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The rising prevalence of type 1 diabetes (T1D) over the past decades has been linked to lifestyle changes, but the underlying mechanisms are largely unknown. Recent findings point to gut-associated mechanisms in the control of T1D pathogenesis. In nonobese diabetic (NOD) mice, a model of T1D, diabetes development accelerates after deletion of the Toll-like receptor 4 (TLR4). We hypothesized that altered intestinal functions contribute to metabolic alterations, which favor accelerated diabetes development in TLR4-deficient (TLR4-/-) NOD mice. In 70-90-day-old normoglycemic (prediabetic) female NOD TLR4+/+ and NOD TLR4-/- mice, gut morphology and microbiome composition were analyzed. Parameters of lipid metabolism, glucose homeostasis, and mitochondrial respiratory activity were measured in vivo and ex vivo Compared with NOD TLR4+/+ mice, NOD TLR4-/- animals showed lower muscle mass of the small intestine, higher abundance of Bacteroidetes, and lower Firmicutes in the large intestine, along with lower levels of circulating short-chain fatty acids (SCFA). These changes are associated with higher body weight, hyperlipidemia, and severe insulin and glucose intolerance, all occurring before the onset of diabetes. These mice also exhibited insulin resistance-related abnormalities of energy metabolism, such as lower total respiratory exchange rates and higher hepatic oxidative capacity. Distinct alterations of gut morphology and microbiota composition associated with reduction of circulating SCFA may contribute to metabolic disorders promoting the progression of insulin-deficient diabetes/T1D development.
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Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Experimental/patologia , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/patologia , Animais , Glicemia/metabolismo , Peso Corporal , Diabetes Mellitus Experimental/sangue , Metabolismo Energético , Ácidos Graxos/metabolismo , Homeostase , Lipopolissacarídeos/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Modelos Biológicos , Oxirredução , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/metabolismo , alfa-2-Glicoproteína-HS/metabolismoRESUMO
The family of chemical structures that interact with a cannabinoid receptor are broadly termed cannabinoids. Traditionally known for their psychotropic effects and their use as palliative medicine in cancer, cannabinoids are very versatile and are known to interact with several orphan receptors besides cannabinoid receptors (CBR) in the body. Recent studies have shown that several key pathways involved in cell growth, differentiation and, even metabolism and apoptosis crosstalk with cannabinoid signaling. Several of these pathways including AKT, EGFR, and mTOR are known to contribute to tumor development and metastasis, and cannabinoids may reverse their effects, thereby by inducing apoptosis, autophagy and modulating the immune system. In this book chapter, we explore how cannabinoids regulate diverse signaling mechanisms in cancer and immune cells within the tumor microenvironment and whether they impart a therapeutic effect. We also provide some important insight into the role of cannabinoids in cellular and whole body metabolism in the context of tumor inhibition. Finally, we highlight recent and ongoing clinical trials that include cannabinoids as a therapeutic strategy and several combinational approaches towards novel therapeutic opportunities in several invasive cancer conditions.
