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1.
Gen Comp Endocrinol ; 330: 114146, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36270337

RESUMO

Since practically a century ago, the insulin pathway was discovered in both vertebrates and invertebrates, implying an evolutionarily ancient origin. After a century of research, it is now clear that the insulin signal transduction pathway is a critical, flexible and pleiotropic pathway, evolving into multiple anabolic functions besides glucose homeostasis. It regulates paramount aspects of organismal well-being like growth, longevity, intermediate metabolism, and reproduction. Part of this diversification has been attained by duplications and divergence of both ligands and receptors riding on a common general signal transduction system. One of the aspects that is strikingly different is its usage in reproduction, particularly in male versus female development and fertility within the same species. This review highlights sexual divergence in metabolism and reproductive tract differences, the occurrence of sexually "exaggerated" traits, and sex size differences that are due to the sexes' differential activity/response to the insulin signaling pathway.


Assuntos
Insulina , Caracteres Sexuais , Animais , Masculino , Feminino , Insulina/metabolismo , Transdução de Sinais/fisiologia , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Reprodução/fisiologia
2.
J Agric Food Chem ; 70(46): 14706-14717, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36367981

RESUMO

Ferulic acid (FA) is one of the most abundant bound phenolics in whole grains, partly contributing to its preventive effects on metabolic syndrome (MetS). The study aims to investigate if FA mediates MetS through the regulation of hepatic metabolisms and the insulin receptor related pathways in the palmitate-treated HepG2 cells (MetS model). We found that FA (50, 100, and 200 µM) dramatically ameliorated the lipid accumulation in the MetS model. FA significantly decreased the activities of the gluconeogenic enzymes, G6Pase and PEPCK, downregulated the lipogenic enzyme FAS-1, and upregulated the lipolytic enzyme CPT-1 by regulating a series of transcriptional factors including HNF4α, FOXO-1, SREBP-1c, and PPAR-γ. Notably, we found that FA's ability to alleviate MetS is achieved by activating the insulin receptor/PI3K/AKT pathway. Our results validated the effects of FA on mediating the metabolic disorders of lipid and glucose pathways and unveiled its potential intracellular mechanisms for the prevention of MetS.


Assuntos
Insulinas , Síndrome Metabólica , Humanos , Metabolismo dos Lipídeos , Glucose/metabolismo , Células Hep G2 , Palmitatos , Síndrome Metabólica/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Receptor de Insulina/metabolismo , Receptor IGF Tipo 1/metabolismo , Insulinas/metabolismo
3.
Cells ; 11(21)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36359767

RESUMO

Sodium-glucose cotransporter-2 inhibitors (SGLT2is), such as empagliflozin, lower blood glucose in type 2 diabetes mellitus and improve cardiorenal outcomes regardless of diabetes presence. Whether SGLT2is exert any effects on the brain's metabolism has not been studied. We conducted a single-arm clinical trial to investigate the effects of once daily administration of oral empagliflozin (25 mg) for 14 days on systemic and brain metabolism in 21 non-diabetics aged 55 years old or older. Empagliflozin lowered circulating insulin and elevated ß-hydroxybutyrate over 34-h periods, both following its first administration and after 14 days of daily administration, with minor alterations in glucose homeostasis. Levels of phosphorylated insulin-like growth factor-1 receptor (pIGF-1R), phosphorylated insulin receptor (pIR), phosphorylated-in-tyrosine insulin receptor substrate-1 (pY-IRS-1), and phosphorylated protein kinase B or AKT (pAKT) were increased in extracellular vesicles enriched for neuronal origin (NEVs) following the first empagliflozin administration, but not after 14 days. Our finding of IGF-1R upregulation in NEVs is promising because several post-mortem and epidemiological studies support the idea that upregulation of IGF signaling may protect against Alzheimer's disease (AD). Moreover, our finding showing activation of insulin signaling and, in particular, the canonical pathway (pIR, pY-IRS-1, pAKT) in NEVs is important because such changes have been repeatedly associated with neuronal survival. Using brain magnetic resonance spectroscopy (MRS), we detected decreased concentrations of the excitatory neurotransmitter glutamate and its precursor glutamine after empagliflozin administration. This finding is also encouraging since glutamatergic excitotoxicity has long been implicated in AD pathology. Overall, our findings may motivate the repurposing of SGLT2is for use in AD and other, related diseases that are characterized by downregulation of IGF-1/insulin signaling in neurons and excitotoxicity.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Cetose , Inibidores do Transportador 2 de Sódio-Glicose , Feminino , Humanos , Pessoa de Meia-Idade , Doença de Alzheimer/metabolismo , Glicemia/metabolismo , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ácido Glutâmico/metabolismo , Insulina/metabolismo , Insulina Regular Humana/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Cetose/metabolismo , Neurônios/metabolismo , Neurotransmissores/metabolismo , Fator de Crescimento Placentário/metabolismo , Fator de Crescimento Placentário/farmacologia , Receptor de Insulina/metabolismo , Transdução de Sinais , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
4.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361695

