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1.
Br J Radiol ; 92(1102): 20181051, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31322913

RESUMO

OBJECTIVE: To determine whether the apparent diffusion coefficient (ADC) on 3T MR imaging including diffusion-weighted MR imaging (DWI) correlate with the standardized uptake value (SUV) on 18F-FDG PET/CT in musculoskeletal tumours. METHODS: This retrospective cohort study included 57 patients (36 males, 21 females, mean age 54 years, range 12-90 years) with pathologically confirmed soft tissue (n = 32) and bone (n = 25) tumours who underwent 3T MR imaging including DWI and whole-body 18F-FDG PET/CT before treatment. 14 patients had follow-up MR imaging and 18F-FDG PET/CT after treatment. The minimum (ADCmin) and mean (ADCmean) ADCs of musculoskeletal tumour, ADC of normal skeletal muscle (ADCmus), SUVmax and SUVmean of musculoskeletal tumour were obtained. Correlation between ADCs and SUVs was assessed using Pearson correlation coefficients (r). ADCmin and SUVmax were compared between pretreatment and posttreatment by t-test. RESULTS: There was inverse correlation between SUVmax and the ratio ADCmin/ADCmus (r = - 0.505 to - 0.495, p ≤ 0.001) and between SUVmean and the ratio ADCmean/ADCmus (r = - 0.501 to - 0.493, p = 0.001). After treatment ADC was significantly increased whereas SUV was significantly decreased (p = 0.001). There was significant correlation in percent change between the initial and follow-up values of ADCmin and SUVmax (r = 0.750 to 0.773, p ≤ 0.005). The ADCmin was increased by 163% and SUVmax was decreased by 61% in 11 patients with treatment response. CONCLUSION: ADC at 3T MR DWI and SUV at 18F-FDG PET/CT have an inverse correlation in musculoskeletal tumours. ADVANCES IN KNOWLEDGE: Our study showed that ADC at 3T DWI and SUV at 18F-FDG PET/CT had an inverse correlation in musculoskeletal tumours.


Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/metabolismo , Imagem de Difusão por Ressonância Magnética/métodos , Fluordesoxiglucose F18/metabolismo , Neoplasias Musculares/diagnóstico por imagem , Neoplasias Musculares/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/patologia , Criança , Feminino , Glucose/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/patologia , Variações Dependentes do Observador , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
2.
PLoS One ; 14(7): e0217712, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31306426

RESUMO

Glycoconjugation to target the Warburg effect provides the potential to enhance selective uptake of anticancer or imaging agents by cancer cells. A Warburg effect targeting group, rationally designed to facilitate uptake by glucose transporters and promote cellular accumulation due to phosphorylation by hexokinase (HK), has been synthesised. This targeting group, the C2 modified glucose analogue 2-(2-[2-(2-aminoethoxy)ethoxy]ethoxy)-D-glucose, has been conjugated to the fluorophore nitrobenzoxadiazole to evaluate its effect on uptake and accumulation in cancer cells. The targeting vector has demonstrated inhibition of glucose phosphorylation by HK, indicating its interaction with the enzyme and thereby confirming the potential to facilitate an intracellular trapping mechanism for compounds it is conjugated with. The cellular uptake of the fluorescent analogue is dependent on the glucose concentration and is so to a greater extent than is that of the widely used fluorescent glucose analogue, 2-NBDG. It also demonstrates selective uptake in the hypoxic regions of 3D spheroid tumour models whereas 2-NBDG is distributed primarily through the normoxic regions of the spheroid. The increased selectivity is consistent with the blocking of alternative uptake pathways.


Assuntos
4-Cloro-7-nitrobenzofurazano/análogos & derivados , Desoxiglucose/análogos & derivados , Sistemas de Liberação de Medicamentos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glucose , Hexoquinase/metabolismo , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Neoplasias , 4-Cloro-7-nitrobenzofurazano/farmacocinética , 4-Cloro-7-nitrobenzofurazano/farmacologia , Hipóxia Celular , Linhagem Celular Tumoral , Desoxiglucose/farmacocinética , Desoxiglucose/farmacologia , Glucose/farmacocinética , Glucose/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia
3.
Planta Med ; 85(9-10): 729-737, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31167298

RESUMO

Rotundic acid and pedunculoside are the most abundant constituents in Ilicis Rotundae Cortex, and possess lipid-lowering activity. In this study, we evaluated the pharmacokinetic interactions of rotundic acid with pedunculoside and other ingredients from Ilicis Rotundae Cortex with rotundic acid and pedunculoside, and preliminarily investigated the effects of gut microbiota on their pharmacokinetics using a pseudo-germ-free rat model. After a single oral administration of each monomer, a monomer mixture, and Ilicis Rotundae Cortex extract to the conventional and pseudo-germ-free rats, rotundic acid and pedunculoside were quantified in plasma by an UPLC/Q-TOF-MS/MS method. The systemic exposure (maximum plasma concentration and area under concentration-time curve) of two analytes in conventional rats were increased in an approximately dose-dependent manner. Oral administration of rotundic acid and pedunculoside in the forms of a monomer mixture and Ilicis Rotundae Cortex extract to the conventional rats significantly decreased the systemic exposure compared with the monomer groups, which demonstrated the existence of significant pharmacokinetic interactions. The pseudo-germ-free rats were prepared by nonabsorbable antibiotic treatment, and the systemic exposure of two analytes were significantly decreased and most of the "time to reach the maximum" values were delayed in comparison to conventional rats, therefore gut microbiota might serve as an efficient absorption promoter. These results provide a scientific basis for the clinical application of the two bioactive constituents and Ilicis Rotundae Cortex.