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Canabinoides/farmacologia , Neoplasias , Receptores de Canabinoides/fisiologia , Transdução de Sinais , Apoptose , Humanos , Metástase Neoplásica , Microambiente TumoralRESUMO
Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with poor patient prognosis. However, the mechanisms that regulate SCLC progression and metastasis remain undefined. Here, we show that the expression of the slit guidance ligand 2 (SLIT2) tumor suppressor gene is reduced in SCLC tumors relative to adjacent normal tissue. In addition, the expression of the SLIT2 receptor, roundabout guidance receptor 1 (ROBO1), is upregulated. We find a positive association between SLIT2 expression and the Yes1 associated transcriptional regulator (YAP1)-expressing SCLC subtype (SCLC-Y), which shows a better prognosis. Using genetically engineered SCLC cells, adenovirus gene therapy, and preclinical xenograft models, we show that SLIT2 overexpression or the deletion of ROBO1 restricts tumor growth in vitro and in vivo. Mechanistic studies revealed significant inhibition of myeloid-derived suppressor cells (MDSCs) and M2-like tumor-associated macrophages (TAMs) in the SCLC tumors. In addition, SLIT2 enhances M1-like and phagocytic macrophages. Molecular analysis showed that ROBO1 knockout or SLIT2 overexpression suppresses the transforming growth factor beta 1 (TGF-ß1)/ß-catenin signaling pathway in both tumor cells and macrophages. Overall, we find that SLIT2 and ROBO1 have contrasting effects on SCLC tumors. SLIT2 suppresses, whereas ROBO1 promotes, SCLC growth by regulating the Tgf-ß1/glycogen synthase kinase-3 beta (GSK3)/ß-catenin signaling pathway in tumor cells and TAMs. These studies indicate that SLIT2 could be used as a novel therapeutic agent against aggressive SCLC.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Fator de Crescimento Transformador beta1/farmacologia , beta Catenina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Quinase 3 da Glicogênio Sintase/farmacologia , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão/genética , Neoplasias Pulmonares/genética , Macrófagos/metabolismoRESUMO
The chronic metabolic disorder diabetes mellitus is a fast-growing global problem with huge social, health, and economic consequences. It is estimated that in 2010 there were globally 285 million people (approximately 6.4% of the adult population) suffering from this disease. This number is estimated to increase to 430 million in the absence of better control or cure. An ageing population and obesity are two main reasons for the increase. Furthermore it has been shown that almost 50% of the putative diabetics are not diagnosed until 10 years after onset of the disease, hence the real prevalence of global diabetes must be astronomically high. This chapter introduces the types of diabetes and diabetic complications such as impairment of immune system, periodontal disease, retinopathy, nephropathy, somatic and autonomic neuropathy, cardiovascular diseases and diabetic foot. Also included are the current management and treatments, and emerging therapies.
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Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Hipoglicemiantes/uso terapêutico , Doença Crônica , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/fisiopatologia , HumanosRESUMO
With the incidence, and prevalence of diabetes mellitus increasing worldwide, diabetic retinopathy is expected to reach epidemic proportions. The aim of this chapter is to introduce diabetic retinopathy, a leading cause of blindness in people of the working age. The clinical course of retinopathy, anatomical changes, its pathogenesis and current treatment are described, followed by an overview of the emerging drug therapies for the potential treatment of this sight-threatening complication of diabetes.
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Diabetes Mellitus Tipo 2/epidemiologia , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/terapia , Retina/patologia , Retinopatia Diabética/patologia , Humanos , Incidência , Prevalência , Fatores de RiscoRESUMO
Chemotherapy forms the backbone of current treatments for many patients with advanced non-small-cell lung cancer (NSCLC). However, the survival rate is low in these patients due to the development of drug resistance, including cisplatin resistance. In this study, we developed a novel strategy to combat the growth of cisplatin-resistant (CR) NSCLC cells. We have shown that treatment with the plant-derived, non-psychotropic small molecular weight molecule, cannabidiol (CBD), significantly induced apoptosis of CR NSCLC cells. In addition, CBD treatment significantly reduced tumor progression and metastasis in a mouse xenograft model and suppressed cancer stem cell properties. Further mechanistic studies demonstrated the ability of CBD to inhibit the growth of CR cell lines by reducing NRF-2 and enhancing the generation of reactive oxygen species (ROS). Moreover, we show that CBD acts through Transient Receptor Potential Vanilloid-2 (TRPV2) to induce apoptosis, where TRPV2 is expressed on human lung adenocarcinoma tumors. High expression of TRPV2 correlates with better overall survival of lung cancer patients. Our findings identify CBD as a novel therapeutic agent targeting TRPV2 to inhibit the growth and metastasis of this aggressive cisplatin-resistant phenotype in NSCLC.
