RESUMO
OBJECTIVES: Actinic keratosis have a high risk of progression to a squamous cell carcinoma. Insulin-like growth factor 1 and its receptor play a relevant role in restoring repair of ultraviolet-induced cell damage. This pathway is reduced in patients older than 65 years. Ablative fractional laser resurfacing could normalize insulin-like growth factor 1 (IGF-1) secretion in elderly by recruiting new fibroblasts. The aim of the study is to evaluate restoration of IGF1 values by PCR in senescent fibroblasts after ablative fractional laser resurfacing. METHODS: We enrolled 30 male patients with multiple actinic keratosis on the scalp, equally divided into two mirror areas of up to 50 cm2 , treating only the right one. We performed one skin biopsy for each area 30 days after treatment. Real-time PCR in fibroblasts was performed to assess the change in IGF1. At baseline and after 6 months, in vivo reflectance confocal microscopy examination was performed in all patients. RESULTS: IGF1 values were increased in the treated side by about 60%. The right areas had fairly complete resolution of actinic keratosis at the last follow-up visit after 6 months with no appearance of new lesions. The mean number of actinic keratosis in the right area was reduced by more than 75% at four- and six-follow-up visits compared to the left area. The improvement in the right area was also evidenced by lower values of the mean AKASI (actinic keratosis area and severity index) score. Reflectance confocal microscopy showed a reduction of keratinocytic disarray and scales after treatment. DISCUSSION: Taken together, all the clinical, laboratory, and in vivo results of our study allowed us to confirm that ablative fractional laser resurfacing is a valuable tool for the treatment of actinic keratosis and cancerization field, both for the management of clinically evident lesions and for preventing the occurrence of squamous cell carcinoma.
Assuntos
Carcinoma de Células Escamosas , Ceratose Actínica , Humanos , Masculino , Idoso , Ceratose Actínica/tratamento farmacológico , Fator de Crescimento Insulin-Like I/uso terapêutico , Dióxido de Carbono/uso terapêutico , Couro Cabeludo , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Lasers , Resultado do TratamentoRESUMO
Diabetes is very common in people over 75. A broad arsenal of treatments is now available. It is important, however, to choose the right treatment regimen to suit the patient's specific glycemic targets.
Assuntos
Glicemia , Hipoglicemiantes , Humanos , Idoso , Hipoglicemiantes/uso terapêuticoRESUMO
Our lab recently reported that the blockade of endothelin-1 (ET-1) receptors attenuates insulin resistance in obese mice; therefore, we hypothesized that patients taking ET-1 receptor antagonists (ERAs) will have improved glycemic control. University of Mississippi Medical Center (2013-2020) electronic health record (EPIC) data were extracted from patients ≥18 years old with a clinical diagnosis of pulmonary hypertension (Food and Drug Administration indication for ERA use) and at least two clinical visits within 2 years. Patients prescribed ERAs (n = 11) were similar in age (61 ± 14 years vs. 60 ± 14 years), body mass index (BMI) (34 ± 8 kg/m 2 vs. 35 ± 11 kg/m2), diabetes prevalence (73% vs. 80%, p = 0.59), and follow-up time (209 ± 74 days vs. 283 ± 180 days) compared with patients not taking ERAs (n = 137). There was a small but similar decrease in BMI at follow-up in the ERA (-1.9 ± 3 kg/m2) and control patients (-1.6 ± 5 kg/m2). At follow-up, hemoglobin A1c (HbA1c) significantly decreased -12% ± 11% of baseline in patients taking ERAs, while this did not occur in the control patients (2% ± 20% increase in HbA1c). In the whole population, baseline HbA1c and ERA prescription predicted the fall in HbA1c, while there was no significant association with demographics, diabetes prevalence, and diabetic treatment. These data suggest a potential role of ET-1 in promoting insulin resistance and warrant further investigation into using these drugs for glycemic control.
