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1.
Nat Immunol ; 22(9): 1175-1185, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34429546

RESUMO

Systematic characterizations of adipose regulatory T (Treg) cell subsets and their phenotypes remain uncommon. Using single-cell ATAC-sequencing and paired single-cell RNA and T cell receptor (TCR) sequencing to map mouse adipose Treg cells, we identified CD73hiST2lo and CD73loST2hi subsets with distinct clonal expansion patterns. Analysis of TCR-sharing data implied a state transition between CD73hiST2lo and CD73loST2hi subsets. Mechanistically, we revealed that insulin signaling occurs through a HIF-1α-Med23-PPAR-γ axis to drive the transition of CD73hiST2lo into a CD73loST2hi adipose Treg cell subset. Treg cells deficient in insulin receptor, HIF-1α or Med23 have decreased PPAR-γ expression that in turn promotes accumulation of CD73hiST2lo adipose Treg cells and physiological adenosine production to activate beige fat biogenesis. We therefore unveiled a developmental trajectory of adipose Treg cells and its dependence on insulin signaling. Our findings have implications for understanding the dynamics of adipose Treg cell subsets in aged and obese contexts.


Assuntos
Tecido Adiposo/imunologia , Resistência à Insulina/imunologia , Insulina/metabolismo , Receptor de Insulina/metabolismo , Linfócitos T Reguladores/imunologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Tecido Adiposo/citologia , Envelhecimento/imunologia , Animais , Células Cultivadas , Sequenciamento de Nucleotídeos em Larga Escala , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Masculino , Complexo Mediador/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/imunologia , PPAR gama/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/citologia
2.
Arch Biochem Biophys ; 710: 109005, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34371008

RESUMO

Glomerular podocytes are a target for the actions of insulin. Accumulating evidence indicates that exposure to nutrient overload induces insulin resistance in these cells, manifested by abolition of the stimulatory effect of insulin on glucose uptake. Numerous recent studies have investigated potential mechanisms of the induction of insulin resistance in podocytes. High glucose concentrations stimulated reactive oxygen species production through NADPH oxidase activation, decreased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, and reduced deacetylase sirtuin 1 (SIRT1) protein levels and activity. Calcium signaling involving transient receptor potential cation channel C, member 6 (TRPC6) also was demonstrated to play an essential role in the regulation of insulin-dependent signaling and glucose uptake in podocytes. Furthermore, podocytes exposed to diabetic environment, with elevated insulin levels become insulin resistant as a result of degradation of insulin receptor (IR), resulting in attenuation of insulin signaling responsiveness. Also elevated levels of palmitic acid appear to be an important factor and contributor to podocytes insulin resistance. This review summarizes cellular and molecular alterations that contribute to the development of insulin resistance in glomerular podocytes.


Assuntos
Resistência à Insulina/fisiologia , Podócitos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Transporte Biológico Ativo , Sinalização do Cálcio , Nefropatias Diabéticas/metabolismo , Estresse do Retículo Endoplasmático , Glucose/metabolismo , Hexosaminas/biossíntese , Humanos , Redes e Vias Metabólicas , Modelos Biológicos , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Receptor de Insulina/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo , Resposta a Proteínas não Dobradas
3.
J Biochem Mol Toxicol ; 35(9): e22840, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34227185

RESUMO

Insulin receptor (IR) was discovered in 1970. Shortcomings in IR transcribed signals were found pro-diabetic, which could also inter-relate obesity and atherosclerosis in a time-dependent manner. Low-density lipoprotein receptor (LDLR) was discovered in 1974. Later studies showed that insulin could modulate LDLR expression and activity. Repression of LDLR transcription in the absence or inactivity of insulin showed a direct cause of atherosclerosis. Leptin receptor (OB-R) was found in 1995 and its resistance became responsible for developing obesity. The three interlinked pathologies namely, diabetes, atherosclerosis, and obesity were later on marked as metabolic syndrome-X (MSX). In 2012, the IR-LDLR inter-association was identified. In 2019, the proficiency of signal transmission from this IR-LDLR receptor complex was reported. LDLR was found to mimic IR-generated signaling path when it remains bound to IR in IR-DLR interlocked state. This was the first time LDLR was found sending messages besides its LDL-clearing activity from blood vessels.