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BACKGROUND: Molecular mechanisms underlying inflammation-associated breast tumor growth are poorly studied. S100A7, a pro-inflammatory molecule has been shown to enhance breast cancer growth and metastasis. However, the S100A7-mediated molecular mechanisms in enhancing tumor growth and metastasis are unclear. METHODS: Human breast cancer tissue and plasma samples were used to analyze the expression of S100A7, cPLA2, and PGE2. S100A7-overexpressing or downregulated human metastatic breast cancer cells were used to evaluate the S100A7-mediated downstream signaling mechanisms. Bi-transgenic mS100a7a15 overexpression, TNBC C3 (1)/Tag transgenic, and humanized patient-derived xenograft mouse models and cPLA2 inhibitor (AACOCF3) were used to investigate the role of S100A7/cPLA2/PGE2 signaling in tumor growth and metastasis. Additionally, CODEX, a highly advanced multiplexed imaging was employed to delineate the effects of S100A7/cPLA2 inhibition on the recruitment of various immune cells. RESULTS: In this study, we found that S100A7 and cPLA2 are highly expressed and correlate with decreased overall survival in breast cancer patients. Further mechanistic studies revealed that S100A7/RAGE signaling promotes the expression of cPLA2 to mediate its oncogenic effects. Pharmacological inhibition of cPLA2 suppressed S100A7-mediated tumor growth and metastasis in multiple pre-clinical models including transgenic and humanized patient-derived xenograft (PDX) mouse models. The attenuation of cPLA2 signaling reduced S100A7-mediated recruitment of immune-suppressive myeloid cells in the tumor microenvironment (TME). Interestingly, we discovered that the S100A7/cPLA2 axis enhances the immunosuppressive microenvironment by increasing prostaglandin E2 (PGE2). Furthermore, CO-Detection by indEXing (CODEX) imaging-based analyses revealed that cPLA2 inhibition increased the infiltration of activated and proliferating CD4+ and CD8+ T cells in the TME. In addition, CD163+ tumor associated-macrophages were positively associated with S100A7 and cPLA2 expression in malignant breast cancer patients. CONCLUSIONS: Our study provides new mechanistic insights on the cross-talk between S100A7/cPLA2 in enhancing breast tumor growth and metastasis by generating an immunosuppressive TME that inhibits the infiltration of cytotoxic T cells. Furthermore, our studies indicate that S100A7/cPLA2 could be used as novel prognostic marker and cPLA2 inhibitors as promising drugs against S100A7-overexpressing aggressive breast cancer.
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Neoplasias da Mama/genética , Fosfolipases A2 Citosólicas/antagonistas & inibidores , Proteína A7 Ligante de Cálcio S100/metabolismo , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Microambiente TumoralRESUMO
The growing burden of obesity and incidence of the aggressive triple negative breast cancer (TNBC) is a challenge, especially amongst vulnerable populations with unmet medical needs and higher mortality from breast cancer. While some mechanisms linking obesity and TNBC have been identified, the complex nature of pathogenesis, in both obesity as well as TNBC poses a real challenge in establishing a causative role of obesity in risk of TNBC. In this review article, we discuss pathological mechanisms identified in the tumor microenvironment (TME) as well as the obese microenvironment (OME), such as inflammation, insulin resistance and survival pathways that contribute to the development and progression of TNBC. Insights into the cross-talk between TME and OME, and their contribution to TNBC development and progression, may pave the way for personalized therapies against TNBC progression, relapse and metastasis.