RESUMO

Insulin-like peptide receptor (ILPR) can effectively regulate ovarian development in invertebrates, but its effect in cuttlefish has not been reported. We isolated and characterized a ILPR gene from Sepiella japonica, referred to as SjILPR. This gene displayed significant homologies to Octopus bimaculoides ILPR, and contained all typical features of insulin receptors and tyrosine kinase domain structure. SjILPR is expressed in all detected tissues, with the highest expression in the ovary. During ovarian development stages, its expression levels in the ovary, pancreas, and liver were correlated to the female reproductive cycle. After the silencing of SjILPR in vivo, comparative transcriptome analysis identified 4314 differentially expressed genes (DEGs) in the injected group, including 2586 down-regulated genes and 1728 up-regulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that 832 DEGs were assigned to 222 pathways, many pathways of which were related to gonadal development. Four down-regulated genes relevant to ovarian development (Vitellogenin 1, Vitellogenin 2, Cathepsin L1-like, and Follistatin) were selected to confirm the accuracy of RNA-seq data by qRT-PCR. These results showed that SjILPR might regulate ovarian development to control reproduction by affecting the expression of the relevant genes in female S. japonica.


Assuntos
Decapodiformes , Receptor de Insulina , Animais , Feminino , Decapodiformes/genética , Decapodiformes/metabolismo , Receptor de Insulina/metabolismo , Insulina/metabolismo , Vitelogeninas/genética , Reprodução/genética , Transcriptoma , Receptores de Peptídeos/metabolismo , Perfilação da Expressão Gênica
5.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361717

RESUMO

Recent studies implicate a key role of dopamine signaling in lifespan regulation. Our previous study found that quetiapine, an atypical antipsychotic drug that has antagonistic activity on dopamine D2-like receptors (D2Rs), shortened the lifespan of Caenorhabditis elegans (C. elegans). However, the detailed mechanism of this effect was not clear. In the present study, we evaluate the effect of quetiapine on aging and explore its underlying molecular mechanism. The results show that quetiapine shortened healthspan in C. elegans. The lifespan-shortening effect is dependent on DOP-2, a D2R expressed in worms. Quetiapine shortens lifespan through the C. elegans insulin and IGF-1 receptor DAF-2, but not the downstream Akt pathway. Quetiapine-induced lifespan reduction is dependent on RSKS-1, a key protein kinase that functions in mTOR signaling. In addition, the quetiapine effect is also related to mitochondrial function. These findings further support the key role of dopamine signaling in lifespan regulation and promote our insight into the mechanism of action of antipsychotic drugs.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Longevidade , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Fumarato de Quetiapina/farmacologia , Fumarato de Quetiapina/metabolismo , Dopamina/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Insulina/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
6.
Biochem Biophys Res Commun ; 636(Pt 2): 31-39, 2022 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-36343488

RESUMO

Both GLP-1 receptor (GLP-1R) and insulin receptor (IR) transmit signals for insulin release and/or cellular metabolism although using distinct sets of transducing molecules and separate pathways. We proposed a possible association of IR and GLP-1R, since they are coexpressed in diverse tissues including the pancreatic ß-cells and crosstalk between their signaling was frequently reported. We showed a specific interaction between GLP-1R and IR which was independent of intracellular receptor domains and not responsive to ligand binding. In signaling, the IRS-1 was coupled more to GLP-1R and less to IR in the receptor complex at IR activation, with subsequent IRS-1 degradation suppressed rather than its activation inhibited. The Gsα recruitment to the activated GLP-1R was inhibited in the GLP-1R/IR complex, with the signaling in cAMP pathway suppressed at IR activation. Therefore, the identified GLP-1R/IR complex recruits their signaling molecules which are differentially modified, leading to a crosstalk between their signaling.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1 , Células Secretoras de Insulina , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptores de Glucagon , Receptor de Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo
7.
Probl Endokrinol (Mosk) ; 68(5): 79-86, 2022 Jun 22.
Artigo em Russo | MEDLINE | ID: mdl-36337021