Assuntos
Microbioma Gastrointestinal/fisiologia , Glucose/análogos & derivados , Triterpenos/farmacocinética , Administração Oral , Animais , Calibragem , Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Microbioma Gastrointestinal/efeitos dos fármacos , Glucose/administração & dosagem , Glucose/farmacocinética , Interações Ervas-Drogas , Masculino , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos , Triterpenos/administração & dosagem
4.
IET Nanobiotechnol ; 13(2): 226-229, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31051455

RESUMO

Diabetes mellitus has been considered as a heterogeneous metabolic disorder characterised by complete or relative impairment in the production of insulin by pancreatic ß-cells or insulin resistance. In the present study, propanoic acid, an active biocomponent isolated from Cassia auriculata is employed for the synthesis of propanoic acid functionalised gold nanoparticles (Pa@AuNPs) and its anti-diabetic activity has been demonstrated in vitro. In vitro cytotoxicity of synthesised Pa@AuNPs was performed in L6 myotubes. The mode of action of Pa@AuNPs exhibiting anti-diabetic potential was validated by glucose uptake assay in the presence of Genistein (insulin receptor tyrosine kinase inhibitor) and Wortmannin (Phosphatidyl inositide kinase inhibitor). Pa@AuNPs exhibited significant glucose uptake in L6 myotubes with maximum uptake at 50 ng/ml. Assays were performed to study the potential of Pa@AuNPs in the inhibition of protein-tyrosine phosphatase 1B, α-glucosidases, and α-amylase activity.


Assuntos
Glucose/metabolismo , Glucose/farmacocinética , Ouro/farmacologia , Hipoglicemiantes/farmacologia , Nanopartículas Metálicas/química , Nanocompostos/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ouro/química , Ouro/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Ratos
5.
Eur J Clin Invest ; 49(7): e13120, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31002171

RESUMO

BACKGROUND: Disturbances in adipose tissue glucose uptake may play a role in the pathogenesis of type 2 diabetes, yet its examination by 2-deoxy-2-[18 F]fluorodeoxyglucose ([18 F]FDG) PET/CT is challenged by relatively low uptake kinetics. We tested the hypothesis that performing [18 F]FDG PET/CT during a hypoglycaemic clamp would improve adipose tissue tracer uptake to allow specific comparison of adipose tissue glucose handling between people with or without type 2 diabetes. DESIGN: We enrolled participants with or without diabetes who were at least overweight, to undergo a hyperinsulinaemic hypoglycaemic clamp or a hyperinsulinaemic euglycaemic clamp (n = 5 per group). Tracer uptake was quantified using [18 F]FDG PET/CT. RESULTS: Hypoglycaemic clamping increased [18 F]FDG uptake in visceral adipose tissue of healthy participants (P = 0.002). During hypoglycaemia, glucose uptake in visceral adipose tissue of type 2 diabetic participants was lower as compared to healthy participants (P < 0.0005). No significant differences were observed in skeletal muscle, liver or pancreas. CONCLUSIONS: The present findings indicate that [18 F]FDG PET/CT during a hypoglycaemic clamp provides a promising new research tool to evaluate adipose tissue glucose metabolism. Using this method, we observed a specific impairment in visceral adipose tissue [18 F]FDG uptake in type 2 diabetes, suggesting a previously underestimated role for adipose tissue glucose handling in type 2 diabetes.


Assuntos
Tecido Adiposo/metabolismo , Hipoglicemia/diagnóstico por imagem , Tecido Adiposo/diagnóstico por imagem , Adulto , Glicemia/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Fluordesoxiglucose F18/farmacocinética , Glucose/administração & dosagem , Glucose/farmacocinética , Humanos , Hipoglicemia/metabolismo , Hipoglicemiantes/administração & dosagem , Masculino , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Edulcorantes/administração & dosagem , Edulcorantes/farmacocinética
6.
Math Biosci Eng ; 16(3): 1082-1114, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30947410

RESUMO

Non-alcoholic fatty liver disease is the most common cause of chronic liver disease. Precipitated by the build up of extra fat in the liver not caused by alcohol, it is still not understood why steatosis occurs where it does in the liver microstructure in non-alcoholic fatty liver disease. It is likely, however, that the location of steatosis is due, at least in part, to metabolic zonation (heterogeneity among liver cells in function and enzyme expression). Recently, there has been an influx of computational and mathematical models in order to investigate the relationship between metabolic zonation and steatosis in non-alcoholic fatty liver disease. Of interest among these models are "compartments-in-series" models. Compartments-in-series models include the spatial distribution of metabolite concentrations via series of compartments that are connected through some representation of blood flow. In this paper, we analyze one such model, focusing specifically at how the number of compartments and inclusion of dispersion in the flow affect simulation results. We find the number of compartments to have a much larger effect than the inclusion of dispersion, however this is likely due to numerical artifacts. Overall, we conclude that considering partial differential equations that are equivalent to compartments-in-series models would be beneficial both in computation and in theoretical analyses.


