RESUMO
Metabolic syndrome (MetS) is an increasing global health threat and strong risk factor for type 2 diabetes (T2D). MetS causes both hyperinsulinemia and islet size overexpansion, and pancreatic ß-cell failure impacts insulin and proinsulin secretion, mitochondrial density, and cellular identity loss. The low-density lipoprotein receptor knockout (LDLr-/-) model combined with high-fat diet (HFD) has been used to study alterations in multiple organs, but little is known about the changes to ß-cell identity resulting from MetS. Osteocalcin (OC), an insulin-sensitizing protein secreted by bone, shows promising impact on ß-cell identity and function. LDLr-/- mice at 12 months were fed chow or HFD for 3 months ± 4.5 ng/h OC. Islets were examined by immunofluorescence for alterations in nuclear Nkx6.1 and PDX1 presence, insulin-glucagon colocalization, islet size and %ß-cell and islet area by insulin and synaptophysin, and mitochondria fluorescence intensity by Tomm20. Bone mineral density (BMD) and %fat changes were examined by Piximus Dexa scanning. HFD-fed mice showed fasting hyperglycemia by 15 months, increased weight gain, %fat, and fasting serum insulin and proinsulin; concurrent OC treatment mitigated weight increase and showed lower proinsulin-to-insulin ratio, and higher BMD. HFD increased %ß and %islet area, while simultaneous OC-treatment with HFD was comparable to chow-fed mice. Significant reductions in nuclear PDX1 and Nkx6.1 expression, increased insulin-glucagon colocalization, and reduction in ß-cell mitochondria fluorescence intensity were noted with HFD, but largely prevented with OC administration. OC supplementation here suggests a benefit to ß-cell identity in LDLr-/- mice and offers intriguing clinical implications for countering metabolic syndrome.
Assuntos
Diabetes Mellitus Tipo 2 , Hiperinsulinismo , Células Secretoras de Insulina , Ilhotas Pancreáticas , Síndrome Metabólica , Animais , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glucagon/metabolismo , Hiperinsulinismo/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Lipoproteínas LDL , Síndrome Metabólica/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteocalcina/metabolismo , Proinsulina/metabolismo , Aumento de PesoRESUMO
Impaired action of insulin in skeletal muscle, termed insulin resistance, leads to increased blood glucose levels resulting in compensatory increase in insulin levels. The elevated blood glucose and insulin levels exacerbate insulin resistance and contribute to the pathogenesis of type 2 diabetes mellitus. In previous studies we found attenuation of free fatty acid-induced muscle cell insulin resistance by rosemary extract (RE). In the present study we investigated the effects of RE on high glucose (HG) and high insulin (HI)-induced muscle cell insulin resistance. Exposure of L6 myotubes to 25 mmol/L glucose and 100 nmol/L insulin for 24 h, to mimic hyperglycemia and hyperinsulinemia, abolished the acute insulin-stimulated glucose uptake, increased the serine phosphorylation of IRS-1 and the phosphorylation/activation of mTOR and p70S6K. Treatment with RE significantly improved the insulin-stimulated glucose uptake and increased the acute insulin-stimulated tyrosine phosphorylation while reducing the HG+HI-induced serine phosphorylation of IRS-1 and phosphorylation of mTOR and p70S6K. Additionally, treatment with RE significantly increased the phosphorylation of AMPK, its downstream effector ACC and the plasma membrane GLUT4 levels. Our data indicate a potential of RE to counteract muscle cell insulin resistance and more studies are required to investigate its effectiveness in vivo. Novelty: RE phosphorylated muscle cell AMPK and ACC under both normal and HG+HI conditions. The HG+HI-induced serine phosphorylation of IRS-1 and activation of mTOR and p70S6K were attenuated by RE. RE restored the insulin-stimulated glucose uptake by enhancing GLUT4 glucose transporter translocation to plasma membrane.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ativação Enzimática/efeitos dos fármacos , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Resistência à Insulina/fisiologia , Fibras Musculares Esqueléticas/metabolismo , Extratos Vegetais/farmacologia , Rosmarinus , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Glicemia/metabolismo , Células Cultivadas , Desoxiglucose/metabolismo , Modelos Animais de Doenças , Transportador de Glucose Tipo 4/metabolismo , Insulina/sangue , Proteínas Substratos do Receptor de Insulina/metabolismo , Fosforilação , Ratos , Serina/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Tirosina/metabolismoRESUMO
BACKGROUND/OBJECTIVES: Catch-up growth, an important risk factor for later obesity and type 2 diabetes, is often characterized by a high rate of fat deposition associated with hyperinsulinemia and glucose intolerance. We tested here the hypothesis that refeeding on a high-fat diet rich in essential polyunsaturated fatty acids (ePUFA) improves glucose homeostasis primarily by enhancing insulin sensitivity in skeletal muscles and adipose tissues. METHODS: Rats were caloric restricted for 2 weeks followed by 1-2 weeks of isocaloric refeeding on either a low-fat (LF) diet, a high-fat (HF) diet based on animal fat and high in saturated and monounsaturated fatty acids (HF SMFA diet), or a HF diet based on vegetable oils (1:1 mixture of safflower and linseed oils) and rich in the essential fatty acids linoleic and α-linolenic acids (HF ePUFA diet). In addition to measuring body composition and a test of glucose tolerance, insulin sensitivity was assessed during hyperinsulinemic-euglycemic clamps at the whole-body level and in individual skeletal muscles and adipose tissue depots. RESULTS: Compared to animals refed the LF diet, those refed the HF-SMFA diet showed a higher rate of fat deposition, higher plasma insulin and glucose responses during the test of glucose tolerance, and markedly lower insulin-stimulated glucose utilization at the whole body level (by a-third to a-half) and in adipose tissue depots (by 2-5 folds) during insulin clamps. While refeeding on the ePUFA diet prevented the increases in fat mass and in plasma insulin and glucose, the results of insulin clamps revealed that insulin-stimulated glucose utilization was not increased in skeletal muscles and only marginally higher in adipose tissues and at the whole-body level. CONCLUSIONS: These results suggest only a minor role for enhanced insulin sensitivity in the mechanisms by which diets high in ePUFA improves glucose homeostasis during catch-up growth.