RESUMO

Donohue syndrome (DS), also called Leprechaunism, is the most severe form of insulin resistance associated with biallelic mutations in INSR gene (OMIM: 147670). The approximate incidence of this syndrome is 1 per 1000000 births. Patients are present with typical clinical features such as intrauterine growth retardation, facial dysmorphism, severe metabolic disturbances, hepatomegaly and hypertrophic cardiomyopathy. Most DS patients die within the first two years of life due to respiratory infections, severe hypoglycemia or progressive cardiomyopathy. Treatment options are limited and no specific therapy exist for DS. Given the similarities between insulin and insulin-like growth factor 1 (IGF-1) receptors, recombinant human IGF-1 (rhIGF-1) has been used to treat severe insulin resistance including DS.We report the case of a male patient with genetically confirmed Donohue syndrome, successfully treated with continuous subcutaneous IGF1 infusion via insulin pump. We observed improvement of glycemic control, liver function and cardiac hypertrophy regression following 15-month IGF1 therapy.


Assuntos
Síndrome de Donohue , Resistência à Insulina , Humanos , Masculino , Síndrome de Donohue/complicações , Síndrome de Donohue/tratamento farmacológico , Síndrome de Donohue/genética , Fator de Crescimento Insulin-Like I/uso terapêutico , Resistência à Insulina/genética , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Receptor de Insulina/uso terapêutico , Insulina/uso terapêutico
8.
Biomolecules ; 12(11)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36358907

RESUMO

The insulin family consists of insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor 2 (IGF-2), their receptors (IR, IGF-1R and IGF-2R), and their binding proteins. All three ligands are involved in cell proliferation, apoptosis, protein synthesis and metabolism due to their homologous sequences and structural similarities. Insulin-like growth factor 2, a member of the insulin family, plays an important role in embryonic development, metabolic disorders, and tumorigenesis by combining with three receptors with different degrees of affinity. The main pathological feature of various fibrotic diseases is the excessive deposition of extracellular matrix (ECM) after tissue and organ damage, which eventually results in organic dysfunction because scar formation replaces tissue parenchyma. As a mitogenic factor, IGF-2 is overexpressed in many fibrotic diseases. It can promote the proliferation of fibroblasts significantly, as well as the production of ECM in a time- and dose-dependent manner. This review aims to describe the expression changes and fibrosis-promoting effects of IGF-2 in the skin, oral cavity, heart, lung, liver, and kidney fibrotic tissues.


Assuntos
Fator de Crescimento Insulin-Like II , Receptor de Insulina , Humanos , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Receptor de Insulina/metabolismo , Fibrose , Matriz Extracelular/metabolismo , Insulina/metabolismo
9.
J Alzheimers Dis ; 90(2): 841-857, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36189587

RESUMO

BACKGROUND: The cascade of events that lead to Alzheimer's disease (AD) consists of several possible underlying signal transduction pathways. Apoptosis signal-regulating kinase 1 (ASK1) and insulin receptor (IR) signaling are implicated in AD. OBJECTIVE: We aimed to determine whether ASK1 activation and IR signaling impairment occurred prior to and during overt AD. METHODS: Immunostaining, immunoblotting, and quantitative PCR were used to assess the levels of ASK1 and IR signaling intermediates. Glucose uptake was determined in AD-patient derived inducible pluripotent stem cells (iPSCs). RESULTS: ASK1 signaling was activated in postmortem brain tissues acquired from APOE4 carriers, a causative heritable factor, and in brain tissues of AD subjects in comparison with those harboring the normal APOE3 variant, which was manifested with an increased phosphorylated ASK1 (p-ASK1) and reduced thioredoxin 1 (TRX1). ASK1 downstream signaling effectors were also significantly elevated in these APOE4 carriers and AD brain tissues. Increased insulin receptor substrate 1 (IRS1) phosphorylation at serine residues, and decreased p-AKT1, p-IRß, and GLUT3 expression were present in all APOE4 carriers and AD samples, suggesting impaired IR signaling leading to insulin resistance. ASK1 activation, IR signaling impairment, and GLUT3 reduction were also present in young AD transgenic mice prior to AD syndromes, AD mice at AD neuropathology onset, and AD iPSCs and their derived neurons prior to p-Tau aggregation. CONCLUSION: We conclude that the activation of oxidative stress-responsive kinases and reduced IR signaling precede and are persistent in AD pathogenesis. Our data further suggest possible crosstalk between ASK1 signaling and insulin resistance in AD etiology.