Assuntos
Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Tecido Adiposo/metabolismo , Alimentos , Glucose/farmacocinética , Hepatócitos/metabolismo , Humanos , Insulina/metabolismo , Metabolismo dos Lipídeos , Lipólise , Fígado/irrigação sanguínea , Modelos Biológicos , Hepatopatia Gordurosa não Alcoólica/metabolismo
7.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(7): 1031-1038, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30980919

RESUMO

Decreased levels of the δ isozyme of diacylglycerol kinase (DGK) in skeletal muscle attenuate glucose uptake and, consequently, are critical for the pathogenesis of type 2 diabetes. We recently found that free myristic acid (14:0), but not free palmitic acid (16:0), increased the DGKδ protein levels and enhanced glucose uptake in C2C12 myotube cells. However, it has been unclear how myristic acid regulates the level of DGKδ2 protein. In the present study, we characterized the myristic acid-dependent increase of DGKδ protein. A cycloheximide chase assay demonstrated that myristic acid, but not palmitic acid, markedly stabilized DGKδ protein. Moreover, other DGK isozymes, DGKη and ζ, as well as glucose uptake-related proteins, such as protein kinase C (PKC) α, PKCζ, Akt and glycogen synthase kinase 3ß, failed to be stabilized by myristic acid. Furthermore, DGKδ was not stabilized in cultured hepatocellular carcinoma cells, pancreas carcinoma cells or neuroblastoma cells, and only a moderate stabilizing effect was observed in embryonic kidney cells. A proteasome inhibitor and a lysosome inhibitor, MG132 and chloroquine, respectively, partly inhibited DGKδ degradation, suggesting that myristic acid prevents, at least in part, the degradation of DGKδ by the ubiquitin-proteasome system and the autophagy-lysosome pathway. Overall, these results strongly suggest that myristic acid attenuates DGKδ protein degradation in skeletal muscle cells and that this attenuation is fatty acid-, protein- and cell line-specific. These new findings provide novel insights into the molecular mechanisms of the pathogenesis of type 2 diabetes mellitus.


Assuntos
Diacilglicerol Quinase/metabolismo , Músculo Esquelético/citologia , Ácido Mirístico/farmacologia , Estabilidade Proteica/efeitos dos fármacos , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/etiologia , Glucose/farmacocinética , Humanos , Isoenzimas/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Proteólise/efeitos dos fármacos
8.
Zygote ; 27(2): 69-77, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30834849

RESUMO

SummaryDirect swim-up procedure is widely used to separate the motile competent spermatozoa from the antioxidant-rich semen. Subsequently, spermatozoa become more vulnerable to reactive oxygen species (ROS) due to their cytological characteristics. The effect of vitamin C, a highly concentrated antioxidant in the semen, on direct swim-up-enriched sperm population is not fully investigated. Therefore, the aim of the present study was to assess the effect of vitamin C on sperm functional properties during direct swim-up procedure. Semen samples were collected from 22 participants. Each semen sample was divided into several aliquots. The first portion was overlaid with sperm medium without ascorbic acid (0 µM AA). The second and third fractions were overlaid with sperm medium supplemented with 300 µM and 600 µM AA; respectively. After 1 h of incubation, basic sperm parameters, intracellular ROS levels, acrosome reaction, chromatin integrity, and glucose uptake were assessed. Swim-up without AA significantly increased the percentage of ROS(+) spermatozoa compared with the raw semen (P<0.01). Interestingly, swim-up with 300 µM AA did not increase the percentage of ROS(+) sperm compared with the raw semen. In parallel, the percentage of sperm with altered chromatin integrity was significantly lower in the 300 µM AA group compared with that in the raw semen (P<0.05). These findings suggest that supplementation of vitamin C to sperm medium could be beneficial for direct swim-up-derived spermatozoa.