Assuntos
Tecido Adiposo/metabolismo , Glicemia/metabolismo , Dieta Hiperlipídica/métodos , Ácidos Graxos Insaturados/administração & dosagem , Resistência à Insulina , Músculo Esquelético/metabolismo , Animais , Peso Corporal , Dieta com Restrição de Gorduras , Gorduras na Dieta/administração & dosagem , Glucose/metabolismo , Técnica Clamp de Glucose , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose , Homeostase , Hiperinsulinismo/metabolismo , Insulina/sangue , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Insulin resistance (IR) is a major metabolic risk factor even before the onset of hyperglycemia. Recently, berberine (BBR) is found to improve hyperglycemia and IR. In this study, we investigated whether BBR could improve IR independent of hyperglycemia. Acute insulin-resistant state was induced in rats by systemic infusion of intralipid (6.6%). BBR was administered via different delivery routes before or after the beginning of a 2-h euglycemic-hyperinsulinemic clamp. At the end of experiment, rats were sacrificed, gastrocnemius muscle was collected for detecting mitochondrial swelling, phosphorylation of Akt and AMPK, as well as the mitochondrial permeability regulator cyclophilin D (CypD) protein expression. We showed that BBR administration markedly ameliorated intralipid-induced IR without affecting blood glucose, which was accompanied by alleviated mitochondrial swelling in skeletal muscle. We used human skeletal muscle cells (HSMCs), AML12 hepatocytes, human umbilical vein endothelial cells, and CypD knockout mice to investigate metabolic and molecular alternations. In either HSMCs or AML12 hepatocytes, BBR (5 µM) abolished palmitate acid (PA)-induced increase of CypD protein levels. In CypD-deficient mice, intralipid-induced IR was greatly attenuated and the beneficial effect of BBR was diminished. Furthermore, we demonstrated that the inhibitory effect of BBR on intralipid-induced IR was mainly mediated by skeletal muscle, but not by intestine, liver, or microvasculature; BBR administration suppressed intralipid-induced upregulation of CypD expression in skeletal muscle. These results suggest that BBR alleviates intralipid-induced IR, which is related to the inhibition of CypD protein expression in skeletal muscle.
Assuntos
Berberina/uso terapêutico , Hiperinsulinismo/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina/fisiologia , Animais , Linhagem Celular , Ciclofilinas/metabolismo , Emulsões , Humanos , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/metabolismo , Masculino , Camundongos , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Fosfolipídeos , Ratos Sprague-Dawley , Óleo de SojaRESUMO
Dietary intake of eicosapentaenoic/docosahexaenoic acid (EPA/DHA) reduces insulin resistance and hepatic manifestations through the regulation of metabolism in the liver. Obese mice present insulin resistance and lipid accumulation in intracellular lipid droplets (LDs). LD-associated proteins perilipin (Plin) have an essential role in both adipogenesis and lipolysis; Plin5 regulates lipolysis and thus contributes to fat oxidation. The purpose of this study was to compare the effects of deodorized refined salmon oil (DSO) and its polyunsaturated fatty acids concentrate (CPUFA) containing EPA and DHA, obtained by complexing with urea, on obesity-induced metabolic alteration. CPUFA maximum content was determined using the Box-Behnken experimental design based on Surface Response Methodology. The optimized CPUFA was administered to high-fat diet (HFD)-fed mice (200 mg/kg/day of EPA + DHA) for 8 weeks. No significant differences (p > 0.05) in cholesterol, glycemia, LDs or transaminase content were found. Fasting insulin and hepatic Plin5 protein level increased in the group supplemented with the EPA + DHA optimized product (38.35 g/100 g total fatty acids) compared to obese mice without fish oil supplementation. The results suggest that processing salmon oil by urea concentration can generate an EPA+DHA dose useful to prevent the increase of fasting insulin and the decrease of Plin5 in the liver of insulin-resistant mice.