Assuntos
Diabetes Mellitus Tipo 2 , Hipertensão Pulmonar , Resistência à Insulina , Animais , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Endotelinas , Hemoglobinas Glicadas/análise , Hipertensão Pulmonar/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina , CamundongosRESUMO
Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including central obesity, hypertension, insulin resistance, dyslipidemia, and hyperglyemia. MetS is found to be a positive predictor of cardiovascular morbidity and mortality. The present study was planned to test the efficacy of vitamin D3 supplementation as compared with cortisol inhibition on MetS parameters. Wistar rats were allocated into four groups: control, untreated MetS, and MetS treated with either vitamin D3 (10 µg/kg) or carbenoxolone (50 mg/kg). MetS was induced by combination of high-fat diet and oral fructose. After the induction period (8 weeks), MetS was confirmed, and treatment modalities started for a further 4 weeks. Compared with untreated MetS, vitamin D3- and carbenoxolone-treated rats showed significant reduction in blood pressure, body mass index, Lee index, waist circumference, retroperitoneal fat, and improvement of dyslipidemia. Meanwhile, treatment with carbenoxolone significantly lowered the elevated liver enzymes, and vitamin D3 resulted in improved insulin sensitivity, enhanced glucose uptake by muscles, and replenished glycogen content in the liver and muscles near control levels. In conclusion, although treatment with vitamin D3 or carbenoxolone reduced the risk factors associated with MetS, vitamin D3 was effective in ameliorating insulin resistance which is the hallmark of MetS.
Assuntos
Resistência à Insulina , Síndrome Metabólica , Animais , Glicemia/metabolismo , Carbenoxolona/farmacologia , Carbenoxolona/uso terapêutico , Colecalciferol/farmacologia , Colecalciferol/uso terapêutico , Síndrome Metabólica/metabolismo , Ratos , Ratos WistarRESUMO
d-chiro-Inositol (DCI), an isomer of inositol, possesses antioxidative and endothelial protective properties. Possibly due to a deficiency of insulin mediators, polycystic ovary syndrome (PCOS) is often associated with insulin resistance (IR) and hyperinsulinemia, likely responsible for an elevated production of reactive oxygen species. We investigated oxidative-related alterations of inositol in the blood of women with PCOS before and after treatment with DCI. A total of 38 normal-weight PCOS women were investigated before and after DCI administration (500 mg/day for 12 weeks; n = 38) by evaluating serum testosterone, serum androstenedione, fasting serum insulin, fasting serum glucose, and parameters of IR. From the blood, we determined biomarkers of oxidative stress: superoxide anion radicals, hydrogen peroxide, nitric oxide, and the index of lipid peroxidation. The activity of catalase and superoxide dismutase and the reduced glutathione (GSH) content in the hemolysate were also assessed. Data showed that PCOS patients' plasma underwent oxidative stress, as indicated by the higher level of prooxidants and reduced cytosolic GSH content. DCI treatment significantly improved the metabolic parameters. Also, serum values of testosterone were reduced. In conclusion, PCOS patients suffer from a systemic oxidative stress that induces endothelial dysfunction. Treatment with DCI is effective in reducing hormonal, metabolic, and oxidative abnormalities in PCOS patients by improving IR.
Assuntos
Resistência à Insulina , Síndrome do Ovário Policístico , Feminino , Humanos , Inositol/farmacologia , Inositol/uso terapêutico , Insulina , Estresse Oxidativo , TestosteronaRESUMO
The activation of Nod-like receptor proteins (NLRP3) containing the pyrin domain inflammasome is a hallmark of the pathogenesis of metabolic disorders. Inhibition of the NLRP3 inflammasome by phytoconstituents has been attempted as a strategy to mitigate these disorders. Therefore, the present study aimed to evaluate the efficacy of an NLRP3 inflammasome inhibitor, parthenolide (PN; 5 mg/kg i.p.) against inflammation and insulin resistance in high-fat diet (HFD) - obese mice. Treatment with PN and pioglitazone (PIO; 30 mg/kg p.o.) attenuated lipopolysaccharide (LPS; 1 ng/ml) - induced elevation of tumor necrosis factor-α and interleukin-1ß in mouse peritoneal macrophages in a dose-dependent manner. Sixty days of PN and PIO treatment marginally reduced obesity-induced insulin resistance in HFD-obese mice. PN treatment also decreased blood glucose from 14th to 60th day, supporting the hypothesis of simultaneous attenuation of inflammation and insulin resistance in obese mice. Thus, PN treatment was also evident with significant improvement in glucose tolerance and peripheral insulin resistance validated through the respective tolerance tests. Therefore, the present study suggests that PN, an NLRP3 inflammasome inhibitor, could be a possible therapeutic agent for attenuating obesity-induced insulin resistance.