Assuntos
Ácido Ascórbico/farmacologia , Separação Celular/métodos , Espermatozoides/fisiologia , Reação Acrossômica , Adulto , Ácido Ascórbico/administração & dosagem , Cromatina/patologia , Meios de Cultura/química , Meios de Cultura/farmacologia , Relação Dose-Resposta a Droga , Glucose/farmacocinética , Humanos , Masculino , Espécies Reativas de Oxigênio/metabolismo , Sêmen/fisiologia , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos
9.
Gastroenterology ; 156(6): 1627-1641.e1, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30742833

RESUMO

BACKGROUND & AIMS: Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) induce substantial weight loss and improve glycemic control in patients with type 2 diabetes, but it is not clear whether these occur via the same mechanisms. We compared absorption rates of glucose and protein, as well as profiles of gastro-entero-pancreatic hormones, in patients who had undergone SG or RYGB vs controls. METHODS: We performed a cross-sectional study of 12 patients who had undergone sleeve gastrectomy, 12 patients who had undergone RYGB, and 12 individuals who had undergone neither surgery (controls), all in Denmark. Study participants were matched for body mass index, age, sex, and postoperative weight loss, and all had stable weights. They received continuous infusions of stable isotopes of glucose, glycerol, phenylalanine, tyrosine, and urea before and during a mixed meal containing labeled glucose and intrinsically phenylalanine-labeled caseinate. Blood samples were collected for 6 hours, at 10- to 60-minute intervals, and analyzed. RESULTS: The systemic appearance of ingested glucose was faster after RYGB and SG vs controls; the peak glucose appearance rate was 64% higher after RYGB, and 23% higher after SG (both P < .05); the peak phenylalanine appearance rate from ingested casein was 118% higher after RYGB (P < .01), but similar between patients who had undergone SG and controls. Larger, but more transient increases in levels of plasma glucose and amino acids were accompanied by higher secretion of insulin, glucagon-like peptide 1, peptide YY, and cholecystokinin after RYGB, whereas levels of ghrelin were lower after SG, compared with RYGB and controls. Total 6-hour oral recovery of ingested glucose and protein was comparable among groups. CONCLUSIONS: Postprandial glucose and protein absorption and gastro-entero-pancreatic hormone secretions differ after SG and RYGB. RYGB was characterized by accelerated absorption of glucose and amino acids, whereas protein metabolism after SG did not differ significantly from controls, suggesting that different mechanisms explain improved glycemic control and weight loss after these surgical procedures. ClinicalTrials.gov ID NCT03046186.


Assuntos
Gastrectomia/métodos , Derivação Gástrica/métodos , Hormônios Gastrointestinais/sangue , Glucose/metabolismo , Absorção Intestinal , Fenilalanina/metabolismo , Adulto , Anastomose em-Y de Roux , Glicemia/metabolismo , Caseínas/metabolismo , Colecistocinina/sangue , Estudos Transversais , Proteínas na Dieta/metabolismo , Feminino , Esvaziamento Gástrico , Grelina/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Glucose/farmacocinética , Glicerol/sangue , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Peptídeo YY/sangue , Fenilalanina/sangue , Fenilalanina/farmacocinética , Período Pós-Prandial/fisiologia
10.
Diabet Med ; 36(5): 620-625, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30706538

RESUMO

AIM: To evaluate the association between skin advanced glycation end products and insulin resistance in Type 1 diabetes. METHODS: The study group consisted of 476 people with Type 1 diabetes (247 men) with a median (interquartile range) age of 42 (33-53) years, disease duration of 24 (19-32) years and HbA1c concentration of 63 (55-74) mmol/mol [7.9 (7.2-8.9)%]. Insulin resistance was assessed according to estimated glucose disposal rate. Advanced glycation product accumulation in the skin was measured by autofluorescence using an AGE Reader. The group was divided into three subgroups based on estimated glucose disposal rate tertiles (<5.5, 5.5-9.5 and >9.5 mg/kg/min, respectively). The higher the estimated glucose disposal rate, the lower the insulin resistance. RESULTS: Skin autofluoresence level decreased with increasing estimated glucose disposal rate; comparing people below the lower tertile, with those between the first and third tertiles, and with those above the third tertile, the median autofluoresences were, respectively: 2.5 (2.2-2.9) vs 2.3 (2.0-2.7) vs 2.1 (1.9-2.5) AU (P<0.0001). A negative correlation was observed between skin autofluorescence and estimated glucose disposal rate (Spearman's correlation coefficient=-0.31, P <0.001). Multiple logistic regression showed a significant, two-way association of insulin resistance with skin autofluorescence. CONCLUSION: The results of this study offer strong evidence for a two-way relationship between insulin resistance and advanced glycation product accumulation in the skin in people with Type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Resistência à Insulina/fisiologia , Pele/metabolismo , Adulto , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/diagnóstico , Angiopatias Diabéticas/metabolismo , Feminino , Fluorescência , Glucose/farmacocinética , Hemoglobina A Glicada/análise , Hemoglobina A Glicada/metabolismo , Produtos Finais de Glicação Avançada/análise , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Óptica , Valor Preditivo dos Testes , Fatores de Risco , Pele/química
11.
Appl Radiat Isot ; 145: 193-197, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30639637