Assuntos
Dieta Hiperlipídica , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Comportamento Alimentar , Hiperinsulinismo/metabolismo , Fígado/metabolismo , Perilipina-5/metabolismo , Ureia/química , Análise de Variância , Animais , Peso Corporal/efeitos dos fármacos , Óleos de Peixe/farmacologia , Gotículas Lipídicas/química , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , OxirreduçãoRESUMO
AIMS/HYPOTHESIS: During pregnancy, maternal metabolic disease and hormonal imbalance may alter fetal beta cell development and/or proliferation, thus leading to an increased risk for developing type 2 diabetes in adulthood. Although thyroid hormones play an important role in fetal endocrine pancreas development, the impact of maternal hypothyroidism on glucose homeostasis in adult offspring remains poorly understood. METHODS: We investigated this using a mouse model of hypothyroidism, induced by administration of an iodine-deficient diet supplemented with propylthiouracil during gestation. RESULTS: Here, we show that, when fed normal chow, adult mice born to hypothyroid mothers were more glucose-tolerant due to beta cell hyperproliferation (two- to threefold increase in Ki67-positive beta cells) and increased insulin sensitivity. However, following 8 weeks of high-fat feeding, these offspring gained 20% more body weight, became profoundly hyperinsulinaemic (with a 50% increase in fasting insulin concentration), insulin-resistant and glucose-intolerant compared with controls from euthyroid mothers. Furthermore, altered glucose metabolism was maintained in a second generation of animals. CONCLUSIONS/INTERPRETATION: Therefore, gestational hypothyroidism induces long-term alterations in endocrine pancreas function, which may have implications for type 2 diabetes prevention in affected individuals.
Assuntos
Glicemia/metabolismo , Intolerância à Glucose/metabolismo , Hipotireoidismo/metabolismo , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/embriologia , Complicações na Gravidez/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Antitireóideos/toxicidade , Proliferação de Células , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Hiperinsulinismo/metabolismo , Resistência à Insulina , Iodo/deficiência , Ilhotas Pancreáticas/metabolismo , Camundongos , Gravidez , Propiltiouracila/toxicidade , Estresse FisiológicoRESUMO
Excess of visceral adipose tissue (VAT) characteristic of obesity leads to a proinflammatory state disrupting the insulin signaling pathway, triggering insulin resistance (IR) and inflammation, the main processes contributing to obesity comorbidities. Ursolic acid (UA), a pentacyclic triterpenoid occurring in a variety of plant foods, exhibits anti-inflammatory properties. The aim of this study was to evaluate UA effects on IR, hyperinsulinemia, and inflammation in experimental diet-induced obesity. Forty male Wistar rats were randomly assigned to eight groups (n = 5). One group was used for time 0. Three groups were labeled as OBE (control): receiving high-fat diet (HFD; fat content 45.24% of energy) during 3, 6, or 9 weeks; three groups UA-PREV: exposed to simultaneous HFD and UA during 3, 6, or 9 weeks to evaluate UA preventive effects; one group UA-REV: receiving HFD for 6 weeks, followed by simultaneous HFD and UA for three additional weeks to analyze UA reversal effects. Measurements were performed after 3, 6, or 9 weeks of treatment. Adiposity was calculated by weighing VAT after sacrifice. Serum markers were quantified through colorimetric and enzyme-linked immunosorbent assay methods. VAT adipokines RNAm expression was evaluated by quantitative reverse transcriptase-polymerase chain reaction. Data were analyzed by Kruskal-Wallis and Mann-Whitney U tests. UA significantly decreased adiposity, IR, hyperinsulinemia, triacylglycerides, and cholesterol levels, and also VAT mRNA expression of MCP-1 (monocyte chemoattractant protein-1), IL (interleukin)-1ß and IL-6, concomitantly increasing adiponectin levels. UA metabolic effects demonstrated in this study support its potential therapeutic utility to improve IR, hyperinsulinemia, and inflammation observed in obesity and diabetes.
Assuntos
Adipocinas/genética , Hiperinsulinismo/tratamento farmacológico , Resistência à Insulina , Obesidade/tratamento farmacológico , Triterpenos/administração & dosagem , Adipocinas/metabolismo , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Humanos , Hiperinsulinismo/etiologia , Hiperinsulinismo/genética , Hiperinsulinismo/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Ratos , Ratos Wistar , Ácido UrsólicoRESUMO
High- and low- Se diets received by dams during gestation and lactation are related to insulin resistance in their pups. High-Se diet leads to an increase in serum insulin levels, which does not function properly, and an anabolic process. Low-Se diet is related to very low insulin values and an extreme catabolic energy imbalance. Selenoproteins have been implicated directly in the general endocrine regulation of appetite and energy homeostasis. To obtain information concerning how Se intake by dams is involved in regulating endocrine energy balance in progeny, three experimental groups of dam rats were used: control (Se: 0.1â¯ppm), Se-supplemented (Se: 0.5â¯ppm) and Se-deficient (Se: 0.01â¯ppm). At the end of lactation (21d old), the pups' appetite profile, Se levels, peptides from gastrointestinal tract (including pancreas), leptin, thyroid hormones, skeletal growth markers and cytokines in serum were measured. Low-Se diet leads to severe growth retardation, underdeveloped glands, a non-functional pancreas, non-operative high serum leptin levels and low GIT-anorexigenic signals. High-Se diet leads to non-operative high insulin secretion, obesity, inflammation and low leptin levels. These results point to Se as an important marker and a possible dietary supplementation treatment for gestating and lactating mothers in order to avoid metabolic disorders such as gestational diabetes or intrauterine growth retardation which could affect their progeny's future health in adulthood.