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia , Sesquiterpenos/farmacologia , Animais , Glicemia/metabolismo , Relação Dose-Resposta a Droga , Interleucina-1beta/metabolismo , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Sesquiterpenos/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In this study, we wanted to verify whether the effect of insulin on calcium homeostasis depends on the heart's development stage. Using a quantitative 3D confocal microscopy, we tested the effect of a high insulin concentration (100 µU) in freshly cultured ventricular cardiomyocytes from newborn and adult rats. Our results showed that the cytosolic basal level of calcium was higher in newborn cardiomyocytes with no change in the nuclear basal calcium level compared with the adult cardiomyocytes; in addition, insulin induced a slow increase of cytosolic and nuclear calcium in newborn ventricular cardiomyocytes, followed by two phases. However, the first phase of slow cytosolic and nuclear calcium increase was absent in adult rat ventricular cardiomyocytes. Furthermore, the time to the onset of increase of cytosolic and nuclear calcium was longer in newborn cardiomyocytes compared with adults. Moreover, the time to peak of the calcium transient was shorter in newborns than in adult cardiomyocytes. These results demonstrate that insulin differently regulates calcium homeostasis in newborns than in adult cardiomyocytes. Thus, newborn rat cardiomyocytes, commonly used in research as a model for adult cardiomyocytes, should be used with caution when dealing with insulin in normal and disease conditions.
Assuntos
Cálcio , Miócitos Cardíacos , Ratos , Animais , Cálcio/farmacologia , Insulina/farmacologia , Células Cultivadas , Ventrículos do CoraçãoRESUMO
The first therapeutic benefits of insulin were recorded after the injection of pancreatic extract, given on January 23, 1922 in Toronto to a 14-year-old teenager. Until then, type I diabetes was always fatal, within weeks or months; the fatal outcome being delayed only at the cost of a drastic low-calorie diet. In previous decades, the importance of the pancreas in the development of diabetes had been pointed out, but all attempts to use a pancreatic extract had failed. It is with the objective of "neutralizing" the destructive effects of pancreatic juice (proteolytic) that the isolation of insulin was carried out by a research team which was totally improbable since it was headed by an orthopedic surgeon, Frederick Banting and a 22-year-old stagiaire, Charles Best. Their work was carried out in the university physiology laboratory of John Macleod and their outcome was made possible thanks to the skills of James Collip who purified the insulin preparation. Scientific reality invites us to emphasize that, Banting works, based on a wrong hypothesis, drew towards an historical discovery. Very quickly recognized as of major importance for medicine, the discovery was greeted by the attribution of the Nobel Prize in 1923. For a hundred years, insulin has not ceased to be an essential drug for tens of millions of patients in the world, but it has been a motor for scientific research: innovation in galenic pharmacy and biopharmacy, in fundamental chemistry as a subject for the study of the structure, analysis and synthesis of proteins, and finally, as a motor for the development of biotechnologies, since insulin was the first drug prepared by DNA-recombinant technology, and marketed in 1982.
Assuntos
Diabetes Mellitus , Insulina , Humanos , História do Século XX , Adolescente , Adulto Jovem , Adulto , Insulina/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/história , Prêmio Nobel , Extratos Pancreáticos/uso terapêutico , DNA/uso terapêuticoRESUMO
OBJECTIVES: In the management of diabetic patients on insulin therapy, adherence to medication is a key element for avoiding chronic complications. The purpose of this study was to evaluate diabetic patients' ability to translate glycemic results into an appropriate insulin dose and thus, adherence to insulins. METHODS: This was an observational, retrospective, monocentric pilot study. Diabetic patients on insulin therapy being followed at the metabolic and endocrine diseases department were divided into two groups depending on their mode of glycemic control at home: capillary glycemia (Notebook group) or interstitial glycemia using the FreeStyle Libre® flash system (FSL group). Adherence was assessed based on the rate of compliance in adapting insulin doses to the prescribed protocols (depending on type of insulin, glycemic targets, and patients' characteristics) by a pharmacy resident and a senior diabetologist. Good adherence was defined as a minimum rate of 80% of conforming insulin injections for each patient. RESULTS: A total of 50 patients were included, 35 in the Notebook group and 15 in the FSL group. Two-thirds of patients were non-adherent to insulin. Dose adjustment errors mainly concerned rapid-acting insulin with 51.1% of non- conformities, 10.0% of which were due to underdosing in the Notebook group and 21.7% to overdosing in the FSL group. Hyperglycemia was predominant in both populations with a median time in range of 19.0% in the FSL group and well below recommendations (>70%). CONCLUSIONS: Despite the use of increasingly efficient, easy-to-use devices in diabetes monitoring, insulin non-adherence and glycemic imbalance are unresolved major issues. Diabetic patients require reinforced medical follow-up for optimal insulin management.