RESUMO

BACKGROUND: The existence of saccharide-holmium complexes, containing mono or polysaccharide molecules, is an attractive hypothesis toward a radiation therapy (RT) with beta-emitters targeting high glucose metabolic human sites. To exam such hypothesis, the aim of this study was to investigate the possible chemical interactions of Ho and glucose molecules and if glucose may be a facilitator to holmium cell internalization based on in vitro uptake assays and mass spectrometry analyses. METHODS: The ionic-solution preparations were based on glucose-anhydrous and holmium-nitrate hydrated in aqueous solution, in non-radioactive condition. The uptakes in MDAMB231 cell lineage were evaluated, at 0 and 50 µg mL-1 holmium solution, in incubation times of 10, 30 and 50 min. The measurements of the holmium mass into the dried cell were evaluated by Neutron Activation Analysis - NAA method. Also, the ionic solution was tested in Electrospray Ionization Mass Spectrometry (ESI-MS) in order to identify Ho and glucose interactions. RESULTS: There were intracellular holmium-uptake in MDAMB-231 of 3.6 ±â€¯0.1, 6.8 ±â€¯0.2 and 9.7 ±â€¯0.3 µg increasing linearly with incubation time. The m/z ions at 523, 586, 649, 991 and 1054 were attributed to the positively loaded species containing Ho+3, glucose (GLU) and NO3-, making up the possible molecular compound formulae, involving Ho, GLU, and anions. CONCLUSIONS: The findings of the in vitro assay and the ESI-MS suggested a suitable holmium cell uptake, increased in function of incubation time, due to the presence of glucose and holmium chemical interactions in solution.


Assuntos
Hólmio/uso terapêutico , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/radioterapia , Linhagem Celular Tumoral , Feminino , Glucose/administração & dosagem , Glucose/farmacocinética , Hólmio/farmacocinética , Humanos , Análise de Ativação de Nêutrons , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Espectrometria de Massas por Ionização por Electrospray
12.
Biochem Biophys Res Commun ; 509(4): 994-1000, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30654941

RESUMO

Skeletal muscle performs 80% of the glucose metabolism in the body. Improvement of insulin resistance and prevention of diabetes by habitual exercise is considered beneficial due to the improved glucose uptake in skeletal muscles. Investigation of the mechanism by which skeletal muscles regulate glucose uptake can contribute to the prevention and treatment of diabetes. Myokines are a kind of cytokine secreted from skeletal muscle, which are expected to regulate muscle metabolism. Interleukin-15 (IL-15) is one such myokine that has been reported to improve glucose metabolism in vitro, although the mechanism remains unclear. In this study, we examined the glucose metabolism of skeletal muscle-specific IL-15 transgenic mice (IL-15TG), and investigated how IL-15 affects glucose metabolism in skeletal muscles. Although High Fat Diet-fed IL-15TG did not exhibit obvious difference in intraperitoneal insulin tolerance test, they had less impaired glucose tolerance compared to wild-type C57BL/6. Phosphorylation of AMP-activated protein kinase (AMPK), Akt substrate of 160 kDa (AS160), tre-2/USP6, BUB2, and cdc16 domain family member 1 (TBC1D1), and translocation of Glucose transporter type 4 (GLUT4) were accelerated in the skeletal muscle of IL-15TG. Our study demonstrated that overexpression of IL-15 in skeletal muscle improves glucose metabolism in skeletal muscle via AMPK pathway. We report the first in-vivo study that describes the signaling pathway of IL-15 in muscle glucose metabolism, and thereby contributes to the elucidation of the regulatory mechanism of muscle glucose metabolism by myokines.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Intolerância à Glucose/tratamento farmacológico , Transportador de Glucose Tipo 4/metabolismo , Interleucina-15/metabolismo , Músculo Esquelético/metabolismo , Animais , Transporte Biológico , Glucose/metabolismo , Glucose/farmacocinética , Resistência à Insulina , Interleucina-15/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Transdução de Sinais
13.
Diabetes Obes Metab ; 21(3): 640-647, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30370686

RESUMO

AIMS: The gastrointestinal tract, particularly the lower gut, may be key to the anti-diabetic action of metformin. We evaluated whether administration of metformin into the distal, vs the proximal, small intestine would be more effective in lowering plasma glucose by stimulating glucagon-like pepetide-1 (GLP-1) and/or slowing gastric emptying (GE) in type 2 diabetes (T2DM). MATERIALS AND METHODS: Ten diet-controlled T2DM patients were studied on three occasions. A transnasal catheter was positioned with proximal and distal infusion ports located 13 and 190 cm beyond the pylorus, respectively. Participants received infusions of (a) proximal + distal saline (control), (b) proximal metformin (1000 mg) + distal saline or (c) proximal saline + distal metformin (1000 mg) over 5 minutes, followed 60 minutes later by a glucose drink containing 50 g glucose and 150 mg 13 C-acetate. "Arterialized" venous blood and breath samples were collected over 3 hours for measurements of plasma glucose, GLP-1, insulin and glucagon, and GE, respectively. RESULTS: Compared with control, both proximal and distal metformin reduced plasma glucose and augmented GLP-1 responses to oral glucose comparably (P < 0.05 each), without affecting plasma insulin or glucagon. GE was slower after proximal metformin than after control (P < 0.05) and tended to be slower after distal metformin, without any difference between proximal and distal metformin. CONCLUSIONS: In diet-controlled T2DM patients, glucose-lowering via a single dose of metformin administered to the upper and lower gut was comparable and was associated with stimulation of GLP-1 and slowing of GE. These observations suggest that the site of gastrointestinal administration is not critical to the glucose-lowering capacity of metformin.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2 , Esvaziamento Gástrico/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/sangue , Glucose/administração & dosagem , Intestino Delgado/efeitos dos fármacos , Metformina/administração & dosagem , Idoso , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Vias de Administração de Medicamentos , Feminino , Glucose/farmacocinética , Teste de Tolerância a Glucose , Humanos , Intestino Delgado/metabolismo , Masculino , Pessoa de Meia-Idade
14.
Acta Diabetol ; 56(4): 449-456, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30593599