Assuntos
Doença de Alzheimer , Resistência à Insulina , Animais , Camundongos , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Insulina/metabolismo , Camundongos Transgênicos , Estresse Oxidativo , Receptor de Insulina/metabolismo , Transdução de Sinais/fisiologia , Humanos
10.
Biophys J ; 121(21): 4063-4077, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36181268

RESUMO

Insulin is a mainstay of therapy for diabetes mellitus, yet its thermal stability complicates global transportation and storage. Cold-chain transport, coupled with optimized formulation and materials, prevents to some degree nucleation of amyloid and hence inactivation of hormonal activity. These issues hence motivate the design of analogs with increased stability, with a promising approach being single-chain insulins (SCIs), whose C domains (foreshortened relative to proinsulin) resemble those of the single-chain growth factors (IGFs). We have previously demonstrated that optimized SCIs can exhibit native-like hormonal activity with enhanced thermal stability and marked resistance to fibrillation. Here, we describe the crystal structure of an ultrastable SCI (C-domain length 6; sequence EEGPRR) bound to modules of the insulin receptor (IR) ectodomain (N-terminal α-subunit domains L1-CR and C-terminal αCT peptide; "microreceptor" [µIR]). The structure of the SCI-µIR complex, stabilized by an Fv module, was determined using diffraction data to a resolution of 2.6 Å. Remarkably, the αCT peptide (IR-A isoform) "threads" through a gap between the flexible C domain and the insulin core. To explore such threading, we undertook molecular dynamics simulations to 1) compare threaded with unthreaded binding modes and 2) evaluate effects of C-domain length on these alternate modes. The simulations (employing both conventional and enhanced sampling simulations) provide evidence that very short linkers (C-domain length of -1) would limit gap opening in the SCI and so impair threading. We envisage that analogous threading occurs in the intact SCI-IR complex-rationalizing why minimal C-domain lengths block complete activity-and might be exploited to design novel receptor-isoform-specific analogs.


Assuntos
Insulina , Receptor de Insulina , Receptor de Insulina/metabolismo , Insulina/metabolismo , Modelos Moleculares , Ligação Proteica , Peptídeos/química
11.
Nat Commun ; 13(1): 6092, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36241662

RESUMO

Insulin signaling is mediated via a network of protein phosphorylation. Dysregulation of this network is central to obesity, type 2 diabetes and metabolic syndrome. Here we investigate the role of phosphatase binding protein Alpha4 (α4) that is essential for the serine/threonine protein phosphatase 2A (PP2A) in insulin action/resistance in adipocytes. Unexpectedly, adipocyte-specific inactivation of α4 impairs insulin-induced Akt-mediated serine/threonine phosphorylation despite a decrease in the protein phosphatase 2A (PP2A) levels. Interestingly, loss of α4 also reduces insulin-induced insulin receptor tyrosine phosphorylation. This occurs through decreased association of α4 with Y-box protein 1, resulting in the enhancement of the tyrosine phosphatase protein tyrosine phosphatase 1B (PTP1B) expression. Moreover, adipocyte-specific knockout of α4 in male mice results in impaired adipogenesis and altered mitochondrial oxidation leading to increased inflammation, systemic insulin resistance, hepatosteatosis, islet hyperplasia, and impaired thermogenesis. Thus, the α4 /Y-box protein 1(YBX1)-mediated pathway of insulin receptor signaling is involved in maintaining insulin sensitivity, normal adipose tissue homeostasis and systemic metabolism.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Adipócitos/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Homeostase , Insulina/metabolismo , Masculino , Camundongos , Fosforilação , Proteína Fosfatase 2/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Serina/metabolismo , Treonina/metabolismo , Tirosina/metabolismo
12.
Nat Commun ; 13(1): 6500, 2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36310231