Assuntos
Diabetes Mellitus , Insulinas , Humanos , Insulina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Estudos Retrospectivos , Pacientes Ambulatoriais , Projetos Piloto , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/induzido quimicamente , Glicemia , Insulina de Ação CurtaRESUMO
This study developed an animal model of gestational obesity and prediabetes in Sprague Dawley rats using 35% sucrose supplementation (SS). Postprandially, insulin stimulates glucose uptake and nutrient partitioning via insulin-dependent action as well as hepatic insulin sensitizing substance (HISS) - dependent action. HISS is glycogenic in heart, kidney, and skeletal muscle (contrasting insulin's lipogenic actions in liver and adipose tissue) and is responsible for the vasodilatory action of insulin. Postprandial insulin sensitivity was quantified using the rapid insulin sensitivity test (RIST). Animals at 15-day gestation and virgin animals received SS for 8 weeks (with a 2-week recovery), 10 weeks, or 22 weeks. SS in pregnant and virgin rats eliminated HISS-dependent glucose uptake, resulting in compensatory hyperinsulinemia and resultant hypertriglyceridemia and obesity. In groups with SS for 8 weeks followed by a 2-week recovery, there was spontaneous partial recovery of HISS-dependent glucose uptake in virgins and complete recovery in pregnancy. The 10-week SS resulted in complete absence of HISS-dependent glucose uptake and produced a model of gestational obesity and prediabetes. The 22-week SS did not produce hyperglycemia or worsen hyperinsulinemia but did increase hypertriglyceridemia above 10-week SS. This substantiates the use of 10-week SS as a model of gestational obesity and (or) prediabetes, allowing further studies into treatments of gestational obesity and insulin resistance.
Assuntos
Resistência à Insulina , Animais , Sacarose Alimentar , Estado Pré-Diabético , Ratos , Ratos Sprague-DawleyRESUMO
Physical exercise is essential for the amelioration of insulin resistance (IR). The mechanisms in charge of improved IR, regulated by exercise, are insufficiently studied. Previous research revealed that Sirtuin 6 (SIRT6) - mediated insulin signaling acts a crucial element in hepatic IR. The objective of our research was to determine the effects of exercise on SIRT6-mediated insulin signaling in liver of IR rats. Forty male Sprague Dawley rats were randomly assigned to four groups (n = 10 rats each): control rats fed with standard chow (Lean group); sedentary rats fed with a high-fat diet (HFD-SED); rats fed with HFD and submitted to 8 week chronic swimming exercise training (HFD-CE); and rats fed HFD and submitted to one acute swimming exercise training (HFD-AE). HFD feeding lead to increased body weight, accumulation of hepatic triglyceride and serum free fatty acids, and enhanced gluconeogenesis. Besides, HFD feeding decreased body insulin sensitivity. Hepatic USP10 and SIRT6 protein levels decreased under obese status. Both chronic and acute exercise intervention alleviated physiological and metabolic status, increased hepatic USP10 and SIRT6 levels, improved insulin signaling transduction, and inhibited gluconeogenesis. These results showed that exercise intervention regulated SIRT6-mediated insulin signaling, which contributes to our understanding of the molecular mechanisms behind IR, in that a regular exercise can mitigate the effects of IR.