Assuntos
Aterosclerose/metabolismo , Diabetes Mellitus/metabolismo , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Receptor de Insulina/metabolismo , Receptores de LDL/metabolismo , Aterosclerose/história , Diabetes Mellitus/história , História do Século XX , História do Século XXI , Humanos , Insulina/história , Insulina/metabolismo , Síndrome Metabólica/história , Obesidade/história , Receptor de Insulina/história , Receptores de LDL/história , Receptores para Leptina/metabolismo
4.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202916

RESUMO

It has been well established that insulin-like growth factors (IGFs) mainly mediate long-term actions in cell fates, whereas insulin predominantly exerts its role on metabolic activity. Indeed, insulin mediates multiple anabolic biological activities in glucose and amino acid transport, lipid and protein synthesis, the induction of glycogen, the inhibition of gluconeogenesis, lipolysis, and protein degradation. The interactions and differences between insulin receptor signaling and IGF-I receptor signaling in the metabolism and the cell fates are quite complicated. Because of the overlapping actions of IGF-I singling with insulin signaling, it has been difficult to distinguish the role of both signaling mechanisms on the metabolism. Furthermore, comprehensive information on the IGF-I function in respective tissues remains insufficient. Therefore, we need to clarify the precise roles of IGF-I signaling on the metabolism separate from those of insulin signaling. This review focuses on the metabolic roles of IGFs in the respective tissues, especially in terms of comparison with those of insulin, by overviewing the metabolic phenotypes of tissue-specific IGF-I and insulin receptor knockout mice, as well as those in mice treated with the dual insulin receptor/IGF-I receptor inhibitor OSI-906.


Assuntos
Metabolismo Energético , Somatomedinas/metabolismo , Animais , Regulação da Expressão Gênica , Humanos , Insulina/metabolismo , Camundongos , Especificidade de Órgãos , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Transdução de Sinais , Somatomedinas/genética
5.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209489

RESUMO

The endocytosis of ligand-bound receptors and their eventual recycling to the plasma membrane (PM) are processes that have an influence on signalling activity and therefore on many cell functions, including migration and proliferation. Like other tyrosine kinase receptors (TKR), the insulin receptor (INSR) has been shown to be endocytosed by clathrin-dependent and -independent mechanisms. Once at the early endosome (EE), the sorting of the receptor, either to the late endosome (LE) for degradation or back to the PM through slow or fast recycling pathways, will determine the intensity and duration of insulin effects. Both the endocytic and the endosomic pathways are regulated by many proteins, the Arf and Rab families of small GTPases being some of the most relevant. Here, we argue for a specific role for the slow recycling route, whilst we review the main molecular mechanisms involved in INSR endocytosis, sorting and recycling, as well as their possible role in cell functions.


Assuntos
Endossomos/metabolismo , Receptor de Insulina/metabolismo , Animais , Proteínas de Transporte , Membrana Celular/metabolismo , Movimento Celular , Proliferação de Células , Clatrina/metabolismo , Endocitose , Humanos , Lisossomos , Ligação Proteica , Transporte Proteico , Receptor de Insulina/agonistas , Vesículas Transportadoras/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo
6.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198511

RESUMO

The insulin receptor (IR) is critically involved in maintaining glucose homeostasis. It undergoes proteolytic cleavage by proprotein convertases, which is an essential step for its activation. The importance of the insulin receptor in liver is well established, but its role in pancreatic ß cells is still controversial. In this study, we investigated the cleavage of the IR by the proprotein convertase FURIN in ß cells and hepatocytes, and the contribution of the IR in pancreatic ß cells and liver to glucose homeostasis. ß-cell-specific Furin knockout (ßFurKO) mice were glucose intolerant, but liver-specific Furin knockout (LFurKO) mice were normoglycemic. Processing of the IR was blocked in ßFurKO cells, but unaffected in LFurKO mice. Most strikingly, glucose homeostasis in ß-cell-specific IR knockout (ßIRKO) mice was normal in younger mice (up to 20 weeks), and only mildly affected in older mice (24 weeks). In conclusion, FURIN cleaves the IR non-redundantly in ß cells, but redundantly in liver. Furthermore, we demonstrated that the IR in ß cells plays a limited role in glucose homeostasis.


