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1.
Gene ; 799: 145847, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34274473

RESUMO

BACKGROUND: Uncontrolled type 1 diabetes mellitus (T1D) impairs reproductive potential of males. Insulin treatment restores metabolic parameters but it is unclear how it protects male reproductive health. Herein, we hypothesized that insulin treatment to T1D rats protects testicular physiology by mediating mechanisms associated with apoptosis and cell cycle. METHODS: Mature male Wistar rats (n = 24) were divided into 3 groups: control, T1D-induced (received 40 mg kg-1 streptozotocin) and insulin-treated T1D (Ins T1D; received 40 mg kg-1 streptozotocin and then treated 0.9 IU/100 gr of insulin for 56 days) (N = 8/group). Expression levels of intrinsic apoptosis pathways regulators (Bcl-2, Bax, Caspase-3 and p53) and core regulators of cell cycle machinery (Cyclin D1, Cdk-4 and p21) were determined in testicular tissue by immunohistochemistry (IHC) and RT-PCR techniques. The percentage of testicular apoptotic cells was evaluated by TUNEL staining. RESULTS: Our data shows that insulin treatment to T1D rats restored (P < 0.05) T1D-induced increased of caspase-3 and p53 expression in testis. Moreover, the testis of T1D rats treated with insulin exhibited increased expression of Cyclin D1 and cdk-4, and a reduced expression of p21 when compared with the expression in testis of T1D rats. Finally, insulin treatment could fairly control T1D-induced apoptosis. Accordingly, treatment of T1D rats with insulin led to a remarkable reduction (p < 0.05) in the percentage of apoptotic cells in the testis. CONCLUSIONS: Insulin treatment is able to restore the network expression of apoptosis and proliferation-related genes caused by T1D in the testis and via this mechanism, preserve the fertility of males.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Insulina/fisiologia , Testículo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Fertilidade , Expressão Gênica/efeitos dos fármacos , Masculino , Substâncias Protetoras/farmacologia , Ratos Wistar , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Testículo/patologia , Testosterona/sangue
2.
Nucleic Acids Res ; 49(W1): W641-W653, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34125906

RESUMO

Uncovering how transcription factors regulate their targets at DNA, RNA and protein levels over time is critical to define gene regulatory networks (GRNs) and assign mechanisms in normal and diseased states. RNA-seq is a standard method measuring gene regulation using an established set of analysis stages. However, none of the currently available pipeline methods for interpreting ordered genomic data (in time or space) use time-series models to assign cause and effect relationships within GRNs, are adaptive to diverse experimental designs, or enable user interpretation through a web-based platform. Furthermore, methods integrating ordered RNA-seq data with protein-DNA binding data to distinguish direct from indirect interactions are urgently needed. We present TIMEOR (Trajectory Inference and Mechanism Exploration with Omics data in R), the first web-based and adaptive time-series multi-omics pipeline method which infers the relationship between gene regulatory events across time. TIMEOR addresses the critical need for methods to determine causal regulatory mechanism networks by leveraging time-series RNA-seq, motif analysis, protein-DNA binding data, and protein-protein interaction networks. TIMEOR's user-catered approach helps non-coders generate new hypotheses and validate known mechanisms. We used TIMEOR to identify a novel link between insulin stimulation and the circadian rhythm cycle. TIMEOR is available at https://github.com/ashleymaeconard/TIMEOR.git and http://timeor.brown.edu.


Assuntos
Regulação da Expressão Gênica , Redes Reguladoras de Genes , RNA-Seq , Software , Ritmo Circadiano/genética , Genômica , Humanos , Insulina/fisiologia , Internet , Mapeamento de Interação de Proteínas , Fatores de Transcrição/metabolismo
3.
Am J Physiol Endocrinol Metab ; 321(1): E156-E163, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34056920

RESUMO

The brain has been traditionally thought to be insensitive to insulin, primarily because insulin does not stimulate glucose uptake/metabolism in the brain (as it does in classic insulin-sensitive tissues such as muscle, liver, and fat). However, over the past 20 years, research in this field has identified unique actions of insulin in the brain. There is accumulating evidence that insulin crosses into the brain and regulates central nervous system functions such as feeding, depression, and cognitive behavior. In addition, insulin acts in the brain to regulate systemic functions such as hepatic glucose production, lipolysis, lipogenesis, reproductive competence, and the sympathoadrenal response to hypoglycemia. Decrements in brain insulin action (or brain insulin resistance) can be observed in obesity, type 2 diabetes (T2DM), aging, and Alzheimer's disease (AD), indicating a possible link between metabolic and cognitive health. Here, we describe recent findings on the pleiotropic actions of insulin in the brain and highlight the precise sites, specific neuronal population, and roles for supportive astrocytic cells through which insulin acts in the brain. In addition, we also discuss how boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Overall, this perspective article serves to highlight some of these key scientific findings, identify unresolved issues, and indicate future directions of research in this field that would serve to improve the lives of people with metabolic and cognitive dysfunctions.