RESUMO

AIMS: 13C-glucose breath tests are reported as an alternative non-invasive method to evaluate glucose metabolism. However, the metabolic results differ based on the site of the carbon atom in the glucose. The aim of this study was to evaluate changes in the metabolism of carbon atoms contained in glucose in patients with diabetes using [1, 2, 3-13C]glucose breath tests. METHODS: Sixteen healthy participants and 20 diabetic patients were enrolled in the study. Three types of breath tests, [1-13C], [2-13C], and [3-13C]glucose breath tests, were performed after an overnight fast. Breath samples were taken at baseline and at 10-min intervals over 150 min, and 13CO2 excretion curves were expressed using non-dispersive infrared isotope spectrometry. RESULTS: 13CO2 levels increased more rapidly, and the peak value of 13CO2 (Cmax) was highest after the administration of [3-13C]glucose followed by [2-13C] and [1-13C]glucose in controls. Delayed 13CO2 excretion and a low area under the curve through 150 min (AUC150) were obtained in diabetic patients. The group with severe diabetes had a significantly lower Cmax and AUC150 in the [1-13C]glucose breath test. CONCLUSIONS: The [1-13C]glucose breath test, which has been used to evaluate glucose metabolism, is suitable for patients with late-stage diabetes, whereas the [2-13C]glucose breath test is ideal in the early stages. Although the [3-13C]glucose breath test is theoretically useful for evaluating the uptake of glucose and the anaerobic glycolysis system, it can be used in practice to distinguish reduced uptake from impaired oxidation of glucose in combination with the other two tests.


Assuntos
Isótopos de Carbono/análise , Isótopos de Carbono/farmacocinética , Diabetes Mellitus Tipo 2/metabolismo , Glucose/análise , Glucose/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Testes Respiratórios/métodos , Estudos de Casos e Controles , Diagnóstico Precoce , Feminino , Gluconeogênese/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Adulto Jovem
15.
Biochem Biophys Res Commun ; 504(4): 899-902, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30224066

RESUMO

Heterogeneity in the metabolic properties of adipocytes in white adipose tissue has been well documented. We sought to investigate metabolic heterogeneity in adipocytes of brown adipose tissue (BAT), focusing on heterogeneity in nutrient uptake. To explore the possibility of metabolic heterogeneity in brown adipocytes, we used nanoscale secondary ion mass spectrometry (NanoSIMS) to quantify uptake of lipids in adipocytes interscapular BAT and perivascular adipose tissue (PVAT) after an intravenous injection of triglyceride-rich lipoproteins (TRLs) containing [2H]triglycerides (2H-TRLs). The uptake of deuterated lipids into brown adipocytes was quantified by NanoSIMS. We also examined 13C enrichment in brown adipocytes after administering [13C]glucose or 13C-labeled mixed fatty acids by gastric gavage. The uptake of 2H-TRLs-derived lipids into brown adipocytes was heterogeneous, with 2H enrichment in adjacent adipocytes varying by more than fourfold. We also observed substantial heterogeneity in 13C enrichment in adjacent brown adipocytes after administering [13C]glucose or [13C]fatty acids by gastric gavage. The uptake of nutrients by adjacent brown adipocytes within a single depot is variable, suggesting that there is heterogeneity in the metabolic properties of brown adipocytes.


Assuntos
Adipócitos Marrons/metabolismo , Nutrientes/farmacocinética , Espectrometria de Massa de Íon Secundário/métodos , Animais , Isótopos de Carbono/análise , Ácidos Graxos/farmacocinética , Glucose/farmacocinética , Lipídeos/farmacocinética , Lipoproteínas/administração & dosagem , Lipoproteínas/farmacocinética , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Receptores de Lipoproteínas/genética
16.
Perit Dial Int ; 38(5): 349-355, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30087174