Assuntos
Furina/deficiência , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Fígado/metabolismo , Receptor de Insulina/metabolismo , Animais , Furina/metabolismo , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Homeostase , Camundongos Knockout , Proteólise , Receptor de Insulina/deficiência , Transdução de Sinais
7.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208786

RESUMO

The accumulation of lipid intermediates may interfere with energy metabolism pathways and regulate cellular energy supplies. As increased levels of long-chain acylcarnitines have been linked to insulin resistance, we investigated the effects of long-chain acylcarnitines on key components of the insulin signalling pathway. We discovered that palmitoylcarnitine induces dephosphorylation of the insulin receptor (InsR) through increased activity of protein tyrosine phosphatase 1B (PTP1B). Palmitoylcarnitine suppresses protein kinase B (Akt) phosphorylation at Ser473, and this effect is not alleviated by the inhibition of PTP1B by the insulin sensitizer bis-(maltolato)-oxovanadium (IV). This result indicates that palmitoylcarnitine affects Akt activity independently of the InsR phosphorylation level. Inhibition of protein kinase C and protein phosphatase 2A does not affect the palmitoylcarnitine-mediated inhibition of Akt Ser473 phosphorylation. Additionally, palmitoylcarnitine markedly stimulates insulin release by suppressing Akt Ser473 phosphorylation in insulin-secreting RIN5F cells. In conclusion, long-chain acylcarnitines activate PTP1B and decrease InsR Tyr1151 phosphorylation and Akt Ser473 phosphorylation, thus limiting the cellular response to insulin stimulation.


Assuntos
Carnitina/análogos & derivados , Fosforilação/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Tirosina/metabolismo , Animais , Células CHO , Carnitina/farmacologia , Cricetulus , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Insulina/metabolismo , Resistência à Insulina , Modelos Biológicos , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/química
8.
FASEB J ; 35(8): e21826, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34320244

RESUMO

In pancreatic cancer, autocrine insulin-like growth factor-1 (IGF-1) and paracrine insulin stimulate both IGF-1 receptor (IGF1R) and insulin receptor (IR) to increase tumor growth and glycolysis. In pancreatic cancer patients, cancer-induced glycolysis increases hepatic gluconeogenesis, skeletal muscle proteolysis, and fat lipolysis and, thereby, causes cancer cachexia. As a protein coexisting with IGF1R and IR, caveolin-1 (cav-1) may be involved in pancreatic cancer-induced cachexia. We undertook the present study to test this hypothesis. Out of wild-type MiaPaCa2 and AsPC1 human pancreatic cancer cell lines, we created their stable sub-lines whose cav-1 expression was diminished with RNA interference or increased with transgene expression. When these cells were studied in vitro, we found that cav-1 regulated IGF1R/IR expression and activation and also regulated cellular glycolysis. We transplanted the different types of MiaPaCa2 cells in growing athymic mice for 8 weeks, using intact athymic mice as tumor-free controls. We found that cav-1 levels in tumor grafts were correlated with expression levels of the enzymes that regulated hepatic gluconeogenesis, skeletal muscle proteolysis, and fat lipolysis in the respective tissues. When the tumors had original or increased cav-1, their carriers' body weight gain was less than the tumor-free reference. When cav-1 was diminished in tumors, the tumor carriers' body weight gain was not changed significantly, compared to the tumor-free reference. In conclusion, cav-1 in pancreatic cancer cells stimulated IGF1R/IR and glycolysis in the cancer cells and triggered cachectic states in the tumor carrier.