RESUMO

Activation of insulin receptor (IR) initiates a cascade of conformational changes and autophosphorylation events. Herein, we determined three structures of IR trapped by aptamers using cryo-electron microscopy. The A62 agonist aptamer selectively activates metabolic signaling. In the absence of insulin, the two A62 aptamer agonists of IR adopt an insulin-accessible arrowhead conformation by mimicking site-1/site-2' insulin coordination. Insulin binding at one site triggers conformational changes in one protomer, but this movement is blocked in the other protomer by A62 at the opposite site. A62 binding captures two unique conformations of IR with a similar stalk arrangement, which underlie Tyr1150 mono-phosphorylation (m-pY1150) and selective activation for metabolic signaling. The A43 aptamer, a positive allosteric modulator, binds at the opposite side of the insulin-binding module, and stabilizes the single insulin-bound IR structure that brings two FnIII-3 regions into closer proximity for full activation. Our results suggest that spatial proximity of the two FnIII-3 ends is important for m-pY1150, but multi-phosphorylation of IR requires additional conformational rearrangement of intracellular domains mediated by coordination between extracellular and transmembrane domains.


Assuntos
Insulina , Receptor de Insulina , Receptor de Insulina/metabolismo , Microscopia Crioeletrônica , Subunidades Proteicas , Insulina/metabolismo , Domínios Proteicos
13.
Acta Histochem ; 124(7): 151960, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36202047

RESUMO

Hepatic encephalopathy (HE), which is caused by neurotoxin agents in the liver, is a complicated condition with a variety of neurological manifestations. Recently, endocrine alterations have been more paid attention to for neurological severity in the course of HE, e.g. adrenal gland. To identify the role of adrenal gland in the context of HE, we evaluated the functional changes of adrenal gland (i.e., plasma corticosterone concentrations and histopathological changes) in mice model of HE. To dig deep into the molecular and genetic underpinnings, a comprehensive enrichment analysis for shared genes between HE and adrenal insufficiency (AI) was also performed. Our results showed a significant reduction in the level of plasma corticosterone and severe cellular necrosis in zona fasciculate of adrenal cortex, possibly indicating adrenal insufficiency. Enrichment analysis indicated four common genes, besides predicted five novel genes and some significant MicroRNAs (miRNAs) and transcription factors for both HE and AI. Couples with, several biological processes, such as DNA damage, inflammatory responses, glycolytic processes, and insulin receptor signaling pathway were predicted in both HE and AI. To sum up, data from experimental tests and bioinformatics analyses suggest that AI play an important role in the pathogenesis and progression of HE.


Assuntos
Insuficiência Adrenal , Encefalopatia Hepática , MicroRNAs , Glândulas Suprarrenais/metabolismo , Insuficiência Adrenal/etiologia , Insuficiência Adrenal/metabolismo , Animais , Biologia Computacional , Corticosterona , Modelos Animais de Doenças , Encefalopatia Hepática/genética , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Neurotoxinas/metabolismo , Receptor de Insulina/metabolismo , Fatores de Transcrição/metabolismo
14.
Nat Commun ; 13(1): 6339, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36284093

RESUMO

Twenty-nine years following the breakthrough discovery that a single-gene mutation of daf-2 doubles Caenorhabditis elegans lifespan, it remains unclear where this insulin/IGF-1 receptor gene is expressed and where it acts to regulate ageing. Using knock-in fluorescent reporters, we determined that daf-2 and its downstream transcription factor daf-16 are expressed ubiquitously. Using tissue-specific targeted protein degradation, we determined that intracellular DAF-2-to-DAF-16 signaling in the intestine plays a major role in lifespan regulation, while that in the hypodermis, neurons, and germline plays a minor role. Notably, intestine-specific loss of DAF-2 activates DAF-16 in and outside the intestine, causes almost no adverse effects on development and reproduction, and extends lifespan by 94% in a way that partly requires non-intestinal DAF-16. Consistent with intestine supplying nutrients to the entire body, evidence from this and other studies suggests that altered metabolism, particularly down-regulation of protein and RNA synthesis, mediates longevity by reduction of insulin/IGF-1 signaling.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Longevidade/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Insulina/metabolismo , Mutação , Intestinos , RNA/metabolismo
15.
Cell Rep ; 41(1): 111436, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36198264