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Tecido Adiposo/metabolismo , Obesidade/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Microambiente Tumoral , Tecido Adiposo/patologia , Animais , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Progressão da Doença , Metabolismo Energético , Feminino , Humanos , Incidência , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Obesidade/epidemiologia , Obesidade/patologia , Obesidade/terapia , Fatores de Risco , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
Background: Induced electric fields (iEFs) control directional breast cancer cell migration. While the connection between migration and metabolism is appreciated in the context of cancer and metastasis, effects of iEFs on metabolic pathways especially as they relate to migration, remain unexplored. Materials and Methods: Quantitative cell migration data in the presence and absence of an epidermal growth factor (EGF) gradient in the microfluidic bidirectional microtrack assay was retrospectively analyzed for additional effects of iEFs on cell motility and directionality. Surrogate markers of oxidative phosphorylation (succinate dehydrogenase [SDH] activity) and glycolysis (lactate dehydrogenase activity) were assessed in MDA-MB-231 breast cancer cells and normal MCF10A mammary epithelial cells exposed to iEFs and EGF. Results: Retrospective analysis of migration results suggests that iEFs increase forward cell migration speeds while extending the time cells spend migrating slowly in the reverse direction or remaining stationary. Furthermore, in the presence of EGF, iEFs differentially altered flux through oxidative phosphorylation in MDA-MB-231 cells and glycolysis in MCF10A cells. Conclusions: iEFs interfere with MDA-MB-231 cell migration, potentially, by altering mitochondrial metabolism, observed as an inhibition of SDH activity in the presence of EGF. The energy intensive process of migration in these highly metastatic breast cancer cells may be hindered by iEFs, thus, through hampering of oxidative phosphorylation.
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Slit2 exerts antitumor effects in various cancers; however, the underlying mechanism, especially its role in regulating the immune, especially in the bone marrow niche, system is still unknown. Elucidating the behavior of macrophages in tumor progression can potentially improve immunotherapy. Using a spontaneous mammary tumor virus promoter-polyoma middle T antigen (PyMT) breast cancer mouse model, we observed that Slit2 increased the abundance of antitumor M1 macrophage in the bone marrow upon differentiation in vitro. Moreover, myeloablated PyMT mice injected with Slit2-treated bone marrow allografts showed a marked reduction in tumor growth, with enhanced recruitment of M1 macrophage in their tumor stroma. Mechanistic studies revealed that Slit2 significantly enhanced glycolysis and reduced fatty acid oxidation in bone marrow-derived macrophages (BMDMs). Slit2 treatment also altered mitochondrial respiration metabolites in macrophages isolated from healthy human blood that were treated with plasma from breast cancer patients. Overall, this study, for the first time, shows that Slit2 increases BMDM polarization toward antitumor phenotype by modulating immune-metabolism. Furthermore, this study provides evidence that soluble Slit2 could be developed as novel therapeutic strategy to enhance antitumor immune response.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neoplasias Mamárias Experimentais/terapia , Metaboloma/efeitos dos fármacos , Proteínas do Tecido Nervoso/fisiologia , Adulto , Idoso , Animais , Antígenos Transformantes de Poliomavirus/genética , Meios de Cultivo Condicionados , Feminino , Glicólise/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Receptores de Lipopolissacarídeos/análise , Macrófagos/imunologia , Macrófagos/metabolismo , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Vírus do Tumor Mamário do Camundongo/genética , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/farmacologia , Quimera por Radiação , Serina-Treonina Quinases TOR/fisiologia , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/química , Carga TumoralRESUMO
Triple-negative breast cancer (TNBC), defined as loss of estrogen, progesterone, and Her2 receptors, is a subtype of highly aggressive breast cancer with worse prognosis and poor survival rate. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine aberrantly expressed in many solid tumors and known to promote tumor progression and metastasis. However, its role in TNBC progression and metastasis is unexplored. Here we have shown that in TNBC patients, MIF expression was significantly enriched in the tumor compared to adjacent normal tissue. Using publically available patient datasets, we showed that MIF overexpression correlates with worse survival in TNBC compared to other hormonal status. Orthotopic implantation of TNBC cells into MIF knockout mice showed reduced tumor growth compared to wild-type mice. In addition, we have shown that MIF downregulation inhibits TNBC growth and progression in a syngeneic mouse model. We further showed that CPSI-1306, a small-molecule MIF inhibitor, inhibits the growth of TNBC cells in vitro. Mechanistic studies revealed that CPSI-1306 induces intrinsic apoptosis by alteration in mitochondrial membrane potential, cytochrome c (Cyt c) release, and activation of different caspases. In addition, CPSI-1306 inhibits the activation of cell survival and proliferation-related molecules. CPSI-1306 treatment also reduced the tumor growth and metastasis in orthotopic mouse models of mammary carcinoma. CPSI-1306 treatment of tumor-bearing mice significantly inhibited TNBC growth and pulmonary metastasis in a dose-dependent manner. Histological analysis of xenograft tumors revealed a higher number of apoptotic cells in CPSI-1306-treated tumors compared to vehicle controls. Our studies, for the first time, show that MIF overexpression in TNBC enhances growth and metastasis. Taken together, our results indicate that using small molecular weight MIF inhibitors could be a promising strategy to inhibit TNBC progression and metastasis.