Assuntos
Resistência à Insulina , Obesidade , Animais , Masculino , RatosRESUMO
Insulin resistance is a feature of pregnancy and is associated with increased levels of angiotensin II (Ang II) and insulin. Therefore, pregnancy may change insulin-induced vasodilation through changes in Ang II receptors. Insulin-induced vasorelaxation was evaluated in phenylephrine-precontracted aortic rings of pregnant and non-pregnant rats, using a conventional isolated organ preparation. Experiments were performed in thoracic or abdominal aorta rings with or without endothelium in the presence and absence of NG-nitro-L-arginine methyl ester (L-NAME) (10-5 M), losartan (10-7 M), or PD123319 (10-7 M). AT1 and AT2 receptor expressions were detected by immunohistochemistry. Insulin-induced vasodilation was endothelium- and nitric oxide-dependent and decreased in the thoracic aorta but increased in the abdominal segment of pregnant rats. The insulin's vasorelaxant effect was increased by losartan mainly on the thoracic aorta. PD123319 decreased insulin-induced vasorelaxation mainly in the pregnant rat abdominal aorta. AT1 receptor expression was decreased while AT2 receptor expression was increased by pregnancy. In conclusion, pregnancy changes insulin-induced vasorelaxation. Moreover, insulin vasodilation is tonically inhibited by AT1 receptors, while AT2 receptors appear to have an insulin-sensitizing effect. The role of pregnancy and Ang II receptors differ depending on the aorta segment. These results shed light on the role of pregnancy and Ang II receptors on the regulation of insulin-mediated vasodilation.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Aorta Torácica/efeitos dos fármacos , Insulina/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Prenhez/fisiologia , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Vasodilatação/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Feminino , Hipoglicemiantes/farmacologia , Músculo Liso Vascular/metabolismo , Gravidez , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/química , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/química , Receptor Tipo 2 de Angiotensina/genética , Vasodilatação/fisiologiaRESUMO
Diabetes mellitus (DM) is a type of metabolic disorder characterized by long-term hyperglycemia. Accumulating evidence shows that long noncoding RNAs (lncRNAs) play significant roles in the occurrence and development of DM. This study intended to investigate the role of lncRNA plasmacytoma variant translocation 1 (PVT1) in rat insulinoma (INS-1) cells damaged by streptozotocin (STZ) and to identify the potential mechanisms. Firstly, PVT1 expression in INS-1 cells was assessed using RT-qPCR after STZ stimulation. After PVT1-knockdown, cell apoptosis, the contents of oxidative stress related markers, and changes in insulin secretion were detected. Results indicated that PVT1 was remarkably upregulated after STZ stimulation. PVT1-knockdown inhibited STZ-induced oxidative stress and apoptosis of INS-1 cells. Moreover, the insulin secretory capacity was notably elevated following PVT1 silencing. Subsequently, a luciferase reporter assay verified that miR-181a-5p was directly targeted by PVT1. The rescue assays revealed that miR-181a-5p inhibitor dramatically abrogated the effects of PVT1 silencing on oxidative stress, apoptosis, and insulin secretion. Taken together, these findings demonstrated that PVT1-knockdown could ameliorate STZ-induced oxidative stress and apoptosis and elevate insulin secretory capacity in pancreatic ß cells by regulating miR-181a-5p, suggesting a promising biomarker in DM diagnosis and treatment.
Assuntos
Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/terapia , Terapia Genética , Secreção de Insulina/genética , Células Secretoras de Insulina/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Inativação Gênica , Insulinoma/genética , MicroRNAs/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Neoplasias Pancreáticas/genética , RatosRESUMO
The management of type 1 diabetes in paediatrics has evolved considerably over the last 20 years, mainly through the use of new technologies. The challenge of managing this disease is to achieve good glycaemic control in order to prevent complications while maintaining a good quality of life. What are the current and future means of achieving this?
Assuntos
Diabetes Mellitus Tipo 1 , Adolescente , Automonitorização da Glicemia , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Humanos , Hipoglicemiantes , Insulina , Sistemas de Infusão de Insulina , Qualidade de VidaRESUMO
The skeletal muscle regulates glucose homeostasis. Here, the effects of vitamin A metabolites including retinoic acid (RA) alone, and in combination with insulin, on glucose utilization were investigated in rat L6 muscle cells during the differentiation process. L6 cells were treated with differentiation medium containing retinol, retinal, RA, and (or) insulin. The glucose levels and pH values in the medium were measured every 2 days. The expression levels of insulin signaling and glycogen synthesis proteins, as well as glycogen content were determined. Retinal and RA reduced the glucose content and pH levels in the medium of the L6 cells. RA acted synergistically with insulin to reduce glucose and pH levels in the medium. The RA- and insulin-mediated reduction of glucose in the medium only occurred when glucose levels were at or above 15 mmol/L. Insulin-induced phosphorylation of Akt Thr308 was further enhanced by RA treatment through the activation of retinoic acid receptor. RA acted synergistically with insulin to phosphorylate glycogen synthase kinase 3ß, and dephosphorylate glycogen synthase (GS), which was associated with increases in the protein and mRNA levels of GS. Increases in glycogen content were induced by insulin, and was further enhanced in the presence of RA. We conclude that activation of the RA signaling pathway enhanced insulin-induced glucose utilization in differentiating L6 cells through increases in glycogenesis.