Assuntos
Encéfalo/fisiologia , Insulina/fisiologia , Doença de Alzheimer , Ansiedade , Barreira Hematoencefálica/metabolismo , Peso Corporal , Encéfalo/efeitos dos fármacos , Colesterol/biossíntese , Cognição , Depressão , Ingestão de Alimentos , Glucose/biossíntese , Humanos , Insulina/metabolismo , Insulina/farmacologia , Metabolismo dos Lipídeos/fisiologia
5.
Diabetes Res Clin Pract ; 175: 108843, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33933498

RESUMO

AIM: To assess the efficacy and tolerability of adjunct therapy with a sodium-glucose cotransporter-2 inhibitor, dapagliflozin, compared with insulin escalation for patients with uncontrolled type 2 diabetes on current insulin therapy. METHODS: A 12-month retrospective case-control study of patients with glycated hemoglobin (HbA1c) > 7% on insulin therapy. The study group received add-on therapy with dapagliflozin (10 mg once daily); the control group received titrated increases of their existing insulin dose by a mean of 21.6% from baseline. The primary endpoint was the change in HbA1c after 12 months. Secondary outcomes included changes in fasting plasma glucose, postprandial 2-h glucose levels, insulin requirements, and body weight. RESULTS: After 12 months, the reduction in HbA1c was significantly greater in the dapagliflozin group than in the control group (from 8.9 ±â€¯1.2% to 8.0 ±â€¯1.0% vs 9.1 ±â€¯1.2% to 8.7 ±â€¯1.5%, respectively). Results for fasting plasma glucose and postprandial 2-h glucose were similar. Dapagliflozin therapy decreased systolic blood pressure (-4.7 mmHg) and body weight (-1.4 kg) significantly, whereas body weight increased by 0.6 kg in the control group. The dapagliflozin group showed significantly fewer hypoglycemic events than the control group (18.5% vs 32.6%, respectively). Daily insulin dose increased by 5.4 ±â€¯6.1 U (21.6%) in the control group but decreased by 1.9 ±â€¯5.3 U (-4.5%) in the dapagliflozin group (p < 0.001). CONCLUSION: As an adjunct to insulin therapy, dapagliflozin therapy significantly improved glycemic control, with the clinical advantages of weight loss, insulin sparing, and less hypoglycemia.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada/métodos , Glucosídeos/uso terapêutico , Insulina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/farmacologia , Estudos de Casos e Controles , Feminino , Glucosídeos/farmacologia , Humanos , Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
6.
Elife ; 102021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33879316

RESUMO

Reduced activity of the insulin/IGF signalling network increases health during ageing in multiple species. Diverse and tissue-specific mechanisms drive the health improvement. Here, we performed tissue-specific transcriptional and proteomic profiling of long-lived Drosophila dilp2-3,5 mutants, and identified tissue-specific regulation of >3600 transcripts and >3700 proteins. Most expression changes were regulated post-transcriptionally in the fat body, and only in mutants infected with the endosymbiotic bacteria, Wolbachia pipientis, which increases their lifespan. Bioinformatic analysis identified reduced co-translational ER targeting of secreted and membrane-associated proteins and increased DNA damage/repair response proteins. Accordingly, age-related DNA damage and genome instability were lower in fat body of the mutant, and overexpression of a minichromosome maintenance protein subunit extended lifespan. Proteins involved in carbohydrate metabolism showed altered expression in the mutant intestine, and gut-specific overexpression of a lysosomal mannosidase increased autophagy, gut homeostasis, and lifespan. These processes are candidates for combatting ageing-related decline in other organisms.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Insulina/fisiologia , Proteoma/metabolismo , Transdução de Sinais , Transcriptoma , Wolbachia/fisiologia , Animais , Drosophila melanogaster/metabolismo , Drosophila melanogaster/microbiologia , Corpo Adiposo/metabolismo , Perfilação da Expressão Gênica
7.
Biochemistry (Mosc) ; 86(3): 350-360, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33838634

