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CONTEXT: The etiological mechanism of bile acid (BA) effects on insulin resistance and obesity is unknown. OBJECTIVE: This work aimed to determine whether plasma BAs are elevated in human obesity and/or insulin resistance. METHODS: This observational study was conducted at an academic research center. Seventy-one adult volunteers formed 4 groups: lean insulin-sensitive (body mass index [BMI]â ≤â 25 kg/m2, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]â <â 2.0, nâ =â 19), overweight/obese nondiabetic who were either insulin sensitive (Obsensitive, BMIâ >â 25 kg/m2, HOMA-IRâ <â 1.5, nâ =â 11) or insulin resistant (Obresistant, BMIâ >â 25 kg/m2, HOMA-IRâ >â 3.0, nâ =â 20), and type 2 diabetes (T2D, nâ =â 21). Main outcome measures included insulin sensitivity by hyperinsulinemic-euglycemic clamp, body composition by dual energy x-ray absorptiometry, abdominal fat distribution, and liver density by computed tomography and plasma BA. RESULTS: In the Obresistant group, glucose infusion rate/fat-free mass (GIR/FFM, an inverse measure of insulin resistance) was significantly lower, and visceral and liver fat higher, compared to lean and Obsensitive individuals, despite similar total adiposity in Obresistant and Obsensitive. Total BA concentrations were higher in Obresistant (2.62â ±â 0.333 mmol/L, Pâ =â .03) and T2D (3.36â ±â 0.582 mmol/L, Pâ < .001) vs Obsensitive (1.16â ±â 0.143 mmol/L), but were similar between Obsensitive and lean (2.31â ±â 0.329 mmol/L) individuals. Total BAs were positively associated with waist circumference (Râ =â 0.245, Pâ =â .041), visceral fat (Râ =â 0.360, Pâ =â .002), and fibroblast growth factor 21 (Râ =â 0.341, Pâ =â .004) and negatively associated with insulin sensitivity (Râ =â -0.395, Pâ =â .001), abdominal subcutaneous fat (Râ =â -0.352, Pâ =â .003), adiponectin (Râ =â -0.375, Pâ =â .001), and liver fat (Hounsfield units, an inverse marker of liver fat, Râ =â -0.245, Pâ =â .04). Conjugated BAs were additionally elevated in T2D individuals (Pâ <â .001). CONCLUSIONS: BA concentrations correlated with abdominal, visceral, and liver fat in humans, though an etiological role in insulin resistance remains to be verified.
Assuntos
Adiposidade/fisiologia , Ácidos e Sais Biliares/sangue , Resistência à Insulina/fisiologia , Gordura Intra-Abdominal/patologia , Fígado/metabolismo , Idoso , Austrália , Composição Corporal , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Fígado Gorduroso/complicações , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Técnica Clamp de Glucose , Humanos , Metabolismo dos Lipídeos/fisiologia , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/complicações , Obesidade Abdominal/diagnóstico , Obesidade Abdominal/metabolismo , Obesidade Abdominal/patologia , Tamanho do ÓrgãoRESUMO
BACKGROUND: Large cohort longitudinal studies have almost unanimously concluded that metabolic health in obesity is a transient phenomenon, diminishing in older age. We aimed to assess the fate of insulin sensitivity per se over time in overweight and obese individuals. METHODS: Individuals studied using the hyperinsulinaemic-euglycaemic clamp at the Garvan Institute of Medical Research from 2008 to 2010 (n = 99) were retrospectively grouped into Lean (body mass index (BMI) < 25 kg/m2) or overweight/obese (BMI ≥ 25 kg/m2), with the latter further divided into insulin-sensitive (ObSen) or insulin-resistant (ObRes), based on median clamp M-value (M/I, separate cut-offs for men and women). Fifty-seven individuals participated in a follow-up study after 5.4 ± 0.1 years. Hyperinsulinaemic-euglycaemic clamp, dual-energy X-ray absorptiometry and circulating cardiovascular markers were measured again at follow-up, using the same protocols used at baseline. Liver fat was measured using computed tomography at baseline and proton magnetic resonance spectroscopy at follow-up with established cut-offs applied for defining fatty liver. RESULTS: In the whole cohort, M/I did not change over time (p = 0.40); it remained significantly higher at follow-up in ObSen compared with ObRes (p = 0.02), and was not different between ObSen and Lean (p = 0.41). While BMI did not change over time (p = 0.24), android and visceral fat increased significantly in this cohort (ptime ≤ 0.0013), driven by ObRes (p = 0.0087 and p = 0.0001, respectively). Similarly, systolic blood pressure increased significantly over time (ptime = 0.0003) driven by ObRes (p = 0.0039). The best correlate of follow-up M/I was baseline M/I (Spearman's r = 0.76, p = 1.1 × 10-7). CONCLUSIONS: The similarity in insulin sensitivity between the ObSen and the Lean groups at baseline persisted over time. Insulin resistance in overweight and obese individuals predisposed to further metabolic deterioration over time.
