab on renal insulin signaling pathway in IR rat model regarding to metformin (MET). The induced IR was confirmed by a high oral glucose tolerance test, an elevation of lipid profile and the homeostatic model assessment of insulin resistance 2 (HOMA-IR 2) values. Subsequently, IR rats were concurrently treated with either MET (100 mg/kg/day) or IFX (one dose 5 mg/kg) besides IR and normal control (NC) groups. Four weeks later, IR control rats displayed hyperglycemia, hyperinsulinemia and elevation in HOMA-IR 2, renal function markers and renal tissue TNF-α, interleukins-1ß and 6 (Il-1ß, IL-6) and suppressor of cytokines signaling 3 (SOCS3) contents as well as glomerulosclerosis when compared to NC group. Additionally, the phosphorylation of renal insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) were markedly impaired. Treatment with either MET or IFX significantly improved IR and kidney functions. The effects of the drugs were achieved by the downregulation of renal inflammatory cytokines and SOCS3 levels and the amelioration of the renal IRS1/PI3K/Akt pathway. In conclusion, MET and IFX ameliorated the TNF-α worsening effect on IR in rat renal tissues by regulating insulin signaling. Interestingly, infliximab was superior to metformin in regulating insulin signaling pathway. Therefore, infliximab could be used as an adjuvant therapy in improving renal IR.


Assuntos
Infliximab/farmacologia , Resistência à Insulina , Insulina/metabolismo , Rim/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Glicemia/análise , Glicemia/metabolismo , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/sangue , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Infliximab/uso terapêutico , Proteínas Substratos do Receptor de Insulina/metabolismo , Rim/metabolismo , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/prevenção & controle , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
16.
Oncol Rep ; 43(2): 525-535, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894287

RESUMO

The initiation and development of several types of cancer have been linked to long non­coding RNA (lncRNA) X inactive­specific transcript (XIST). Yet, the pattern of expression, function, as well as the molecular mechanism underlying XIST in laryngeal squamous cell carcinoma (LSCC) lack characterization. Therefore, the present study aimed to determine the function and putative mechanism of XIST in the development of LSCC. It was revealed that the level of XIST was significantly higher in LSCC tissues that were associated with advanced Tumor­Node­Metastasis (TNM) stage and the presence of lymph node metastasis. Furthermore, the ability of human LSCC TU212 cells to proliferate, form colonies, migrate and invade was significantly suppressed, while cell apoptosis was significantly increased following knockdown of XIST. Further investigation revealed that XIST knockdown increased the expression of microRNA­144 (miR­144) by acting as an endogenous sponge of miR­144. Inhibition of miR­144 caused a partial reversal of the inhibitory effects mediated following depletion of XIST in LSCC cells. Moreover, an miR­144 target called insulin receptor substrate 1 (IRS1) was significantly decreased by XIST depletion in LSCC cells. IRS1 expression was positively correlated with XIST expression in LSCC tissues. In addition, knockdown of XIST impaired tumor growth in vivo by regulating the miR­144/IRS1 axis. The present study demonstrated that the progression of LSCC is promoted by XIST sponging miR­144 to regulate IRS1 expression, suggesting that XIST can serve as a putative target in the therapy of LSCC.


Assuntos
Carcinoma de Células Escamosas/patologia , Proteínas Substratos do Receptor de Insulina/genética , Neoplasias Laríngeas/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Regulação para Cima
17.
Horm Metab Res ; 52(1): 49-57, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31945791

RESUMO

Polycystic ovarian syndrome (PCOS) is the most common endocrine disease that causes reproductive abnormalities in fertile women. It is closely related to the persistent anovulatory, insulin resistance, and high androgen. However, the molecular mechanisms underlying the pathological development of PCOS are still unclear. In this study, we aimed to explore the distinctive metabolic patterns in insulin combined with human chorionic gonadotrophin induced PCOS. The dynamic changes of endogenous metabolites in the development of PCOS were studied using untargeted metabolomic approaches based on nuclear magnetic resonance. The results showed that the degree of PCOS disorder metabolites at different periods was not exactly the same. Twelve significantly differential endogenous metabolites from different time points were selected as potential biomarkers relate to pathological process of PCOS. Among them, six metabolites showed a good diagnostic accuracy with PCOS model. The arginine and proline metabolic pathway was considered as one of the most crucial pathways that affects occurrence and development of PCOS. In addition, IRS-1, Akt, PI3K, IκB, and NF-κB (p65) were significantly changed in the ovary tissue of PCOS rats, which revealed that the IRS-1-PI3K/Akt and NF-κB signal pathway may be involved in the development of PCOS. This study demonstrated that metabolomic analysis is a powerful tool for providing novel insight into understanding the pathogenesis of PCOS and provide a basic reference for the diagnosis of PCOS at the onset stage.