RESUMO

Prevention or amelioration of declining ß cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by ß cells to robustly replicate in response to acute insulin resistance induced by S961, a pharmacological insulin receptor antagonist. Interestingly, pathways that include CENP-A and the transcription factor E2F1 that are independent of insulin signaling and its substrates appeared to mediate S961-induced ß cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks ß-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of ß cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables ß cells to duplicate, while E2F1 inhibition limits their growth even in the presence of adipocytes. These data suggest insulin resistance-induced proliferative signals from adipocytes activate E2F1, a potential therapeutic target, to promote ß cell compensation.


Assuntos
Resistência à Insulina , Células Secretoras de Insulina , Animais , Proliferação de Células , Proteína Centromérica A/metabolismo , Fator de Transcrição E2F1/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Knockout , Receptor de Insulina/metabolismo
16.
Nat Metab ; 4(9): 1202-1213, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36131205

RESUMO

Insulin signaling is essential for glucose metabolism, and insulin decreases insulin receptor (InsR) levels in a dose-dependent and time-dependent manner. However, the regulatory mechanisms of InsR reduction upon insulin stimulation remain poorly understood. Here, we show that Eph receptor B4 (EphB4), a tyrosine kinase receptor that modulates cell adhesion and migration, can bind directly to InsR, and this interaction is markedly enhanced by insulin. Due to the adaptor protein 2 (Ap2) complex binding motif in EphB4, the interaction of EphB4 and InsR facilitates clathrin-mediated InsR endocytosis and degradation in lysosomes. Hepatic overexpression of EphB4 decreases InsR and increases hepatic and systemic insulin resistance in chow-fed mice, whereas genetic or pharmacological inhibition of EphB4 improve insulin resistance and glucose intolerance in obese mice. These observations elucidate a role for EphB4 in insulin signaling, suggesting that EphB4 might represent a therapeutic target for the treatment of insulin resistance and type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Receptor EphB4 , Receptor de Insulina , Animais , Clatrina , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Resistência à Insulina/genética , Fígado/metabolismo , Camundongos , Receptor EphB4/metabolismo , Receptor de Insulina/metabolismo
17.
Front Endocrinol (Lausanne) ; 13: 986616, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093068

RESUMO

Background: Type 2 diabetes (T2D) is characterized by a decreased insulin sensitivity. Magnesium (Mg2+) deficiency is common in people with T2D. However, the molecular consequences of low Mg2+ levels on insulin sensitivity and glucose handling have not been determined in adipocytes. The aim of this study is to determine the role of Mg2+ in the insulin-dependent glucose uptake. Methods: First, the association of low plasma Mg2+ with markers of insulin resistance was assessed in a cohort of 395 people with T2D. Secondly, the molecular role of Mg2+ in insulin-dependent glucose uptake was studied by incubating 3T3-L1 adipocytes with 0 or 1 mmol/L Mg2+ for 24 hours followed by insulin stimulation. Radioactive-glucose labelling, enzymatic assays, immunocytochemistry and live microscopy imaging were used to analyze the insulin receptor phosphoinositide 3-kinases/Akt pathway. Energy metabolism was assessed by the Seahorse Extracellular Flux Analyzer. Results: In people with T2D, plasma Mg2+ concentration was inversely associated with markers of insulin resistance; i.e., the lower Mg2+, the more insulin resistant. In Mg2+-deficient adipocytes, insulin-dependent glucose uptake was decreased by approximately 50% compared to control Mg2+condition. Insulin receptor phosphorylation Tyr1150/1151 and PIP3 mass were not decreased in Mg2+-deficient adipocytes. Live imaging microscopy of adipocytes transduced with an Akt sensor (FoxO1-Clover) demonstrated that FoxO1 translocation from the nucleus to the cytosol was reduced, indicting less Akt activation in Mg2+-deficient adipocytes. Immunocytochemistry using a Lectin membrane marker and at the membrane located Myc epitope-tagged glucose transporter 4 (GLUT4) demonstrated that GLUT4 translocation was diminished in insulin-stimulated Mg2+-deficient adipocytes compared to control conditions. Energy metabolism in Mg2+ deficient adipocytes was characterized by decreased glycolysis, upon insulin stimulation. Conclusions: Mg2+ increases insulin-dependent glucose uptake in adipocytes and suggests that Mg2+ deficiency may contribute to insulin resistance in people with T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Adipócitos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Insulina/farmacologia , Magnésio , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/metabolismo
19.
Hum Exp Toxicol ; 41: 9603271221126487, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36169646