Assuntos
Caquexia/etiologia , Caveolina 1/metabolismo , Glicólise/fisiologia , Neoplasias Pancreáticas/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Animais , Caveolina 1/genética , Linhagem Celular Tumoral , Deleção de Genes , Regulação da Expressão Gênica/fisiologia , Humanos , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética
9.
Diabetes ; 70(8): 1874-1884, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34074726

RESUMO

We previously reported genotype-phenotype correlations in 12 missense variants causing severe insulin resistance, located in the second and third fibronectin type III (FnIII) domains of the insulin receptor (INSR), containing the α-ß cleavage and part of insulin-binding sites. This study aimed to identify genotype-phenotype correlations in FnIII domain variants of IGF1R, a structurally related homolog of INSR, which may be associated with growth retardation, using the recently reported crystal structures of IGF1R. A structural bioinformatics analysis of five previously reported disease-associated heterozygous missense variants and a likely benign variant in the FnIII domains of IGF1R predicted that the disease-associated variants would severely impair the hydrophobic core formation and stability of the FnIII domains or affect the α-ß cleavage site, while the likely benign variant would not affect the folding of the domains. A functional analysis of these variants in CHO cells showed impaired receptor processing and autophosphorylation in cells expressing the disease-associated variants but not in those expressing the wild-type form or the likely benign variant. These results demonstrated genotype-phenotype correlations in the FnIII domain variants of IGF1R, which are presumably consistent with those of INSR and would help in the early diagnosis of patients with disease-associated IGF1R variants.


Assuntos
Antígenos CD/genética , Estatura/genética , Transtornos do Crescimento/genética , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética , Animais , Antígenos CD/metabolismo , Células CHO , Cricetinae , Cricetulus , Estudos de Associação Genética , Humanos , Resistência à Insulina/genética , Mutação de Sentido Incorreto , Fenótipo , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Estudos Retrospectivos
10.
Cell Death Dis ; 12(7): 643, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162829

RESUMO

Among the principal causative factors for the development of complications related to aging is a diet rich in fats and sugars, also known as the Western diet. This diet advocates numerous changes that might increase the susceptibility to initiate cancer and/or to create a tissue microenvironment more conducive to the growth of malignant cells, thus favoring the progression of cancer and metastasis. Hypercaloric diets in general lead to oxidative stress generating reactive oxygen species and induce endoplasmic reticulum stress. Our results demonstrate that mice bearing tumors fed with a Western diet presented bigger tumor mass with increased insulin sensitivity in these tissues. Several markers of insulin signaling, such as AKT phosphorylation and mTOR pathway, are promoted in tumors of Western diet-fed animals. This process is associated with increased macrophage infiltration, activation of unfolded protein response pathway, and initiation of epithelial-mesenchymal transition (EMT) process in these tumor tissues. Summing up, we propose that the Western diet accelerates the aging-related processes favoring tumor development.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Dieta Ocidental/efeitos adversos , Transição Epitelial-Mesenquimal , Mediadores da Inflamação/metabolismo , Melanoma Experimental/metabolismo , Neoplasias Cutâneas/metabolismo , Resposta a Proteínas não Dobradas , Fatores Etários , Animais , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Fatores de Tempo , Carga Tumoral , Microambiente Tumoral , Resposta a Proteínas não Dobradas/genética
11.
Diab Vasc Dis Res ; 18(3): 14791641211027324, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34190643