RESUMO

Incretin hormones analogues, including glucagon-like peptide type 1 (GLP-1), exhibit complex glucose-lowering, anorexigenic, and cardioprotective properties. Mechanisms of action of GLP-1 and its analogues are well known for pancreatic ß-cells, hepatocytes, and other tissues. Nevertheless, local effects of GLP-1 and its analogues in adipose tissue remain unclear. In the present work effects of the GLP-1 synthetic analogue, liraglutide, on adipogenesis and insulin sensitivity of the 3T3-L1 adipocytes were examined. Enhancement of insulin sensitivity of mature adipocytes by the GLP-1 synthetic analogue liraglutide mediated by adenylate cyclase was demonstrated. The obtained results imply existence of the positive direct insulin-sensitizing effect of liraglutide on mature adipocytes.


Assuntos
Adenilil Ciclases/metabolismo , Adipócitos/efeitos dos fármacos , Resistência à Insulina , Insulina/metabolismo , Liraglutida/farmacologia , Células 3T3-L1 , Adipócitos/metabolismo , Adipócitos/fisiologia , Adipogenia/efeitos dos fármacos , Animais , Hipoglicemiantes/farmacologia , Insulina/fisiologia , Camundongos , Obesidade/metabolismo , Obesidade/fisiopatologia
8.
Acta Diabetol ; 58(8): 989-996, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33811293

RESUMO

The pathophysiology of takotsubo syndrome (TTS) is elusive. Heightened adrenergic surge via the sympathetic nervous system (mainly by norepinephrine secretion) and/or elevated blood-borne catecholamines (mainly epinephrine, secreted by the adrenals) probably mediate TTS. Patients with TTS have a low prevalence of diabetes mellitus (DM), and it has been postulated that DM, via its associated neuropathy, prevents the emergence of TTS. Insulin, in animal experiments, has been shown to greatly attenuate the effects of NE on the cardiomyocytes; also, insulin in a limited clinical experience, has been found to improve heart function in patients with neurogenic stress-cardiomyopathy and TTS. Accordingly, it is postulated that high levels of insulin encountered in patients with type 2 DM are at the roots of the protective effect of DM for the emergence of TTS. Thus, a role of insulin in the pathophysiology, diagnosis, prognosis, and therapy of TTS appears to be plausible, and needs exploration.


Assuntos
Insulina/fisiologia , Cardiomiopatia de Takotsubo , Animais , Catecolaminas/fisiologia , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Masculino , Prevalência , Prognóstico , Sistema Nervoso Simpático/fisiopatologia , Cardiomiopatia de Takotsubo/etiologia , Cardiomiopatia de Takotsubo/fisiopatologia , Cardiomiopatia de Takotsubo/terapia
9.
Biomed Pharmacother ; 139: 111560, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33839491

RESUMO

BACKGROUND: Fetuin-A, also known as α2-Heremans-Schmid glycoprotein (AHSG), is an abundant plasmatic serum protein synthesized predominantly in liver and adipose tissue. This glycoprotein is known to negatively regulate insulin signaling through the inhibition of insulin receptor (IR) autophosphorylation and tyrosine kinase activity, which participates in insulin resistance (IR) and metabolic syndrome development. Recent studies demonstrated that IR and associated metabolic disorders, are closely related to the gut microbiota and modulating it by probiotics could be effective in metabolic diseases management. OBJECTIVE: In this present work we aimed to evaluate the effects of a probiotics-rich emulsion on reducing the IR induced by free fatty acids accumulation in human hepatocarcinoma cell line, and to elucidate the implicated molecular pathways, with a specific emphasis on the hepatokin Fetuin-A-related axis. RESULTS: Here we showed, that probiotics improve HepG2 viability, protect against apoptosis under normal and IR conditions. Moreover, the emulsion was successful in attenuating oxidative stress as well as improving mitochondrial metabolism and dynamics. Interestingly, application of the probiotics to lipotoxic HepG2 cells resulted in significant reduction of Fetuin-A/TLR4/JNK/NF-κB pathway activation, which suggests a protective effect against inflammation, obesity as well as liver related insulin resistant. CONCLUSION: Overall, the presented data reports clearly on the potent potential of probiotics formulated in an emulsion vehicle to enhance metabolic functions of affected IR HepG2 cells, and suggest the possibility of using such preparations as insulin sensitizing therapy, playing at the same time protective role for the development of liver related insulin resistant.