RESUMO

BACKGROUND: Glucose is the most commonly used osmotic medium in peritoneal dialysis (PD) solutions, and its use has been associated with both local and systemic adverse effects. Previous, single-center, observational cohort studies have reported conflicting findings regarding whether a relationship exists between peritoneal glucose exposure and peritoneal small solute transport rate. METHODS: In this secondary analysis of the balANZ multicenter, multinational, randomized controlled trial of a neutral pH, ultra-low glucose degradation product (biocompatible) versus conventional PD solutions over a 2-year period, the relationship between time varying peritoneal glucose exposure and change in peritoneal solute transport rate, (measured as dialysate to plasma creatinine ratio at 4 hours [D:PCr4h]), was evaluated using multivariable, multilevel linear regression. Baseline peritoneal glucose exposure was also assessed as either a continuous or categorical variable. RESULTS: The study included 165 patients (age 58.1 ± 14.2 years, 55% male, 33% diabetic). Peritoneal glucose exposure increased over time (coefficient 1.49, 95% confidence interval [CI] 1.07 - 1.92 and was not significantly associated with change in D:PCr4h (coefficient 0.00004, 95% CI -0.0001 - 0.0002, p = 0.68). Similar results were found when peritoneal glucose exposure was examined as a baseline continuous or categorical variable. A significant 2-way interaction was observed with PD solution type, whereby a progressive increase in D:PCr4h was seen in the patients receiving conventional PD solution, but not in those receiving biocompatible solution. CONCLUSIONS: Increases in peritoneal solute transport rate in PD patients over time were not associated with peritoneal glucose exposure, although a strong and positive association with PD solution glucose degradation product content was identified. Peritoneal glucose exposure may be a less important consideration than peritoneal glucose degradation product exposure with respect to peritoneal membrane function over time.


Assuntos
Soluções para Diálise/farmacocinética , Glucose/farmacocinética , Falência Renal Crônica/terapia , Diálise Peritoneal/métodos , Peritônio/metabolismo , Transporte Biológico , Feminino , Seguimentos , Humanos , Falência Renal Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
17.
J Neurochem ; 146(6): 722-734, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29964293

RESUMO

Depression is one of the most debilitating neuropsychiatric disorders. Most of the current antidepressants have long remission time and low recovery rate. This study explores the impact of ketamine on neuronal and astroglial metabolic activity in prefrontal cortex in a social defeat (SD) model of depression. C57BL/6 mice were subjected to a social defeat paradigm for 5 min a day for 10 consecutive days. Ketamine (10 mg/kg, intraperitoneal) was administered to mice for two consecutive days following the last defeat stress. Mice were infused with [1,6-13 C2 ]glucose or [2-13 C]acetate to assess neuronal and astroglial metabolic activity, respectively, together with proton-observed carbon-edited nuclear magnetic resonance spectroscopy in prefrontal cortex tissue extract. The 13 C labeling of amino acids from glucose and acetate was decreased in SD mice. Ketamine treatment in SD mice restored sucrose preference, social interaction and immobility time to control values. Acute subanesthetic ketamine restored the 13 C labeling of brain amino acids from glucose as well as acetate in SD mice to the respective control values, suggesting that rates of neuronal and astroglial tricarboxylic acid (TCA) cycle and neurotransmitter cycling were re-established to normal levels. The finding of improved energy metabolism in SD mice suggests that fast anti-depressant action of ketamine is linked with improved neurotransmitter cycling.


Assuntos
Analgésicos/uso terapêutico , Astrócitos/metabolismo , Transtorno Depressivo , Ketamina/uso terapêutico , Neurônios/metabolismo , Estresse Psicológico/complicações , Acetatos/farmacocinética , Animais , Astrócitos/efeitos dos fármacos , Isótopos de Carbono/farmacocinética , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/etiologia , Transtorno Depressivo/patologia , Transtorno Depressivo/psicologia , Modelos Animais de Doenças , Preferências Alimentares/efeitos dos fármacos , Glucose/farmacocinética , Hierarquia Social , Relações Interpessoais , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Sacarose/administração & dosagem , Edulcorantes/administração & dosagem , Natação/psicologia
18.
Obesity (Silver Spring) ; 26(7): 1153-1160, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29722480

RESUMO

OBJECTIVE: Indole-3-carbinol (I3C), a naturally occurring compound found in cruciferous vegetables, and its metabolite 3,3'-diindolylmethane (DIM) reduce body mass and serum glucose levels in high-fat-diet-induced obese mice. This study aimed to determine whether I3C or DIM could increase glucose uptake via enhanced insulin sensitivity in 3T3-L1 adipocytes, as well as the mechanism involved. METHODS: 3T3-L1 preadipocytes were differentiated by using a mixture of adipogenic inducers, including a suboptimal concentration of insulin. RESULTS: DIM, but not I3C, increased adipocyte differentiation through upregulation of peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α. DIM also enhanced glucose uptake by increasing expression of glucose transporter 4 in adipocytes. This was associated with DIM-enhanced phosphorylation of the signaling intermediates Akt, insulin receptor substrate-1, and insulin receptor early in differentiation. CONCLUSIONS: Our findings suggest that DIM may improve insulin sensitivity through the activation of the insulin signaling pathway, leading to enhanced glucose uptake.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Glucose/farmacocinética , Indóis/farmacologia , Insulina/metabolismo , Células 3T3-L1 , Adipócitos/fisiologia , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
19.
PLoS One ; 13(5): e0196844, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29723250