Assuntos
Síndrome do Ovário Policístico/urina , Urina/química , Animais , Feminino , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Metabolômica , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
18.
Nutrients ; 12(1)2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31947955

RESUMO

Maternal obesity increases the risk of metabolic dysregulation in rodent offspring, especially when offspring are exposed to a high-fat (HF), obesogenic diet later in life. We previously demonstrated that maternal choline supplementation (MCS) in HF-fed mouse dams during gestation prevents fetal overgrowth and excess adiposity. In this study, we examined the long-term metabolic influence of MCS. C57BL/6J mice were fed a HF diet with or without choline supplementation prior to and during gestation. After weaning, their pups were exposed to either a HF or control diet for 6 weeks before measurements. Prenatal and post-weaning dietary treatments led to sexually dimorphic responses. In male offspring, while post-weaning HF led to impaired fasting glucose and worse glucose tolerance (p < 0.05), MCS in HF dams (HFCS) attenuated these changes. HFCS (versus maternal normal fat control) appeared to improve metabolic functioning of visceral adipose tissue during post-weaning HF feeding, preventing the elevation in leptin and increasing (p < 0.05) mRNA expression of insulin receptor substrate 1 (Irs1) that promotes peripheral insulin signaling in male offspring. In contrast, MCS had minimal effects on metabolic outcomes of female offspring. In conclusion, MCS during HF feeding in mice improves long-term blood glucose homeostasis in male offspring when they are faced with a postnatal obesogenic environment.


Assuntos
Glicemia/efeitos dos fármacos , Colina/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Adiposidade , Animais , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/etiologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Gordura Intra-Abdominal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/etiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Desmame
19.
Endocrinology ; 161(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31748790

RESUMO

Decidualization, the process by which fibroblastic human endometrial stromal cells (HESC) differentiate into secretory decidual cells, is a critical event during the establishment of pregnancy. It is dependent on the steroid hormone progesterone acting through the nuclear progesterone receptor (PR). Previously, we identified insulin receptor substrate 2 (IRS2) as a factor that is directly regulated by PR during decidualization. IRS2 is an adaptor protein that functionally links receptor tyrosine kinases, such as insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R), and their downstream effectors. IRS2 expression was induced in HESC during in vitro decidualization and siRNA-mediated downregulation of IRS2 transcripts resulted in attenuation of this process. Further use of siRNAs targeted to IR or IGF1R transcripts showed that downregulation of IR, but not IGF1R, led to impaired decidualization. Loss of IRS2 transcripts in HESC suppressed phosphorylation of both ERK1/2 and AKT, downstream effectors of insulin signaling, which mediate gene expression associated with decidualization and regulate glucose uptake. Indeed, downregulation of IRS2 resulted in reduced expression and membrane localization of the glucose transporters GLUT1 and GLUT4, resulting in lowered glucose uptake during stromal decidualization. Collectively, these data suggest that the PR-regulated expression of IRS2 is necessary for proper insulin signaling for controlling gene expression and glucose utilization, which critically support the decidualization process to facilitate pregnancy. This study provides new insight into the mechanisms by which steroid hormone signaling intersects with insulin signaling in the uterus during decidualization, which has important implications for pregnancy complications associated with insulin resistance and infertility.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Decídua/efeitos dos fármacos , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Progesterona/farmacologia , Diferenciação Celular/genética , Células Cultivadas , Decídua/citologia , Decídua/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Fosforilação/efeitos dos fármacos , Gravidez , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Células Estromais/citologia , Células Estromais/metabolismo , Útero/citologia , Útero/metabolismo
20.
Food Funct ; 11(1): 392-403, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31821397

RESUMO

The GLUT4 and PI3K/AKT signaling pathways are the key sensors of energy status and they regulate glucose and lipid metabolism. Phloretin activates the PI3K/AKT pathway by promoting GLUT4 translocation and expression, thereby improving glucose consumption and tolerance. As metformin can regulate glucose metabolism, we hypothesized that phloretin can amplify its gluco-regulatory effects. Male Sprague Dawley rats were fed with a high-fat and high-sugar diet for 8 weeks and injected with a low dose of streptozotocin to induce type 2 diabetes. The diabetic rats were randomized to receive phloretin (100 mg kg-1 d-1), metformin (250 mg kg-1 d-1), or phloretin + metformin via oral gavage for another 4 weeks. Random blood glucose, serum insulin, free fatty acid, total cholesterol, triglyceride, and low-density lipoprotein levels were detected in type 2 diabetic rats. Hematoxylin-eosin and Oil Red O staining were used to observe the pathological changes in the liver, pancreas, and adipose tissues of type 2 diabetic rats. The expression levels of IRS-1, PI3K, P-AKT, and GLUT4 in skeletal muscle were detected using western blotting. Phloretin plus metformin improved fasting blood glucose levels, glucose tolerance, and insulin sensitivity in type 2 diabetic rats. In addition, this combination reduced lipid accumulation, improved the pathological changes in the liver, pancreas, and adipose tissue, and increased IRS-1, PI3K, P-AKT, and GLUT4 expression in skeletal muscle and the liver of type 2 diabetic rats. Thus, phloretin can be used in a potential combination therapy with metformin for the prevention and rescue of type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Resistência à Insulina , Metformina/uso terapêutico , Floretina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Transportador de Glucose Tipo 4/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Fígado/patologia , Masculino , Pâncreas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
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