Assuntos
Carcinoma Hepatocelular/metabolismo , Insulina/fisiologia , Ácido Oleico/farmacologia , Palmitatos/farmacologia , Probióticos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Emulsões , Ácidos Graxos não Esterificados/metabolismo , Microbioma Gastrointestinal , Células Hep G2 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , NF-kappa B/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Probióticos/administração & dosagem , Receptor 4 Toll-Like/efeitos dos fármacos , alfa-2-Glicoproteína-HS/efeitos dos fármacos
10.
Biomed Pharmacother ; 139: 111577, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33839493

RESUMO

INTRODUCTION: Diabetes mellitus is related to cognitive impairments and molecular abnormalities of the hippocampus. A growing body of evidence suggests that Urtica dioica (Ud) and exercise training (ET) have potential therapeutic effects on diabetes and its related complications. Therefore, we hypothesized that the combined effect of exercise training (ET) and Ud might play an important role in insulin signaling pathway, oxidative stress, neuroinflammation, and cognitive impairment in diabetic rats. METHODS: Forty animals were divided into five groups (N = 8): healthy-sedentary (H-sed), diabetes-sedentary (D-sed), diabetes-exercise training (D-ET), diabetes-Urtica dioica (D-Ud), diabetes-exercise training-Urtica dioica (D-ET-Ud). Streptozotocin (STZ) (Single dosage; 45 mg/kg, i.p.) was used to induce diabetes. Then, ET (moderate intensity/5day/week) and Ud extract (50 mg/kg, oral/daily) were administered for six weeks. We also investigated the effects of ET and Ud on cognitive performance (assessed through Morris Water Maze tests), antioxidant capacity, and lipid peroxidation markers in hippocampus. Furthermore, we measured levels of insulin sensitivity and signaling factors (insulin-Ins, insulin receptor-IR and insulin-like growth factor-1 receptor-IGF-1R), and neuroinflammatory markers (IL-1 ß, TNF-α). This was followed by TUNEL assessment of the apoptosis rate in all regions of the hippocampus. RESULTS: D-sed rats compared to H-sed animals showed significant impairments (P < 0.001) in hippocampal insulin sensitivity and signaling, oxidative stress, neuroinflammation, and apoptosis, which resulted in cognitive dysfunction. Ud extract and ET treatment effectively improved these impairments in D-ET (P < 0.001), D-Ud (P < 0.05), and D-ET-Ud (P < 0.001) groups compared to D-sed rats. Moreover, diabetes mediated hippocampal oxidative stress, neuroinflammation, insulin signaling deficits, apoptosis, and cognitive dysfunction was further reversed by chronic Ud+ET administration in D-ET-Ud rats (P < 0.001) compared to D-sed animals. CONCLUSIONS: Ud extract and ET ameliorate cognitive dysfunction via improvement in hippocampal oxidative stress, neuroinflammation, insulin signaling pathway, and apoptosis in STZ-induced diabetic rats. The results of this study provide new experimental evidence for using Ud+ET in the treatment of hippocampal complications and cognitive dysfunction caused by diabetes.


Assuntos
Cognição/efeitos dos fármacos , Diabetes Mellitus Experimental/psicologia , Diabetes Mellitus Experimental/terapia , Encefalite/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Insulina/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Condicionamento Físico Animal , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Urtica dioica/química , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Resistência à Insulina , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar , Comportamento Sedentário
11.
Endocrinology ; 162(7)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33782700

RESUMO

The incretin effect-the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance-was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the champion. When the action of both incretins is prevented, glucose tolerance is pathologically impaired. Thus, after 100 years of research, we now know that insulinotropic hormones from the gut are indispensable for normal glucose tolerance. The loss of the incretin effect in type 2 diabetes, therefore, contributes greatly to the impaired postprandial glucose control.