Assuntos
Suplementos Nutricionais/toxicidade , Metabolismo Energético/efeitos dos fármacos , Hiperinsulinismo/induzido quimicamente , Obesidade/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Selênio/toxicidade , Animais , Animais Recém-Nascidos , Metabolismo Energético/fisiologia , Feminino , Hiperinsulinismo/metabolismo , Lactação/efeitos dos fármacos , Lactação/metabolismo , Masculino , Obesidade/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Selênio/administração & dosagemRESUMO
Atypical antipsychotics, such as olanzapine, are commonly prescribed to patients with schizophrenic symptoms and other psychiatric disorders. However, weight gain and metabolic disturbance cause adverse effects, impair patient compliance and limit clinical utility. Thus, a better understanding of treatment-acquired adverse effects and identification of targets for therapeutic intervention are believed to offer more clinical benefits for patients with schizophrenia. Beyond its nutritional effects, studies have indicated that supplementation of chromium brings about beneficial outcomes against numerous metabolic disorders. In this study, we investigated whether olanzapine-induced weight gain and metabolic disturbance involved chromium dynamic mobilization in a female Sprague-Dawley rat model, and whether a dietary supplement of chromium improved olanzapine-acquired adverse effects. Olanzapine medicated rats experienced weight gain and adiposity, as well as the development of hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, and inflammation. The olanzapine-induced metabolic disturbance was accompanied by a decrease in hepatic Akt and AMP-activated Protein Kinase (AMPK) actions, as well as an increase in serum interleukin-6 (IL-6), along with tissue chromium depletion. A daily intake of chromium supplements increased tissue chromium levels and thermogenic uncoupling protein-1 (UCP-1) expression in white adipose tissues, as well as improved both post-olanzapine weight gain and metabolic disturbance. Our findings suggest that olanzapine medicated rats showed a disturbance of tissue chromium homeostasis by inducing tissue depletion and urinary excretion. This loss may be an alternative mechanism responsible for olanzapine-induced weight gain and metabolic disturbance.
Assuntos
Adiposidade/efeitos dos fármacos , Antipsicóticos/efeitos adversos , Cloretos/farmacologia , Compostos de Cromo/farmacologia , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Hiperlipidemias/metabolismo , Olanzapina/efeitos adversos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adiposidade/genética , Administração Oral , Animais , Cloretos/metabolismo , Compostos de Cromo/metabolismo , Feminino , Regulação da Expressão Gênica , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Hiperglicemia/prevenção & controle , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/genética , Hiperinsulinismo/prevenção & controle , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/genética , Hiperlipidemias/prevenção & controle , Inflamação , Resistência à Insulina/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Aumento de Peso/efeitos dos fármacosRESUMO
Hypothalamic neurons detect changes in circulating hormones such as leptin and insulin and put forward outputs to sustain energy and glucose homeostasis. Because leptin and insulin receptors colocalize in ~40-60% of neurons in the hypothalamus, we characterized the metabolic phenotype of mice with selective deletion of the insulin receptor (InsR) in LepR cells. LRΔInsR mice presented no difference in body weight and insulin levels but increased fat mass. In the light phase, LRΔInsR mice exhibited increased food intake, locomotor activity, carbon dioxide production, and respiratory exchange rate. These mice showed reduced fat oxidation and reduced expression of cluster of differentiation 36 and AMP-activated protein kinase-α1 in the liver, increased glucose oxidation in the light phase, and overall reduced basal glucose levels. To verify the impact of InsR deletion in LepR cells in obesity, we generated ob/ ob InsRfl, ob/ ob LRcre, and ob/ ob LRΔInsR mice. The ob/ ob LRΔInsR mice had higher body weight, fat mass, and expression of genes related to fat metabolism in the liver. No difference in food intake despite increased neuropeptide Y and agouti-related peptide expression, and no difference in energy expenditure, fat, or glucose oxidation was found in ob/ ob LRΔInsR compared with LRcre or LRΔInsR controls. Remarkably, basal glucose levels were reduced, and the expression of genes associated with glucose metabolism in the liver was higher. Insulin signaling in LepR cells is required for the proper fat and glucose oxidation. These effects are independent of leptin given that the leptin-deficient ob/ ob LRΔInsR mice also presented reduced glycemia and higher adiposity. The mechanisms underlying these responses remain to be unveiled.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Leptina/metabolismo , Neurônios/metabolismo , Obesidade/metabolismo , Receptor de Insulina/genética , Receptores para Leptina/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antígenos CD36/metabolismo , Metabolismo Energético , Feminino , Deleção de Genes , Homeostase , Hiperinsulinismo/metabolismo , Hipotálamo/citologia , Hipotálamo/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos ObesosRESUMO