Assuntos
Glucose/metabolismo , Glicogênio/biossíntese , Insulina/farmacologia , Músculo Esquelético/metabolismo , Tretinoína/farmacologia , Animais , Linhagem Celular , RatosRESUMO
High salt intake (HS) is associated with obesity and insulin resistance. ET-1, a peptide released in response to HS, inhibits the actions of insulin on cultured adipocytes through ET-1 type B (ETB) receptors; however, the in vivo implications of ETB receptor activation on lipid metabolism and insulin resistance is unknown. We hypothesized that activation of ETB receptors in response to HS intake promotes dyslipidemia and insulin resistance. In normal salt (NS) fed rats, no significant difference in body mass or epididymal fat mass was observed between control and ETB deficient rats. After 2 weeks of HS, ETB-deficient rats had significantly lower body mass and epididymal fat mass compared to controls. Nonfasting plasma glucose was not different between genotypes; however, plasma insulin concentration was significantly lower in ETB-deficient rats compared to controls, suggesting improved insulin sensitivity. In addition, ETB-deficient rats had higher circulating free fatty acids in both NS and HS groups, with no difference in plasma triglycerides between genotypes. In a separate experiment, ETB-deficient rats had significantly lower fasting blood glucose and improved glucose and insulin tolerance compared to controls. These data suggest that ET-1 promotes adipose deposition and insulin resistance via the ETB receptor.
Assuntos
Dislipidemias/metabolismo , Endotelina-1/metabolismo , Resistência à Insulina , Insulina/metabolismo , Receptor de Endotelina B/deficiência , Tecido Adiposo/metabolismo , Adiposidade , Animais , Glicemia/análise , Glicemia/metabolismo , Peso Corporal , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/etiologia , Ácidos Graxos não Esterificados/sangue , Humanos , Insulina/sangue , Masculino , Mutação , Ratos , Ratos Transgênicos , Receptor de Endotelina B/genética , Cloreto de Sódio na Dieta/efeitos adversosRESUMO
Pregnancy requires adaptation of maternal insulin sensitivity. In the fed state, a pulse of insulin stimulates glucose uptake and nutrient energy storage via insulin-dependent as well as hepatic insulin sensitizing substance (HISS)-dependent action. HISS is released by the liver in the fed state in the presence of signals integrated through the liver and a pulse of insulin. HISS promotes glucose storage as glycogen in heart, kidney, and skeletal muscle but not in gut, liver, or adipose tissue. HISS is also responsible for the vasodilatory action previously attributed to insulin. The rapid insulin sensitivity test (RIST), a dynamic euglycemic clamp, can quantitate both HISS-dependent and insulin-dependent glucose uptake. The RIST was used to characterize postprandial insulin sensitivity in the Sprague Dawley rat and the changes in the partitioning of nutrient energy throughout gestation. Early pregnancy demonstrated increased insulin sensitivity attributable to HISS-dependent glucose uptake with unchanged insulin-dependent glucose uptake, preserved plasma insulin concentration, and reduced plasma triglyceride concentration compared to the virgin. In late pregnancy, there was reduced HISS-dependent and insulin-dependent glucose uptake accompanied by increased plasma insulin and triglyceride concentration compared to the virgin. These results suggest an important role for HISS in glucose partitioning in pregnancy.