Assuntos
Glicemia/fisiologia , Polipeptídeo Inibidor Gástrico/fisiologia , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Homeostase/fisiologia , Incretinas/fisiologia , Insulina/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Polipeptídeo Inibidor Gástrico/antagonistas & inibidores , Peptídeo 1 Semelhante ao Glucagon/antagonistas & inibidores , Humanos , Secreção de Insulina/efeitos dos fármacos , Período Pós-Prandial , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores
12.
Elife ; 102021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33739284

RESUMO

G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/IGF signalling is reduced in fly models of C9orf72 repeat expansion using RNA sequencing of adult brain. We further demonstrate that activation of insulin/IGF signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/IGF signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/IGF signalling could be an effective therapeutic approach against C9orf72 ALS/FTD.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/toxicidade , Expansão das Repetições de DNA , Drosophila melanogaster/fisiologia , Demência Frontotemporal/genética , Insulina/fisiologia , Transdução de Sinais , Animais , Proteína C9orf72/genética , Feminino
13.
Life Sci Alliance ; 4(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33526430

RESUMO

Cell to cell communication facilitates tissue development and physiology. Under pathological conditions, brain tumors disrupt glia-neuron communication signals that in consequence, promote tumor expansion at the expense of surrounding healthy tissue. The glioblastoma is one of the most aggressive and frequent primary brain tumors. This type of glioma expands and infiltrates into the brain, causing neuronal degeneration and neurological decay, among other symptoms. Here, we describe in a Drosophila model how glioblastoma cells produce ImpL2, an antagonist of the insulin pathway, which targets neighboring neurons and causes mitochondrial disruption as well as synapse loss, both early symptoms of neurodegeneration. Furthermore, glioblastoma progression requires insulin pathway attenuation in neurons. Restoration of neuronal insulin activity is sufficient to rescue synapse loss and to delay the premature death caused by glioma. Therefore, signals from glioblastoma to neuron emerge as a potential field of study to prevent neurodegeneration and to develop anti-tumoral strategies.


Assuntos
Glioblastoma/metabolismo , Insulina/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Modelos Animais de Doenças , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiologia , Drosophila melanogaster , Glioblastoma/fisiopatologia , Glioma/metabolismo , Glioma/fisiopatologia , Insulina/fisiologia , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/fisiologia , Doenças Neurodegenerativas/fisiopatologia , Neuroglia/metabolismo , Neurônios/metabolismo , Transdução de Sinais
14.
Int J Mol Sci ; 22(3)2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494161

RESUMO

In 2021, the 100th anniversary of the isolation of insulin and the rescue of a child with type 1 diabetes from death will be marked. In this review, we highlight advances since the ingenious work of the four discoverers, Frederick Grant Banting, John James Rickard Macleod, James Bertram Collip and Charles Herbert Best. Macleoad closed his Nobel Lecture speech by raising the question of the mechanism of insulin action in the body. This challenge attracted many investigators, and the question remained unanswered until the third part of the 20th century. We summarize what has been learned, from the discovery of cell surface receptors, insulin action, and clearance, to network and precision medicine.


Assuntos
Insulina , Descoberta do Conhecimento , Animais , Diabetes Mellitus Tipo 1 , Endocitose , História do Século XX , Humanos , Insulina/fisiologia , Descoberta do Conhecimento/história , Mapas de Interação de Proteínas , Receptor de Insulina/metabolismo , Pesquisadores
16.
Biochem Biophys Res Commun ; 534: 248-253, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33280816

RESUMO

We here investigated molecular basis of notch receptor GLP-1 in controlling simulated microgravity stress in Caenorhabditis elegans. glp-1 expression was decreased by simulated microgravity. Meanwhile, glp-1 mutation caused resistance to toxicity of simulated microgravity. GLP-1 acted in germline cells to control toxicity of simulated microgravity. In germline cells, RNAi knockdown of glp-1 increased daf-16 expression. RNAi knockdown of daf-16 suppressed resistance to toxicity of simulated microgravity in glp-1 mutant. In simulated microgravity treated worms, germline RNAi knockdown of glp-1 decreased expressions of daf-28, ins-39, and ins-8 encoding insulin peptides, and resistance to simulated microgravity toxicity could be detected in daf-28(RNAi), ins-39(RNAi), and ins-8(RNAi) worms. In simulated microgravity treated worms, RNAi knockdown of daf-28, ins-39, or ins-8 in germline cells further increased expression and nucleus localization of transcriptional factor DAF-16 in intestinal cells. Therefore, the GLP-1-activated germline-intestine communication of insulin signaling is required for control of simulated microgravity toxicity in C. elegans.