Dietary supplementation with melinjo (Gnetum gnemon L.) seed extract (MSE) has been proposed as an anti-obesity strategy. However, it remains unclear how MSE modulates energy balance. We tested the hypothesis that dietary MSE reduces energy intake and/or increases physical activity and metabolic thermogenesis in brown and white adipose tissue (BAT and WAT) in mice. Twenty-four C57BL/6 J mice were provided with normal diet, high-fat diet (HFD), or HFD with 1% MSE added, for 17â¯weeks. Food intake, spontaneous locomotor activity, hepatic triglyceride (TG) content, and blood parameters were examined. Mitochondrial thermogenesis-associated molecule and inflammatory marker expression levels in BAT and WAT were examined by quantitative PCR and western blotting. Dietary MSE did not affect energy intake or spontaneous locomotor activity, but significantly suppressed HFD-induced fat accumulation, hyperglycemia, and hyperinsulinemia. Homeostasis model assessment of insulin resistance score and hepatic TG content were both lower in the MSE-supplemented HFD-fed group than in the HFD-fed group, indicating reduced insulin resistance and a less fatty liver. Dietary MSE upregulated thermogenic uncoupling protein 1 (UCP1) and mitochondrial marker cytochrome c oxidase subunit IV protein expression in BAT; this was closely associated with sirtuin 1 mRNA induction. mRNAs of adipose inflammatory markers, such as monocyte chemotactic 1 and interleukin-1, were induced by HFD but suppressed by MSE. Considering that UCP1 protein expression is the most physiologically relevant parameter to assess the thermogenic capacities of BAT, our results indicate that dietary MSE supplementation induces BAT thermogenesis and reduces obesity-associated adipose tissue inflammation, hepatic steatosis, and insulin resistance.
Assuntos
Tecido Adiposo Marrom/metabolismo , Gnetum , Inflamação/metabolismo , Resistência à Insulina , Obesidade/metabolismo , Extratos Vegetais/farmacologia , Proteína Desacopladora 1/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Dieta Hiperlipídica , Suplementos Nutricionais , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Hiperglicemia/metabolismo , Hiperglicemia/prevenção & controle , Hiperinsulinismo/metabolismo , Hiperinsulinismo/prevenção & controle , Inflamação/etiologia , Inflamação/prevenção & controle , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Obesidade/etiologia , Obesidade/prevenção & controle , Extratos Vegetais/uso terapêutico , Sementes , Sirtuína 1/metabolismo , Termogênese/efeitos dos fármacos , Triglicerídeos/metabolismoRESUMO
Context: Obesity-related hyperinsulinism may impede lifestyle-initiated weight loss. Objective: Proof-of-concept study to investigate the amplifying effects of diazoxide (DZX)-mediated insulin suppression on lifestyle-induced weight loss in nondiabetic, hyperinsulinemic, obese men. Design: Twelve-month study comprising an initial 6-month, double-blind trial, followed by a partially de-blinded 6-month extension in men with obesity with a body mass index of 30 to 37.5 kg/m2 and a fasting serum C-peptide level >1.00 nM. Patients were randomized into three treatment groups: DZX + placebo (DZX + PL), DZX + metformin (DZX + MTF), and double PL (PL + PL). Results: At 6 months, DZX treatment was associated with a 6.1-kg PL-subtracted decline in fat mass (FM), and at 12 months, FM had decreased by a total of 15.7 ± 2.5 kg. Twelve months of DZX treatment was also associated with a significant decline in systolic (-6.6%) and diastolic (-8.6%) blood pressure and low-density lipoprotein-cholesterol (-18%) and triglycerides (-43%) and a 39% rise in high-density lipoprotein-cholesterol. These effects were achieved at the cost of a small rise in fasting glucose (95% CI: 0.2 to 1.0 mM) and hemoglobin A1c (95% CI: -0.08% to 0.44%). There were no differences between DZX monotherapy and the combination of DZX + MTF. Conclusion: High-dose DZX treatment of 1 year resulted in a substantial decrease in FM, blood pressure, and lipid levels at the cost of a small rise in blood glucose levels.
Assuntos
Diazóxido/administração & dosagem , Estilo de Vida Saudável/fisiologia , Hiperinsulinismo/terapia , Antagonistas da Insulina/administração & dosagem , Obesidade/terapia , Redução de Peso/efeitos dos fármacos , Adulto , Glicemia/análise , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Diazóxido/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/epidemiologia , Hiperglicemia/prevenção & controle , Hiperinsulinismo/sangue , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Hipoglicemiantes/administração & dosagem , Insulina/sangue , Insulina/metabolismo , Antagonistas da Insulina/efeitos adversos , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Obesidade/metabolismo , Canais de Potássio/agonistas , Canais de Potássio/metabolismo , Resultado do Tratamento , Redução de Peso/fisiologiaRESUMO
SCOPE: Hepatic LDL receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) regulate the clearance of plasma LDL-cholesterol (LDL-C): LDLR promotes it, and PCSK9 opposes it. These proteins also express in pancreatic ß cells. Using cultured hepatocytes, we previously showed that the plant flavonoid quercetin-3-glucoside (Q3G) inhibits PCSK9 secretion, stimulated LDLR expression, and enhanced LDL-C uptake. Here, we examine whether Q3G supplementation could reverse the hyperlipidemia and hyperinsulinemia of mice fed a high-cholesterol diet, and how it affects hepatic and pancreatic LDLR and PCSK9 expression. METHODS AND RESULTS: For 12 weeks, mice are fed a low- (0%) or high- (1%) cholesterol diet (LCD or HCD), supplemented or not with Q3G at 0.05 or 0.1% (w/w). Tissue LDLR and PCSK9 is analyzed by immunoblotting, plasma PCSK9 and insulin by ELISA, and plasma cholesterol and glucose by colorimetry. In LCD-fed mice, Q3G has no effect. In HCD-fed mice, it attenuates the increase in plasma cholesterol and insulin, accentuates the decrease in plasma PCSK9, and increases hepatic and pancreatic LDLR and PCSK9. In cultured pancreatic ß cells, however, it stimulates PCSK9 secretion. CONCLUSION: In mice, dietary Q3G could counter HCD-induced hyperlipidemia and hyperinsulinemia, in part by oppositely modulating hepatic and pancreatic PCSK9 secretion.