Assuntos
Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose , Caspases/metabolismo , Movimento Celular , Sobrevivência Celular , Citocromos c/metabolismo , Progressão da Doença , Ativação Enzimática , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas In Vitro , Inflamação , Oxirredutases Intramoleculares/antagonistas & inibidores , Isoxazóis/farmacologia , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Morfolinas/farmacologia , Metástase Neoplásica , Transplante de Neoplasias , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/patologia , CicatrizaçãoRESUMO
Interactions between cells and their environment influence key physiologic processes such as their propensity to migrate. However, directed migration controlled by extrinsically applied electrical signals is poorly understood. Using a novel microfluidic platform, we found that metastatic breast cancer cells sense and respond to the net direction of weak (â¼100 µV cm-1), asymmetric, non-contact induced Electric Fields (iEFs). iEFs inhibited EGFR (Epidermal Growth Factor Receptor) activation, prevented formation of actin-rich filopodia, and hindered the motility of EGF-treated breast cancer cells. The directional effects of iEFs were nullified by inhibition of Akt phosphorylation. Moreover, iEFs in combination with Akt inhibitor reduced EGF-promoted motility below the level of untreated controls. These results represent a step towards isolating the coupling mechanism between cell motility and iEFs, provide valuable insights into how iEFs target multiple diverging cancer cell signaling mechanisms, and demonstrate that electrical signals are a fundamental regulator of cancer cell migration.
Assuntos
Neoplasias da Mama/patologia , Movimento Celular , Campos Eletromagnéticos , Actinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/metabolismo , Feminino , Humanos , Metástase Neoplásica , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The chemokine CXCL12 has been shown to regulate breast tumor growth, however, its mechanism in initiating distant metastasis is not well understood. Here, we generated a novel conditional allele of Cxcl12 in mice and used a fibroblast-specific Cre transgene along with various mammary tumor models to evaluate CXCL12 function in the breast cancer metastasis. Ablation of CXCL12 in stromal fibroblasts of mice significantly delayed the time to tumor onset and inhibited distant metastasis in different mouse models. Elucidation of mechanisms using in vitro and in vivo model systems revealed that CXCL12 enhances tumor cell intravasation by increasing vascular permeability and expansion of a leaky tumor vasculature. Furthermore, our studies revealed CXCL12 enhances permeability by recruiting endothelial precursor cells and decreasing endothelial tight junction and adherence junction proteins. High expression of stromal CXCL12 in large cohort of breast cancer patients was directly correlated to blood vessel density and inversely correlated to recurrence and overall patient survival. In addition, our analysis revealed that stromal CXCL12 levels in combination with number of CD31+ blood vessels confers poorer patient survival compared to individual protein level. However, no correlation was observed between epithelial CXCL12 and patient survival or blood vessel density. Our findings describe the novel interactions between fibroblasts-derived CXCL12 and endothelial cells in facilitating tumor cell intrvasation, leading to distant metastasis. Overall, our studies indicate that cross-talk between fibroblast-derived CXCL12 and endothelial cells could be used as novel biomarker and strategy for developing tumor microenvironment based therapies against aggressive and metastatic breast cancer.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimiocina CXCL12/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Invasividade Neoplásica/patologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Neoplasias Mamárias Animais , Camundongos , Camundongos Transgênicos , Metástase Neoplásica/patologia , Microambiente Tumoral/fisiologiaRESUMO