Assuntos
Proteínas de Caenorhabditis elegans/fisiologia , Caenorhabditis elegans/metabolismo , Insulina/fisiologia , Receptores Notch/fisiologia , Simulação de Ausência de Peso , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/antagonistas & inibidores , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Células Germinativas/metabolismo , Intestinos , Especificidade de Órgãos , Interferência de RNA , Receptores Notch/antagonistas & inibidores , Receptores Notch/genética , Transdução de Sinais , Estresse Fisiológico
17.
Am J Physiol Endocrinol Metab ; 320(3): E425-E437, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33356994

RESUMO

Aerobic exercise in type 1 diabetes (T1D) causes rapid increase in glucose utilization due to muscle work during exercise, followed by increased insulin sensitivity after exercise. Better understanding of these changes is necessary for models of exercise in T1D. Twenty-six individuals with T1D underwent three sessions at three insulin rates (100%, 150%, 300% of basal). After 3-h run-in, participants performed 45 min aerobic exercise (moderate or intense). We determined area under the curve for endogenous glucose production (AUCEGP) and rate of glucose disappearance (AUCRd) over 45 min from exercise start. A novel application of linear regression of Rd across the three insulin sessions allowed separation of insulin-mediated from non-insulin-mediated glucose uptake before, during, and after exercise. AUCRd increased 12.45 mmol/L (CI = 10.33-14.58, P < 0.001) and 13.13 mmol/L (CI = 11.01-15.26, P < 0.001) whereas AUCEGP increased 1.66 mmol/L (CI = 1.01-2.31, P < 0.001) and 3.46 mmol/L (CI = 2.81-4.11, P < 0.001) above baseline during moderate and intense exercise, respectively. AUCEGP increased during intense exercise by 2.14 mmol/L (CI = 0.91-3.37, P < 0.001) compared with moderate exercise. There was significant effect of insulin infusion rate on AUCRd equal to 0.06 mmol/L per % above basal rate (CI = 0.05-0.07, P < 0.001). Insulin-mediated glucose uptake rose during exercise and persisted hours afterward, whereas non-insulin-mediated effect was limited to the exercise period. To our knowledge, this method of isolating dynamic insulin- and non-insulin-mediated uptake has not been previously employed during exercise. These results will be useful in informing glucoregulatory models of T1D. The study has been registered at www.clinicaltrials.gov as NCT03090451.NEW & NOTEWORTHY Separating insulin and non-insulin glucose uptake dynamically during exercise in type 1 diabetes has not been done before. We use a multistep process, including a previously described linear regression method, over three insulin infusion sessions, to perform this separation and can graph these components before, during, and after exercise for the first time.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Exercício Físico/fisiologia , Glucose/farmacocinética , Insulina/fisiologia , Adolescente , Adulto , Glicemia/metabolismo , Feminino , Humanos , Hiperinsulinismo/metabolismo , Hipoglicemia/metabolismo , Insulina/administração & dosagem , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Esforço Físico/fisiologia , Adulto Jovem
18.
Artigo em Inglês | MEDLINE | ID: mdl-33013714

RESUMO

The androgenic gland (AG)-a unique crustacean endocrine organ that secretes factors such as the insulin-like androgenic gland (IAG) hormone-is a key player in crustacean sex differentiation processes. IAG expression induces masculinization, while the absence of the AG or a deficiency in IAG expression results in feminization. Therefore, by virtue of its universal role as a master regulator of crustacean sexual development, the IAG hormone may be regarded as the sexual "IAG-switch." The switch functions within an endocrine axis governed by neuropeptides secreted from the eyestalks, and interacts downstream with specific insulin receptors at its target organs. In recent years, IAG hormones have been found-and sequenced-in dozens of decapod crustacean species, including crabs, prawns, crayfish and shrimps, bearing different types of reproductive strategies-from gonochorism, through hermaphroditism and intersexuality, to parthenogenesis. The IAG-switch has thus been the focus of efforts to manipulate sex developmental processes in crustaceans. Most sex manipulations were performed using AG ablation or knock-down of the IAG gene in males in order to sex reverse them into "neo-females," or using AG implantation/injecting AG extracts or cells into females to produce "neo-males." These manipulations have highlighted the striking crustacean sexual plasticity in different species and have permitted the manifestation of either maleness or femaleness without altering the genotype of the animals. Furthermore, these sex manipulations have not only facilitated fundamental studies of crustacean sexual mechanisms, but have also enabled the development of the first IAG-switch-based monosex population biotechnologies, primarily for aquaculture but also for pest control. Here, we review the crustacean IAG-switch, a unique crustacean endocrine mechanism, from the early discoveries of the AG and the IAG hormone to recent IAG-switch-based manipulations. Moreover, we discuss this unique early pancrustacean insulin-based sexual differentiation control mechanism in contrast to the extensively studied mechanisms in vertebrates, which are based on sex steroids.