Assuntos
Glucose/metabolismo , Resistência à Insulina , Fígado/metabolismo , Animais , Feminino , Insulina/sangue , Período Pós-Prandial , Gravidez , Ratos Sprague-Dawley , Triglicerídeos/sangueRESUMO
We have previously shown that cooperative, interdependent binding by the pioneer factors FoxO1 and FoxA1/2 is required for recruitment of RNA polymerase II and H3K27 acetylation to the promoters of insulin-regulated genes. However, the underlying mechanisms are unknown. In this study, we demonstrate that, in HepG2 cells, FoxO1 and FoxA2 form a complex on DNA that is disrupted by insulin treatment. Insulin-mediated phosphorylation of FoxO1 and FoxA2 does not impair their cooperative binding to mononucleosome particles assembled from the IGFBP1 promoter, indicating that direct disruption of complex formation by phosphorylation is not responsible for the loss of interdependent FoxO1:FoxA1/2 binding following insulin treatment. Since FoxO1 and FoxA1/2 binding is required for the establishment and maintenance of transcriptionally active chromatin at insulin-regulated genes, we hypothesized that cooperative FoxO1 and FoxA1/2 binding dictates the chromatin remodeling events required for the initial activation of these genes. In support of this idea, we demonstrate that FoxO1 and FoxA2 cooperatively open linker histone compacted chromatin templates containing the IGFBP1 promoter. Taken together, these results provide a mechanism for how interdependent FoxO1:FoxA1/2 binding is negatively impacted by insulin and provide a developmental context for cooperative gene activation by these factors.
Assuntos
Cromatina/metabolismo , DNA/metabolismo , Proteína Forkhead Box O1/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Insulina/metabolismo , Cromatina/genética , DNA/genética , Proteína Forkhead Box O1/genética , Células Hep G2 , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/genética , Humanos , Insulina/genética , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/biossíntese , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fosforilação/genética , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Elementos de RespostaRESUMO
Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) are excellent models for studying acute brain ischemia because they show high resistance to reductions in blood flow and oxygen delivery without evidence of neurological damage. In this study, we analyzed the insulin signaling pathway and regulation of mitochondrial substrate oxidation in three regions of ground squirrel brain (forebrain, cerebellum, and brainstem), comparing summer, late torpor, and interbout arousal conditions. We found select decreases in phospho-Akt in the cerebellum during torpor compared with summer animals, as well as select increases in the forebrain during interbout arousal, suggesting that Akt may influence either metabolism or cytoprotective pathways. The phosphoprotein abundance of glycogen synthase kinase 3 beta (GSK3ß) showed the most consistent trend across all three brain regions, with peak increases observed during deep torpor, suggesting a crucial role for this protein during hibernation. Furthermore, all three regions of the brain showed increased phospho-protein abundance of pyruvate dehydrogenase at serine 232 during both deep torpor and interbout arousal, and serine 300 during interbout arousal only, whereas other phosphorylation sites showed a region-specific expression pattern. Information collected from these studies sheds light on the molecular controls governing insulin signaling and fuel utilization in the brain of hibernating ground squirrels.
Assuntos
Apoptose , Encéfalo/metabolismo , Glucose/metabolismo , Glicogênio Sintase Quinase 3 beta/síntese química , Fosfoproteínas/síntese química , Sciuridae/metabolismo , Animais , Glicogênio Sintase Quinase 3 beta/química , Glicogênio Sintase Quinase 3 beta/metabolismo , Insulina/metabolismo , Fosfoproteínas/química , Fosfoproteínas/metabolismoRESUMO
We investigated the structural and functional adaptations of the pancreas during weight cycling in animals submitted to hypoestrogenism. Female Wistar rats were distributed among the following test groups: ShamAL (AL, ad libitum); OVXAL (ovariectomized); and OVXcycle (dietary restriction with weight cycling). The ShamAL and OVXAL groups received commercial feed ad libitum, whereas the OVXcycle group received 21 days of commercial feed ad libitum, and 21 days of caloric restriction, with caloric intake amounting to 40% of the amount of feed consumed by the rats in the OVXAL group. The tolerance tests for glucose and insulin were applied. After euthanasia, the pancreas and adipose tissue were collected. The disappearance of glucose during the insulin assay occurred at a higher rate in tissues from the OVXcycle group, compared with the OVXAL group. Fasting glycemia and perirenal adipose tissue were lower in the OVXcycle group. By comparison with the ShamAL and OVXAL groups, the OVXcycle group showed higher protein expression of the M1 and M3 receptors and SOD1-2, as well as higher carbachol-induced insulin secretion. Under highly stimulatory conditions with 16.7 mmol/L glucose, the OVXAL and OVXcycle groups presented lower insulin secretion compared with the ShamAL group. Morphological analysis revealed higher iron deposition in the OVXAL islets by comparison with the OVXcycle group. These results show that ovariectomy accelerated the loss of pancreatic islet function, and that weight cycling could restore the function of the islets.