RESUMO

BACKGROUND: Insulin exerts vasculoprotective effects on endothelial cells (ECs) and growth-promoting effects on vascular smooth muscle cells (SMCs) in vitro, and suppresses neointimal growth in vivo. Here we determined the role of ECs and SMCs in the effect of insulin on neointimal growth. METHODS: Mice with transgene CreERT2 under the control of EC-specific Tie2 (Tie2-Cre) or SMC-specific smooth muscle myosin heavy chain promoter/enhancer (SMMHC-Cre) or littermate controls were crossbred with mice carrying a loxP-flanked insulin receptor (IR) gene. After CreERT2-loxP-mediated recombination was induced by tamoxifen injection, mice received insulin pellet or sham (control) implantation, and underwent femoral artery wire injury. Femoral arteries were collected for morphological analysis 28 days after wire injury. RESULTS: Tamoxifen-treated Tie2-Cre+ mice showed lower IR expression in ECs, but not in SMCs, than Tie2-Cre- mice. Insulin treatment reduced neointimal area after arterial injury in Tie2-Cre- mice, but had no effect in Tie2-Cre+ mice. Tamoxifen-treated SMMHC-Cre+ mice showed lower IR expression in SMCs, but not in ECs, than SMMHC-Cre- mice. Insulin treatment reduced neointimal area in SMMHC-Cre- mice, whereas unexpectedly, it failed to inhibit neointima formation in SMMHC-Cre+ mice. CONCLUSION: Insulin action in both ECs and SMCs is required for the "anti-restenotic" effect of insulin in vivo.


Assuntos
Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Neointima , Receptor de Insulina/agonistas , Lesões do Sistema Vascular/tratamento farmacológico , Animais , Modelos Animais de Doenças , Implantes de Medicamento , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/lesões , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/lesões , Artéria Femoral/metabolismo , Artéria Femoral/patologia , Masculino , Camundongos Knockout , Músculo Liso Vascular/lesões , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Lesões do Sistema Vascular/metabolismo , Lesões do Sistema Vascular/patologia
12.
Toxicol Lett ; 349: 40-50, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34118311

RESUMO

Previously, we reported that prolonged arsenic exposure impaired neuronal insulin signaling. Here we have further identified novel molecular mechanisms underlying neuronal insulin signaling impairment by arsenic. Arsenic treatment altered insulin dose-response curve and reduced maximum insulin response in differentiated human neuroblastoma SH-SY5Y cells, suggesting that arsenic hindered neuronal insulin signaling in a non-competitive like manner. Mechanistically, arsenic suppressed insulin receptor (IR) kinase activity, as witnessed by a decreased insulin-activated autophosphorylation of IR at Y1150/1151. Arsenic decreased the level of insulin receptor substrate 1 (IRS1) but increased the protein ratio between PI3K regulatory subunit, p85, and PI3K catalytic subunit, p110. Interestingly, co-immunoprecipitation demonstrated that arsenic did not alter a level of PI3K-p110/PI3K-p85 complex while increased PI3K-p85 levels in a PI3K-p110 depletion supernatant resulted from PI3K-p110 immunoprecipitation. These results indicated that arsenic increased PI3K-p85 which was free from PI3K-p110 binding. In addition, arsenic significantly increased interaction between IRS1 and PI3K-p85 but not PI3K-p110, suggesting that there may be a fraction of free PI3K-p85 interacting with IRS1. In vitro PI3K activity demonstrated that arsenic lowered PI3K activity in both basal and insulin-stimulated conditions. These results suggested that the increase in free PI3K-p85 by arsenic might compete with PI3K heterodimer for the same IRS1 binding site, in turn blocking the activation of its catalytic subunit, PI3K-p110. Taken together, our results provide additional insights into mechanisms underlying the impairment of neuronal insulin signaling by arsenic through the reduction of IR autophosphorylation, the increase in free PI3K-p85, and the impeding of PI3K activity.