Increased oxidative stress is implicated in the pathogenesis of experimental diabetic neuropathy, but translational evidence in recent-onset diabetes is scarce. We aimed to determine whether markers of systemic oxidative stress are associated with diabetic sensorimotor polyneuropathy (DSPN) in recent-onset diabetes. In this cross-sectional study, we measured serum concentrations of extracellular superoxide dismutase (SOD3), thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH) in 107 type 1 and 215 type 2 diabetes patients from the German Diabetes Study baseline cohort and 37 glucose-tolerant individuals (controls). DSPN was defined by electrophysiological and clinical criteria (Toronto Consensus, 2011). SOD3 and GSH concentrations were lower in individuals with type 1 and type 2 diabetes compared with concentrations in controls (P<0.0001). In contrast, the TBARS concentration was higher in participants with type 1 diabetes and type 2 diabetes compared with levels in controls (P<0.0001). In addition, the SOD3 concentration was higher in participants with type 1 diabetes compared to concentrations in those with type 2 diabetes (P<0.0001). A low SOD3 concentration was associated with DSPN in individuals with type 1 diabetes (ß=-0.306, P=0.002), type 2 diabetes (ß=-0.164, P=0.017), and in both groups combined (ß=-0.206, P=0.0003). Lower SOD3 concentrations were associated with decreased motor nerve conduction velocity (NCV) in men and, to a lesser degree, with reduced sensory NCV in women with diabetes. In conclusion, several biomarkers of oxidative stress are altered in recent-onset diabetes, with only a lower SOD3 concentration being linked to the presence of DSPN, suggesting a role for reduced extracellular antioxidative defense against superoxide in the early development of DSPN.
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Complicações do Diabetes , Polineuropatias/sangue , Polineuropatias/etiologia , Superóxido Dismutase/sangue , Adulto , Biomarcadores , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Estresse Oxidativo , Nervos Periféricos/fisiopatologia , Polineuropatias/diagnóstico , Fatores Sexuais , Avaliação de SintomasRESUMO
Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and may result primarily from increased hepatic de novo lipogenesis (PRIM) or secondarily from adipose tissue lipolysis (SEC). We studied mice with hepatocyte- or adipocyte-specific SREBP-1c overexpression as models of PRIM and SEC. PRIM mice featured increased lipogenic gene expression in the liver and adipose tissue. Their selective, liver-specific insulin resistance was associated with increased C18:1-diacylglycerol content and protein kinase Cε translocation. SEC mice had decreased lipogenesis mediated by hepatic cholesterol responsive element-binding protein and featured portal/lobular inflammation along with total, whole-body insulin resistance. Hepatic mitochondrial respiration transiently increased and declined with aging along with higher muscle reactive oxygen species production. In conclusion, hepatic insulin resistance originates from lipotoxicity but not from lower mitochondrial capacity, which can even transiently adapt to increased peripheral lipolysis. Peripheral insulin resistance is prevented during increased hepatic lipogenesis only if adipose tissue lipid storage capacity is preserved.