Assuntos
Decápodes/fisiologia , Sistema Endócrino/fisiologia , Insulina/fisiologia , Diferenciação Sexual/fisiologia , Animais , Proteínas de Artrópodes/fisiologia , Hormônios de Invertebrado , Transdução de Sinais
19.
BMC Biol ; 18(1): 124, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928209

RESUMO

BACKGROUND: The increasing age of global populations highlights the urgent need to understand the biological underpinnings of ageing. To this end, inhibition of the insulin/insulin-like signalling (IIS) pathway can extend healthy lifespan in diverse animal species, but with trade-offs including delayed development. It is possible that distinct cell types underlie effects on development and ageing; cell-type-specific strategies could therefore potentially avoid negative trade-offs when targeting diseases of ageing, including prevalent neurodegenerative diseases. The highly conserved diversity of neuronal and non-neuronal (glial) cell types in the Drosophila nervous system makes it an attractive system to address this possibility. We have thus investigated whether IIS in distinct glial cell populations differentially modulates development and lifespan in Drosophila. RESULTS: We report here that glia-specific IIS inhibition, using several genetic means, delays development while extending healthy lifespan. The effects on lifespan can be recapitulated by adult-onset IIS inhibition, whereas developmental IIS inhibition is dispensable for modulation of lifespan. Notably, the effects we observe on both lifespan and development act through the PI3K branch of the IIS pathway and are dependent on the transcription factor FOXO. Finally, IIS inhibition in several glial subtypes can delay development without extending lifespan, whereas the same manipulations in astrocyte-like glia alone are sufficient to extend lifespan without altering developmental timing. CONCLUSIONS: These findings reveal a role for distinct glial subpopulations in the organism-wide modulation of development and lifespan, with IIS in astrocyte-like glia contributing to lifespan modulation but not to developmental timing. Our results enable a more complete picture of the cell-type-specific effects of the IIS network, a pathway whose evolutionary conservation in humans make it tractable for therapeutic interventions. Our findings therefore underscore the necessity for cell-type-specific strategies to optimise interventions for the diseases of ageing.


Assuntos
Proteínas de Drosophila/fisiologia , Drosophila melanogaster/fisiologia , Insulina/fisiologia , Longevidade , Fosfatidilinositol 3-Quinases/fisiologia , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Neuroglia/classificação , Neuroglia/fisiologia , Transdução de Sinais
20.
Biochem Biophys Res Commun ; 532(4): 535-540, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-32896381

RESUMO

N-myristoylation is a ubiquitous protein lipidation in eukaryotes, but regulatory roles for myristoylation on proteins still remain to be explored. Here, we show that N-myristoylation of Caveolin-2 (Cav-2) controls insulin signaling. Alternative translation initiation (ATI)-yielded truncated form of non-N-myristoylable Cav-2ß and various conditional Cav-2 mutants were compared to full-length form of N-myristoylable Cav-2α. Insulin induced insulin receptor (IR) tyrosine kinase-catalyzed Tyr-19 phosphorylation of N-myristoylable M14A Cav-2 and triggered activation of IR signaling cascade. In contrast, insulin induced ubiquitination of non-N-myristoylable M1A and G2A Cav-2 to facilitate protein-tyrosine phosphatase 1B interaction with IR which desensitized IR signaling through internalization. Metabolic labeling and click chemistry showed palmitoylation of M14A but not M1A and G2A Cav-2. Insulin did not induce phosphorylation of M1A and G2A Cav-2 and Cav-2ß. Like Cav-2α, G2A Cav-2 and Cav-2ß formed large homo-oligomers localized in lipid rafts. These findings show Cav-2 N-myristoylation plays a crucial role to coordinate its phosphorylation, palmitoylation, and ubiquitination to control insulin signaling.


Assuntos
Caveolina 2/metabolismo , Insulina/fisiologia , Transdução de Sinais , Animais , Caveolina 2/química , Linhagem Celular , Humanos , Lipoilação , Microdomínios da Membrana/metabolismo , Ácido Mirístico/metabolismo , Fosforilação , Ratos , Receptor de Insulina/metabolismo , Tirosina/metabolismo , Ubiquitinação
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