Assuntos
Arsenitos/toxicidade , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Insulina/farmacologia , Neurônios/efeitos dos fármacos , Compostos de Sódio/toxicidade , Antígenos CD/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Neurônios/enzimologia , Neurônios/patologia , Fosforilação , Ligação Proteica , Receptor de Insulina/agonistas , Receptor de Insulina/metabolismo , Transdução de Sinais
13.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071721

RESUMO

Changes in lifestyle in developed countries have triggered the prevalence of obesity and type 2 diabetes mellitus (T2DM) in the latest years. Consequently, these metabolic diseases associated to insulin resistance, and the morbidity associated with them, accounts for enormous costs for the health systems. The best way to face this problem is to identify potential therapeutic targets and/or early biomarkers to help in the treatment and in the early detection. In the insulin receptor signaling cascade, the activities of protein tyrosine kinases and phosphatases are coordinated, thus, protein tyrosine kinases amplify the insulin signaling response, whereas phosphatases are required for the regulation of the rate and duration of that response. The focus of this review is to summarize the impact of transmembrane receptor protein tyrosine phosphatase (RPTPs) in the insulin signaling cascade and secretion, and their implication in metabolic diseases such as obesity and T2DM.


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Insulina/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Animais , Humanos , Resistência à Insulina , Obesidade , Prevalência , Proteínas Tirosina Fosfatases/metabolismo , Receptor de Insulina/metabolismo , Transdução de Sinais/fisiologia
14.
Am J Physiol Endocrinol Metab ; 321(1): E130-E145, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34056923

RESUMO

Insulin receptors are highly expressed in the heart and vasculature. Insulin signaling regulates cardiac growth, survival, substrate uptake, utilization, and mitochondrial metabolism. Insulin signaling modulates the cardiac responses to physiological and pathological stressors. Altered insulin signaling in the heart may contribute to the pathophysiology of ventricular remodeling and heart failure progression. Myocardial insulin signaling adapts rapidly to changes in the systemic metabolic milieu. What may initially represent an adaptation to protect the heart from carbotoxicity may contribute to amplifying the risk of heart failure in obesity and diabetes. This review article presents the multiple roles of insulin signaling in cardiac physiology and pathology and discusses the potential therapeutic consequences of modulating myocardial insulin signaling.


Assuntos
Insulina/metabolismo , Miocárdio/metabolismo , Transdução de Sinais/fisiologia , Animais , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Diabetes Mellitus , Coração/fisiologia , Insuficiência Cardíaca , Humanos , Resistência à Insulina/fisiologia , Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Obesidade , Receptor de Insulina/metabolismo , Remodelação Ventricular
15.
Biomed Pharmacother ; 140: 111735, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34020251

RESUMO

Bark is the traditional medicinal component of Eucommia ulmoides Oliver (E. ulmoides). However, the demand for E. ulmoides medicinal materials seriously limits their sustainability. To alleviate resource constraints, the bioactivity of E. ulmoides leaves and its pharmacodynamic basis were investigated. In the present study, extracts of E. ulmoides leaves were found to display potential renal protective properties in rat glomerular mesangial (HBZY-1) cells treated with high levels of glucose, suggesting that they possess potential factors capable of treating diabetic nephropathy. Ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was used to comprehensively characterize the chemical components of E. ulmoides leaves. A total of 83 possible chemical components, including 12 iridoids, 13 flavonoids, 14 lignans, 20 phenylpropanoids, 14 phenolic acids, and 10 additional components, were identified in E. ulmoides leaves. Network pharmacology was used for a preliminary exploration of the potential mechanism of action of renal protection afforded by E. ulmoides leaves towards diabetic nephropathy. The network pharmacology results were verified using a series of biological experiments. The present study provided the basis for the comprehensive development and utilization of E. ulmoides leaves and the discovery of potential drugs.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Eucommiaceae , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Aldeído Redutase/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Glucose/toxicidade , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Folhas de Planta/química , Substâncias Protetoras/química , Ratos , Receptor de Insulina/metabolismo , Espectrometria de Massas em Tandem
16.
J Biol Chem ; 297(1): 100818, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34029592