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Resistência à Insulina/fisiologia , Lipogênese/genética , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Adipócitos/metabolismo , Animais , Diglicerídeos/metabolismo , Feminino , Hepatócitos/metabolismo , Lipólise/genética , Fígado/citologia , Fígado/fisiopatologia , Camundongos , Camundongos Transgênicos , Hepatopatia Gordurosa não Alcoólica/genética , Proteína Quinase C-épsilon/metabolismo , Transporte Proteico , Espécies Reativas de Oxigênio/metabolismoRESUMO
Type 1 diabetes has been recently linked to nonalcoholic fatty liver disease (NAFLD), which is known to associate with insulin resistance, obesity, and type 2 diabetes. However, the role of insulin resistance and hyperglycemia for hepatic energy metabolism is yet unclear. To analyze early abnormalities in hepatic energy metabolism, we examined 55 patients with recently diagnosed type 1 diabetes. They underwent hyperinsulinemic-normoglycemic clamps with [6,6-(2)H2]glucose to assess whole-body and hepatic insulin sensitivity. Hepatic γATP, inorganic phosphate (Pi), and triglyceride concentrations (hepatocellular lipid content [HCL]) were measured with multinuclei magnetic resonance spectroscopy ((31)P/(1)H-MRS). Glucose-tolerant humans served as control (CON) (n = 57). Whole-body insulin sensitivity was 44% lower in patients than in age- and BMI-matched CON. Hepatic γATP was 15% reduced (2.3 ± 0.6 vs. 2.7 ± 0.6 mmol/L, P < 0.001), whereas hepatic Pi and HCL were similar in patients when compared with CON. Across all participants, hepatic γATP correlated negatively with glycemia and oxidized LDL. Carriers of the PPARG G allele (rs1801282) and noncarriers of PPARGC1A A allele (rs8192678) had 21 and 13% lower hepatic ATP concentrations. Variations in genes controlling oxidative metabolism contribute to a reduction in hepatic ATP in the absence of NAFLD, suggesting that alterations in hepatic mitochondrial function may precede diabetes-related liver diseases.
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Trifosfato de Adenosina/metabolismo , Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 1/genética , Metabolismo Energético/genética , Fígado/metabolismo , Adulto , Alelos , Índice de Massa Corporal , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Feminino , Técnica Clamp de Glucose , Humanos , Resistência à Insulina/genética , Metabolismo dos Lipídeos/genética , Fígado/patologia , Masculino , Estresse Oxidativo/fisiologia , PPAR gama/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fosfatos/metabolismo , Triglicerídeos/metabolismoRESUMO
For long the presence of insulin resistance in type 1 diabetes has been questioned. Detailed metabolic analyses revealed 12%-61% and up to 20% lower whole-body (skeletal muscle) and hepatic insulin sensitivity in type 1 diabetes, depending on the population studied. Type 1 diabetes patients feature impaired muscle adenosine triphosphate (ATP) synthesis and enhanced oxidative stress, predominantly relating to hyperglycemia. They may also exhibit abnormal fasting and postprandial glycogen metabolism in liver, while the role of hepatic energy metabolism for insulin resistance remains uncertain. Recent rodent studies point to tissue-specific differences in the mechanisms underlying insulin resistance. In non-obese diabetic mice, increased lipid availability contributes to muscle insulin resistance via diacylglycerol/protein kinase C isoforms. Furthermore, humans with type 1 diabetes respond to lifestyle modifications or metformin by 20%-60% increased whole-body insulin sensitivity, likely through improvement in both glycemic control and oxidative phosphorylation. Intensive insulin treatment and islet transplantation also increase but fail to completely restore whole-body and hepatic insulin sensitivity. In conclusion, insulin resistance is a feature of type 1 diabetes, but more controlled trials are needed to address its contribution to disease progression, which might help to optimize treatment and reduce comorbidities.