RESUMO

Transforming growth factor-ß1 (TGF-ß1) is a major mediator of peritoneal fibrosis and reportedly affects expression of the H3K4 methyltransferase, SET7/9. SET7/9-induced H3K4 mono-methylation (H3K4me1) critically activates transcription of fibrosis-related genes. In this study, we examined the effect of SET7/9 inhibition on peritoneal fibrosis in mice and in human peritoneal mesothelial cells (HPMCs). We also examined SET7/9 expression in nonadherent cells isolated from the effluent of peritoneal dialysis (PD) patients. Murine peritoneal fibrosis was induced by intraperitoneal injection of methylglyoxal (MGO) into male C57/BL6 mice over 21 days. Sinefungin, a SET7/9 inhibitor, was administered subcutaneously just before MGO injection (10 mg/kg). SET7/9 expression was elevated in both MGO-injected mice and nonadherent cells isolated from the effluent of PD patients. SET7/9 expression was positively correlated with dialysate/plasma ratio of creatinine in PD patients. Sinefungin was shown immunohistochemically to suppress expression of mesenchymal cells and collagen deposition, accompanied by decreased H3K4me1 levels. Peritoneal equilibration tests showed that sinefungin attenuated the urea nitrogen transport rate from plasma and the glucose absorption rate from the dialysate. In vitro, sinefungin suppressed TGF-ß1-induced expression of fibrotic markers and inhibited H3K4me1. These findings suggest that inhibiting the H3K4 methyltransferase SET7/9 ameliorates peritoneal fibrosis.


Assuntos
Adenosina/análogos & derivados , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Fibrose Peritoneal/prevenção & controle , Adenosina/farmacologia , Adenosina/uso terapêutico , Animais , Células Cultivadas , Colágeno Tipo I/biossíntese , Colágeno Tipo I/genética , Soluções para Diálise/farmacocinética , Epitélio , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/farmacocinética , Código das Histonas/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/fisiologia , Humanos , Masculino , Metilação/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Nitrogênio/farmacocinética , Omento/citologia , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/induzido quimicamente , Fibrose Peritoneal/etiologia , Regiões Promotoras Genéticas/genética , Aldeído Pirúvico/toxicidade , Fator de Crescimento Transformador beta1/fisiologia
20.
Perit Dial Int ; 38(5): 356-362, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29674410

RESUMO

BACKGROUND: In end-stage renal disease patients treated with peritoneal dialysis (PD), the osmotic conductance to glucose (OCG) represents the intrinsic ability of the membrane to transport water in response to a crystalloid osmotic gradient. A progressive loss of OCG in long-term PD patients indicates the development of fibrosis in the peritoneal interstitium, and helps identify patients at risk for encapsulating peritoneal sclerosis. The double mini-peritoneal equilibration test (PET) has been proposed as a simple method to assess OCG using the difference in initial ultrafiltration rates generated by 2 successive dwells using 1.36% and 3.86% glucose-based, 1-h PET. However, the presence of a large peritoneal residual volume (RV) may potentially interfere with the correct evaluation of drained volumes, limiting the reliability of OCG assessed by the double mini-PET. METHODS: We retrospectively reviewed data from 53 peritoneal function tests in 35 consecutive PD patients starting PD at our center between March 2013 and March 2017. The test consisted of a uni-PET (double mini-PET combined with a 3.86%, 4-h PET) performed at PD start, then yearly. In addition to peritoneal solute transport rate and net ultrafiltration, the tests provided information about osmotic water transport (OCG, sodium sieving, and free-water transport) as well as the RV estimated from albumin dilution. RESULTS: Contrary to sodium sieving, net ultrafiltration, and free-water transport, OCG did not correlate with any of the other parameters of osmotic water transport. In multivariate regression analyses, the RV was identified as the only determinant of OCG, while it did not alter the robust association between sodium sieving/free-water transport and their respective determinants. Considering only baseline tests or the whole series of tests, the presence of a large intraperitoneal RV was associated with discrepant values between OCG and sodium sieving, and with an artificial increase in OCG. CONCLUSIONS: A large RV leads to significant overestimation of OCG using the double mini-PET, potentially reducing the ability of OCG to identify patients with progressive fibrosis in the peritoneal interstitium. On the other hand, sieving of the dialysate sodium, a biochemical surrogate for OCG, is independent of the RV and may therefore be more reliable. A call for caution is warranted in patients with a large RV to avoid misinterpretation of OCG values derived from the double mini-PET.


Assuntos
Glucose/farmacocinética , Falência Renal Crônica/terapia , Diálise Peritoneal/métodos , Peritônio/metabolismo , Transporte Biológico , Soluções para Diálise/farmacocinética , Feminino , Seguimentos , Humanos , Falência Renal Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Osmose , Reprodutibilidade dos Testes , Estudos Retrospectivos
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