RESUMO

The cleavage of the insulin receptor by ß-secretase 1 (BACE1) in the liver increases during diabetes, which contributes to reduce insulin receptor levels and impair insulin signaling. However, the precise signaling events that lead to this increased cleavage are unclear. We showed that BACE1 cleaves the insulin receptor in the early secretory pathway. Indeed, coimmunoprecipitation experiments reveal the interaction of the proforms of the two proteins. Moreover, fragments of insulin receptor are detected in the early secretory pathway and a mutated form of BACE1 that retains its prodomain cleaves an early secretory pathway-resident form of the insulin receptor. We showed that BACE1 proform levels are regulated by proteasome and/or lysosome-dependent degradation systems whose efficiencies are dependent on the O-GlcNacylation process. Our results showed that enhanced O-GlcNacylation reduces the efficiency of intracellular protein degradation systems, leading to the accumulation of the proform of BACE1 in the early secretory pathway where it cleaves the precursor of the insulin receptor. All these dysregulations are found in the livers of diabetic mice. In addition, we performed a screen of molecules according to their ability to increase levels of the insulin receptor at the surface of BACE1-overexpressing cells. This approach identified the aminosterol Claramine, which accelerated intracellular trafficking of the proform of BACE1 and increased autophagy. Both of these effects likely contribute to the reduced amount of the proform of BACE1 in the early secretory pathway, thereby reducing insulin receptor cleavage. These newly described properties of Claramine are consistent with its insulin sensitizing effect.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Colestanos/farmacologia , Receptor de Insulina/metabolismo , Espermina/análogos & derivados , Animais , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glicosilação/efeitos dos fármacos , Células HEK293 , Células Hep G2 , Humanos , Fígado/patologia , Modelos Biológicos , Ligação Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Proteostase/efeitos dos fármacos , Via Secretória/efeitos dos fármacos , Espermina/farmacologia , Ubiquitina/metabolismo , Ubiquitinação/efeitos dos fármacos
17.
Biomolecules ; 11(4)2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918477

RESUMO

Insulin (InsR) and insulin-like growth factor-1 (IGF1R) receptors mediate the metabolic and growth-promoting actions of insulin and IGF1/IGF2, respectively. Evidence accumulated in recent years indicates that, in addition to their typical cell-surface localization pattern and ligand-activated mechanism of action, InsR and IGF1R are present in the cell nucleus of both normal and transformed cells. Nuclear translocation seems to involve interaction with a small, ubiquitin-like modifier protein (SUMO-1), although this modification is not always a prerequisite. Nuclear InsR and IGF1R exhibit a number of biological activities that classically fit within the definition of transcription factors. These nuclear activities include, among others, sequence-specific DNA binding and transcriptional control. Of particular interest, nuclear IGF1R was capable of binding and stimulating its cognate gene promoter. The physiological relevance of this autoregulatory mechanism needs to be further investigated. In addition to its nuclear localization, studies have identified IGF1R in the Golgi apparatus, and this particular distribution correlated with a migratory phenotype. In summary, the newly described roles of InsR and IGF1R as gene regulators, in concert with their atypical pattern of subcellular distribution, add a further layer of complexity to traditional models of cell signaling. Furthermore, and in view of the emerging role of IGF1R as a potential therapeutic target, a better understanding of the mechanisms responsible for nuclear IGF1R transport and identification of IGF1R interactors might help optimize target directed therapies in oncology.


Assuntos
Neoplasias/patologia , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Núcleo Celular/metabolismo , Complexo de Golgi/metabolismo , Humanos , Neoplasias/metabolismo , Transdução de Sinais , Sumoilação , Ativação Transcricional
18.
Biomolecules ; 11(4)2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918805

RESUMO

The newly established CD3FLAG-mIR transgenic mouse model on a C57Bl/6 background has a FLAG tag on the mouse Insulin Receptor (mIR), specifically on T cells, as the FLAG-tagged mIR gene was engineered behind CD3 promoter and enhancer. The IR is a chemotactic molecule for insulin and the Flag-tagged mIR T cells in the BL/6-CD3FLAGmIR transgenic mice can migrate into the pancreas, as shown by immunofluorescent staining. While the transgenic mice do not become diabetic, there are phenotypic and metabolic changes in the islets. The transgenic islets become enlarged and disorganized by 15 weeks and those phenotypes continue out to 35 weeks of age. We examined the islets by RT-PCR for cell markers, ER stress markers, beta cell proliferation markers, and cytokines, as well as measuring serum insulin and insulin content in the pancreas at 15, 25, and 35 weeks of age. In transgenic mice, insulin in serum was increased at 15 weeks of age and glucose intolerance developed by 25 weeks of age. Passage of transgenic spleen cells into C57Bl/6 RAG-/- mice resulted in enlarged and disorganized islets with T infiltration by 4 to 5 weeks post-transfer, replicating the transgenic mouse studies. Therefore, migration of non-antigen-specific T cells into islets has ramifications for islet organization and function.