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Diabetes Mellitus Tipo 1/metabolismo , Resistência à Insulina , Tecido Adiposo/metabolismo , Animais , Humanos , Fígado/metabolismo , Camundongos , Estresse OxidativoRESUMO
The association of hepatic mitochondrial function with insulin resistance and non-alcoholic fatty liver (NAFL) or steatohepatitis (NASH) remains unclear. This study applied high-resolution respirometry to directly quantify mitochondrial respiration in liver biopsies of obese insulin-resistant humans without (n = 18) or with (n = 16) histologically proven NAFL or with NASH (n = 7) compared to lean individuals (n = 12). Despite similar mitochondrial content, obese humans with or without NAFL had 4.3- to 5.0-fold higher maximal respiration rates in isolated mitochondria than lean persons. NASH patients featured higher mitochondrial mass, but 31%-40% lower maximal respiration, which associated with greater hepatic insulin resistance, mitochondrial uncoupling, and leaking activity. In NASH, augmented hepatic oxidative stress (H2O2, lipid peroxides) and oxidative DNA damage (8-OH-deoxyguanosine) was paralleled by reduced anti-oxidant defense capacity and increased inflammatory response. These data suggest adaptation of the liver ("hepatic mitochondrial flexibility") at early stages of obesity-related insulin resistance, which is subsequently lost in NASH.
Assuntos
Fígado Gorduroso/patologia , Fígado/patologia , Mitocôndrias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Adulto , Respiração Celular , Fígado Gorduroso/complicações , Fígado Gorduroso/metabolismo , Feminino , Humanos , Peróxido de Hidrogênio/metabolismo , Resistência à Insulina , Peroxidação de Lipídeos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Estresse OxidativoRESUMO
OBJECTIVE: Muscle insulin resistance has been implicated in the development of steatosis and dyslipidemia by changing the partitioning of postprandial substrate fluxes. Also, insulin resistance may be due to reduced mitochondrial function. We examined the association between mitochondrial activity, insulin sensitivity, and steatosis in a larger human population. RESEARCH DESIGN AND METHODS: We analyzed muscle mitochondrial activity from ATP synthase flux (fATP) and ectopic lipids by multinuclei magnetic resonance spectroscopy from 113 volunteers with and without diabetes. Insulin sensitivity was assessed from M values using euglycemic-hyperinsulinemic clamps and/or from oral glucose insulin sensitivity (OGIS) using oral glucose tolerance tests. RESULTS: Muscle fATP correlated negatively with hepatic lipid content and HbA1c. After model adjustment for study effects and other confounders, fATP showed a strong negative correlation with hepatic lipid content and a positive correlation with insulin sensitivity and fasting C-peptide. The negative correlation of muscle fATP with age, HbA1c, and plasma free fatty acids was weakened after adjustment. Body mass, muscle lipid contents, plasma lipoproteins, and triglycerides did not associate with fATP. CONCLUSIONS: The association of impaired muscle mitochondrial activity with hepatic steatosis supports the concept of a close link between altered muscle and liver energy metabolism as early abnormalities promoting insulin resistance.
Assuntos
Jejum , Fígado Gorduroso/metabolismo , Mitocôndrias Musculares/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Adulto , Feminino , Humanos , Resistência à Insulina , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/enzimologia , Adulto JovemRESUMO
Although insulin resistance is known to underlie type 2 diabetes, its role in the development of type 1 diabetes has been gaining increasing interest. In a model of type 1 diabetes, the nonobese diabetic (NOD) mouse, we found that insulin resistance driven by lipid- and glucose-independent mechanisms is already present in the liver of prediabetic mice. Hepatic insulin resistance is associated with a transient rise in mitochondrial respiration followed by increased production of lipid peroxides and c-Jun N-terminal kinase activity. At the onset of diabetes, increased adipose tissue lipolysis promotes myocellular diacylglycerol accumulation. This is paralleled by increased myocellular protein kinase C θ activity and serum fetuin A levels. Muscle mitochondrial oxidative capacity is unchanged at the onset but decreases at later stages of diabetes. In conclusion, hepatic and muscle insulin resistance manifest at different stages and involve distinct cellular mechanisms during the development of diabetes in the NOD mouse.