Assuntos
Hiperlipidemias/prevenção & controle , Hipolipemiantes/uso terapêutico , Fígado/metabolismo , Pâncreas/metabolismo , Pró-Proteína Convertase 9/metabolismo , Quercetina/análogos & derivados , Receptores de LDL/metabolismo , Animais , Linhagem Celular Tumoral , Colesterol na Dieta/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Regulação da Expressão Gênica , Transportador de Glucose Tipo 2/agonistas , Transportador de Glucose Tipo 2/antagonistas & inibidores , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Hiperinsulinismo/sangue , Hiperinsulinismo/metabolismo , Hiperinsulinismo/patologia , Hiperinsulinismo/prevenção & controle , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hipolipemiantes/administração & dosagem , Hipolipemiantes/efeitos adversos , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Especificidade de Órgãos , Pâncreas/patologia , Pró-Proteína Convertase 9/sangue , Pró-Proteína Convertase 9/genética , Quercetina/administração & dosagem , Quercetina/efeitos adversos , Quercetina/uso terapêutico , Receptores de LDL/genéticaRESUMO
PURPOSE: Sirtuin 1 may regulate glucose and lipid metabolism. We aimed to assess adipose tissue and skeletal muscle sirtuin 1 expression in relation to insulin sensitivity, the expression of proinflammatory and metabolic genes, and to study the regulation of sirtuin 1 expression by hyperinsulinemia and circulating free fatty acids elevation. METHODS: We examined 60 normal-weight, 42 overweight and 15 obese young subjects. The hyperinsulinemic-euglycemic clamp technique was applied throughout to measure insulin sensitivity. In 20 subjects, two 6 h clamps were performed, one of them with concurrent Intralipid/heparin infusion. Biopsies of subcutaneous adipose tissue and skeletal muscle were collected for the measurement of gene and protein expression. RESULTS: Obese subjects had lower adipose sirtuin 1 in comparison with normal-weight and overweight participants. Muscle sirtuin 1 did not differ between the groups. Adipose tissue sirtuin 1 was related to insulin sensitivity, adipose tissue SLC2A4. The relationship between adipose tissue sirtuin 1 and insulin sensitivity was still present after controlling for BMI, however, it disappeared after controlling for adipose tissue SLC2A4. Muscle sirtuin 1 was not related to insulin sensitivity. Hyperisulinemia decreased adipose tissue and increased muscle sirtuin 1 expression. Intralipid/heparin infusion negated these effects. CONCLUSIONS: Adipose tissue, but not muscle, sirtuin 1 is associated with insulin sensitivity in humans, possibly because of its correlation with adipose tissue SLC2A4 expression. Insulin differentially regulates adipose tissue and skeletal muscle sirtuin 1 expression in the short-term and circulating free fatty acids elevation negates these effects, which may be associated with lipid-induced insulin resistance.
Assuntos
Tecido Adiposo/metabolismo , Resistência à Insulina , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Sirtuína 1/metabolismo , Adiponectina/metabolismo , Adolescente , Adulto , Peso Corporal , Emulsões , Ácidos Graxos não Esterificados/sangue , Transportador de Glucose Tipo 4/metabolismo , Heparina , Humanos , Hiperinsulinismo/metabolismo , Masculino , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosfolipídeos , Óleo de Soja , Adulto JovemRESUMO
In vivo and in vitro studies suggested that chromium enhances insulin sensitivity by promoting insulin receptor signaling. However, its effect on insulin clearance has not been yet identified. Nigella sativa, a widely used spice, possesses an antidiabetic activity. We, therefore, hypothesized that chromium picolinate may alter insulin clearance by modulating insulin-degrading enzyme (IDE) in insulin-resistant rats. We evaluated also the effect of Nigella sativa oil on insulin signaling and degradation with respect to chromium picolinate. To assess these hypotheses, insulin resistance was induced in 30 male Wistar albino rats through daily oral administration of high-fructose water (HFW, 20% w/v) for 45 days. These rats were then divided into three groups (n = 10/group). They were given either no treatment (control group) or Nigella sativa oil (500 mg/kg bw/day) or chromium picoloinate (200 µg/kg bw/day) orally along with HFW (20% w/v) for 45 days. Nigella sativa oil or chromium picolinate concurrent administration with HFW significantly decreased body weight, serum lipids, glucagon, insulin resistance, and hepatic IDE level but increased its mRNA expression and insulin receptor phosphorlyation as well as high-density lipoprotein cholesterol (HDL-C) level as compared to control group values, suggesting their potential as modulators for insulin signaling and clearance. However, Nigella sativa oil exerted better improvement in feeding efficacy ratio as well as the levels of glucagon, insulin, insulin resistance, hepatic IDE level and insulin receptor phosphorylation than chromium picolinate, suggesting its greater insulin sensitizing capacity. Our data, for the first time, prove that Nigella sativa oil and chromium picolinate monotherapy can reduce fructose-induced insulin resistance by reduction of hepatic IDE protein and activation of insulin receptor signaling.