RESUMO

The present study was designed to investigate the antidiabetic effect of nerolidol on high-fat diet and streptozotocin-induced diabetic rats. Type 2 diabetes was induced in animals by feeding them a high-fat diet for 4 weeks and administering a single intraperitoneal dose of streptozotocin (35 mg/kg body weight). Diabetic rats were treated with nerolidol (25 mg/kg BW) for 28 days. Results showed that nerolidol treatment significantly reduced (p < 0.05) the level of elevated glucose, glycosylated hemoglobin and improved (p < 0.05) the body weight and insulin level. Nerolidol also considerably improved (p < 0.05) the carbohydrate metabolic enzyme activities and increased the glycogen storage in the liver of diabetic rats. Increased serum triglycerides, total cholesterol (C), low-density lipoproteins-C and very low-density lipoproteins-C levels were significantly lowered (p < 0.05), while reduction of serum high-density lipoprotein-C was alleviated after administration of nerolidol. In addition, nerolidol attenuated oxidative stress markers by significantly increasing (p < 0.05) the levels of superoxide dismutase, catalase, reduced glutathione, and lowering (p < 0.05) the level of thiobarbituric acid reactive substances, and lipid hydroperoxide. Similarly, nerolidol showed its pharmacological effects against hepatic markers via restoring (p < 0.05) the alleviated level of alanine transaminase, aspartate aminotransferase, and alkaline phosphatase. Finally, it improved insulin-dependent glucose transport in skeletal muscle by enhancing and activating glucose transporter protein-4. These findings confirmed the antidiabetic potential of nerolidol in type 2 diabetic rats. This may be related to a high antioxidant capacity, the restoration of plasma insulin and lipid levels, and the activation of insulin signaling in STZ/HFD-induced diabetic rats.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Alanina Transaminase/metabolismo , Fosfatase Alcalina , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases/metabolismo , Glicemia , Peso Corporal , Catalase/metabolismo , Colesterol , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica , Proteínas Facilitadoras de Transporte de Glucose/uso terapêutico , Glutationa/metabolismo , Hemoglobina A Glicada/metabolismo , Glicogênio/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina , Peróxidos Lipídicos/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/uso terapêutico , Lipoproteínas LDL/metabolismo , Ratos , Receptor de Insulina/metabolismo , Receptor de Insulina/uso terapêutico , Sesquiterpenos , Estreptozocina/uso terapêutico , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Triglicerídeos
20.
Nat Commun ; 13(1): 5594, 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36151101

RESUMO

Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity and mortality with limited therapeutic options. A previously reported selective IR agonist without sequence homology to insulin, S597, activates IR and mimics insulin's action on glycemic control. To elucidate the mechanism of IR activation by S597, we determine cryo-EM structures of the mouse IR/S597 complex. Unlike the compact T-shaped active IR resulting from the binding of four insulins to two distinct sites, two S597 molecules induce and stabilize an extended T-shaped IR through the simultaneous binding to both the L1 domain of one protomer and the FnIII-1 domain of another. Importantly, S597 fully activates IR mutants that disrupt insulin binding or destabilize the insulin-induced compact T-shape, thus eliciting insulin-like signaling. S597 also selectively activates IR signaling among different tissues and triggers IR endocytosis in the liver. Overall, our structural and functional studies guide future efforts to develop insulin mimetics targeting insulin resistance caused by defects in insulin binding and stabilization of insulin-activated state of IR, demonstrating the potential of structure-based drug design for insulin-resistant diseases.


Assuntos
Resistência à Insulina , Receptor de Insulina , Animais , Insulina/metabolismo , Camundongos , Peptídeos/farmacologia , Subunidades Proteicas , Receptor de Insulina/metabolismo
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