Assuntos
Secreção de Insulina , Células Secretoras de Insulina/patologia , Pancreatite/genética , Receptor de Insulina/genética , Linfócitos T/metabolismo , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Estresse do Retículo Endoplasmático , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pancreatite/metabolismo , Pancreatite/patologia , Receptor de Insulina/metabolismo , Linfócitos T/fisiologia , Transgenes
19.
J Biol Chem ; 296: 100712, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33915127

RESUMO

The retinal insulin receptor (IR) exhibits basal kinase activity equivalent to that of the liver of fed animals, but unlike the liver, does not fluctuate with feeding and fasting; it also declines rapidly after the onset of insulin-deficient diabetes. The ligand(s) that determine basal IR activity in the retina has not been identified. Using a highly sensitive insulin assay, we found that retinal insulin concentrations remain constant in fed versus fasted rats and in diabetic versus control rats; vitreous fluid insulin levels were undetectable. Neutralizing antibodies against insulin-like growth factor 2 (IGF-2), but not insulin-like growth factor 1 (IGF-1) or insulin, decreased IR kinase activity in normal rat retinas, and depletion of IGF-2 from serum specifically reduced IR phosphorylation in retinal cells. Immunoprecipitation studies demonstrated that IGF-2 induced greater phosphorylation of the retinal IR than the IGF-1 receptor. Retinal IGF-2 mRNA content was 10-fold higher in adults than pups and orders of magnitude higher than in liver. Diabetes reduced retinal IGF-2, but not IGF-1 or IR, mRNA levels, and reduced IGF-2 and IGF-1 content in vitreous fluid. Finally, intravitreal administration of IGF-2 (mature and pro-forms) increased retinal IR and Akt kinase activity in diabetic rats. Collectively, these data reveal that IGF-2 is the primary ligand that defines basal retinal IR activity and suggest that reduced ocular IGF-2 may contribute to reduced IR activity in response to diabetes. These findings may have importance for understanding the regulation of metabolic and prosurvival signaling in the retina.


Assuntos
Fator de Crescimento Insulin-Like II/metabolismo , Receptor de Insulina/metabolismo , Retina/metabolismo , Animais , Insulina/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais
20.
Int J Mol Sci ; 22(8)2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33919569

RESUMO

Type 2 diabetes (T2D) is a worldwide health problem, ranked as one of the leading causes for severe morbidity and premature mortality in modern society. Management of blood glucose is of major importance in order to limit the severe outcomes of the disease. However, despite the impressive success in the development of new antidiabetic drugs, almost no progress has been achieved with regard to the development of novel insulin-sensitizing agents. As insulin resistance is the most eminent factor in the patho-etiology of T2D, it is not surprising that an alarming number of patients still fail to meet glycemic goals. Owing to its wealth of chemical structures, the plant kingdom is considered as an inventory of compounds exerting various bioactivities, which might be used as a basis for the development of novel medications for various pathologies. Antidiabetic activity is found in over 400 plant species, and is attributable to varying mechanisms of action. Nevertheless, relatively limited evidence exists regarding phytochemicals directly activating insulin signaling, which is the focus of this review. Here, we will list plants and phytochemicals that have been found to improve insulin sensitivity by activation of the insulin signaling cascade, and will describe the active constituents and their mechanism of action.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Receptor de Insulina/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Humanos , Compostos Fitoquímicos/metabolismo , Receptor de Insulina/genética , Transdução de Sinais
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