Assuntos
Frutose/toxicidade , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/tratamento farmacológico , Insulina/metabolismo , Insulisina/metabolismo , Nigella sativa/química , Ácidos Picolínicos/uso terapêutico , Óleos de Plantas/uso terapêutico , Animais , Hiperinsulinismo/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
Alpha-lipoic acid (ALA) is known to lower insulin resistance (IR), which is common among migraineurs. To assess the effect of ALA on headache in migraineurs with IR, we performed an exploratory study on a cohort of patients with migraine, followed at our Headache Center. The 32 patients took ALA 400 mg b.i.d. for 6 months in addition to their on-going treatment. The percentage of patients with a reduction of at least 50% of the attacks was 0.53 (confidence interval [95% CI] 0.36-0.70) at 2 months, 0.56 (0.39-0.73) at 4 months, and 0.69 (0.53-0.85) at 6 months. The incidence rate ratio of attacks at 6 months versus baseline was 0.48 (0.43-0.53, P < .001), corresponding to a mean (95% CI) number of attacks of 5 (4-6) versus 11 (10-12). The number of days of treatment in the previous month was 7.7 (6.8-8.7) at baseline, 5.4 (4.6-6.2) at 2 months, 5.3 (4.5-6.1) at 4 months, and 4.3 (3.6-5.0) at 6 months. Baseline and 120-min glucose and insulin and quantitative insulin sensitivity check index (QUICKI) and the Stumvoll index did not change at 6 months versus baseline. This exploratory study shows that the administration of ALA may be associated with a reduction in the number of attacks and the days of treatment in migraineurs with IR. A randomized controlled trial is needed to test this possibility.
Assuntos
Antioxidantes/uso terapêutico , Hiperinsulinismo/dietoterapia , Resistência à Insulina , Enxaqueca com Aura/dietoterapia , Enxaqueca sem Aura/dietoterapia , Ácido Tióctico/uso terapêutico , Adulto , Biomarcadores/sangue , Glicemia/análise , Estudos de Coortes , Terapia Combinada , Feminino , Seguimentos , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/complicações , Hiperinsulinismo/metabolismo , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Enxaqueca com Aura/complicações , Enxaqueca com Aura/fisiopatologia , Enxaqueca com Aura/terapia , Enxaqueca sem Aura/complicações , Enxaqueca sem Aura/fisiopatologia , Enxaqueca sem Aura/terapia , Ambulatório Hospitalar , Índice de Gravidade de DoençaRESUMO
CONTEXT: We have previously shown that an antidepressant-like effect of probiotics in rats was associated with a higher plasma level of the microbial tryptophan metabolite indole-3-propionic acid (IPA). OBJECTIVE: We therefore wanted to study the isolated effect of IPA on behaviour and glucose metabolism in rats. METHODS: Male Sprague-Dawley rats were fed control or IPA-enriched diet for six weeks (n = 12 per group) and assessed in the elevated plus maze, open field and forced swim test. Blood glucose, metabolic hormones and the white blood cell (WBC) composition were analysed. RESULTS: IPA (mean intake 27.3 mg/kg/day) significantly lowered fasting blood glucose level by 0.42 mM (95% CI 0.11-0.73). Similarly, fasting plasma insulin levels and the homeostatic model assessment (HOMA) index of insulin resistance were reduced, whereas plasma metabolic hormones, behaviour and WBC composition remained unaffected by IPA. CONCLUSIONS: Our findings highlight IPA as a promising candidate for treatment of metabolic disorders associated with insulin resistance.
Assuntos
Suplementos Nutricionais , Hiperinsulinismo/prevenção & controle , Hipoglicemiantes/uso terapêutico , Indóis/uso terapêutico , Resistência à Insulina , Estado Pré-Diabético/prevenção & controle , Propionatos/uso terapêutico , Animais , Ansiedade/sangue , Ansiedade/imunologia , Ansiedade/metabolismo , Ansiedade/prevenção & controle , Comportamento Animal , Glicemia/análise , Depressão/sangue , Depressão/imunologia , Depressão/metabolismo , Depressão/prevenção & controle , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Suplementos Nutricionais/efeitos adversos , Hiperinsulinismo/sangue , Hiperinsulinismo/imunologia , Hiperinsulinismo/metabolismo , Hipoglicemiantes/efeitos adversos , Indóis/efeitos adversos , Insulina/sangue , Contagem de Leucócitos , Masculino , Estado Pré-Diabético/sangue , Estado Pré-Diabético/imunologia , Estado Pré-Diabético/metabolismo , Propionatos/efeitos adversos , Distribuição Aleatória , Ratos Sprague-DawleyRESUMO
Alzheimer's disease (AD) is progressive neurodegenerative disorder characterized by accumulation of senile plaques, neurofibrillary tangles (NFT) and neurodegeneration. The diabetes mellitus (DM) is one of the risk factors for AD pathogenesis by impairment in insulin signaling and glucose metabolism in central as well as peripheral system. Insulin resistance, impaired glucose and lipid metabolism are leading to the Aß (Aß) aggregation, Tau phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, memory impairment and also mark over Aß transport through central to peripheral and vice versa. Several pathways, like enzymatic degradation of Aß, forkhead box protein O1 (FOXO) signaling, insulin signaling shared common pathological mechanism for both AD and DM. Recent evidence showed that hyperinsulinemia and hyperglycemia affect the onset and progression of AD differently. Some researchers have suggested that hyperglycemia influences vascular tone, while hyperinsulinemia may underlie mitochondrial deficit. The objective of this review is to determine whether existing evidence supports the concept that impairment in insulin signaling and glucose metabolism play an important role in pathogenesis of AD. In the first part of this review, we tried to explain the interconnecting link between AD and DM, whereas the second part includes more information on insulin resistance and its involvement in AD pathogenesis. In the final part of this review, we have focused more toward the AD treatment by targeting insulin signaling like anti-diabetic, antioxidant, nutraceuticals and dietary supplements. To date, more researches should be done in this field in order to explore the pathways in insulin signaling, which might ameliorate the treatment options and reduce the risk of AD due to DM.
Assuntos
Doença de Alzheimer/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Humanos , Hiperinsulinismo/metabolismo , Resistência à Insulina/fisiologia , Estresse Oxidativo , Fosforilação , Risco , Fatores de Risco , Transdução de Sinais , Proteínas tau/metabolismoRESUMO
Growth factor signaling via insulin receptor (IR) and IGF-1 receptor (IGF1R) plays several important roles in the pathogenesis of metabolic syndrome and diabetes. OSI-906 (linsitinib), an anti-tumor drug, is an orally bioavailable dual inhibitor of IR and IGF1R. To investigate the recovery from metabolic changes induced by the acute inhibition of IR and IGF1R in adult mice, mice were treated with OSI-906 or a vehicle for 7 days and the results were analyzed on the last day of injection (Day 7) or after 7 or 21 days of withdrawal (Day 14 or Day 28). On day 7, the visceral white fat mass was significantly reduced in mice treated with OSI-906 accompanied by a reduced expression of leptin and an increased expression of the lipolysis-related genes Lpl and Atgl. Interestingly, the lipoatrophy and the observed changes in gene expression were completely reversed on day 14. Similarly, liver steatosis and ß cell proliferation were transiently observed on day 7 but had disappeared by day 14. Taken together, these results suggest that this model for the acute inhibition of systemic IR/IGF1R signaling may be useful for investigating the recovery from metabolic disorders induced by impaired growth factor signaling.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/metabolismo , Imidazóis/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Lipodistrofia/metabolismo , Pirazinas/farmacologia , Animais , Proliferação de Células , Suplementos Nutricionais , Fígado Gorduroso/sangue , Fígado Gorduroso/diagnóstico , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Hiperinsulinismo/sangue , Hiperinsulinismo/metabolismo , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Imidazóis/administração & dosagem , Leptina/administração & dosagem , Lipodistrofia/sangue , Lipodistrofia/diagnóstico , Camundongos , Pirazinas/administração & dosagem , Retirada de Medicamento Baseada em Segurança , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
Toll-like receptor 4 (TLR4) plays an essential role in innate immunity through inflammatory cytokine induction. Recent studies demonstrated that the abnormal activation of TLR4 has a pivotal role in obesity-induced inflammation, which is associated with several diseases, including hyperinsulinemia, hypertriglyceridemia, and cardiovascular disease. Here we demonstrate that (-)-epigallocatechin-3-O-gallate, a natural agonist of the 67-kDa laminin receptor (67LR), suppressed TLR4 expression through E3 ubiquitin-protein ring finger protein 216 (RNF216) up-regulation. Our data indicate cyclic GMP mediates 67LR agonist-dependent RNF216 up-regulation. Moreover, we show that the highly absorbent 67LR agonist (-)-epigallocatechin-3-O-(3-O-methyl)-gallate (EGCG3â³Me) significantly attenuated TLR4 expression in the adipose tissue. EGCG3â³Me completely inhibited the high-fat/high-sucrose (HF/HS)-induced up-regulation of tumor necrosis factor α in adipose tissue and serum monocyte chemoattractant protein-1 increase. Furthermore, this agonist intake prevented HF/HS-induced hyperinsulinemia and hypertriglyceridemia. Taken together, 67LR presents an attractive target for the relief of obesity-induced inflammation.