RESUMO
OBJECTIVE: Alterations in lipids in muscle and plasma have been documented in insulin-resistant people with obesity. Whether these lipid alterations are a reflection of insulin resistance or obesity remains unclear. METHODS: Nondiabetic sedentary individuals not treated with lipid-lowering medications were studied (n = 51). Subjects with body mass index (BMI) > 25 kg/m(2) (n = 28) were stratified based on median glucose infusion rate during a hyperinsulinemic-euglycemic clamp into insulin-sensitive and insulin-resistant groups (above and below median, obesity/insulin-sensitive and obesity/insulin-resistant, respectively). Lean individuals (n = 23) served as a reference group. Lipidomics was performed in muscle and plasma by liquid chromatography electrospray ionization-tandem mass spectrometry. Pathway analysis of gene array in muscle was performed in a subset (n = 35). RESULTS: In muscle, insulin resistance was characterized by higher levels of C18:0 sphingolipids, while in plasma, higher levels of diacylglycerol and cholesterol ester, and lower levels of lysophosphatidylcholine and lysoalkylphosphatidylcholine, indicated insulin resistance, irrespective of overweight/obesity. The sphingolipid metabolism gene pathway was upregulated in muscle in insulin resistance independent of obesity. An overweight/obesity lipidomic signature was only apparent in plasma, predominated by higher triacylglycerol and lower plasmalogen species. CONCLUSIONS: Muscle C18:0 sphingolipids may play a role in insulin resistance independent of excess adiposity.
Assuntos
Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Sobrepeso/metabolismo , Adiposidade , Adulto , Idoso , Índice de Massa Corporal , Ésteres do Colesterol/sangue , Diglicerídeos/metabolismo , Feminino , Glucose/metabolismo , Técnica Clamp de Glucose , Humanos , Insulina/sangue , Metabolismo dos Lipídeos/genética , Lisofosfatidilcolinas/sangue , Masculino , Pessoa de Meia-Idade , Plasmalogênios/sangue , Transdução de Sinais , Esfingolipídeos/metabolismo , Triglicerídeos/sangue , Regulação para CimaRESUMO
Adipocyte differentiation and its impact on restriction or expansion of particular adipose tissue depots have physiological and pathophysiological significance in view of the different functions of these depots. Brown or "beige" fat [brown adipose tissue (BAT)] expansion can enhance thermogenesis, lipid oxidation, insulin sensitivity, and glucose tolerance; conversely expanded visceral fat [visceral white adipose tissue (VAT)] is associated with insulin resistance, low grade inflammation, dyslipidemia, and cardiometabolic risk. The largest depot, subcutaneous white fat [subcutaneous white adipose tissue (SAT)], has important beneficial characteristics including storage of lipid "out of harms way" and secretion of adipokines, especially leptin and adiponectin, with positive metabolic effects including lipid oxidation, energy utilization, enhanced insulin action, and an anti-inflammatory role. The absence of these functions in lipodystrophies leads to major metabolic disturbances. An ability to expand white adipose tissue adipocyte differentiation would seem an important defense mechanism against the detrimental effects of energy excess and limit harmful accumulation of lipid in "ectopic" sites, such as liver and muscle. Adipocyte differentiation involves a transcriptional cascade with PPARγ being most important in SAT but less so in VAT, with increased angiogenesis also critical. The transcription factor, Islet1, is fairly specific to VAT and in vitro inhibits adipocyte differentiation. The physiological importance of Islet1 requires further study. Basic control of differentiation is similar in BAT but important differences include the effect of PGC-1α on mitochondrial biosynthesis and upregulation of UCP1; also PRDM16 plays a pivotal role in expression of the BAT phenotype. Modulation of the capacity or function of these different adipose tissue depots, by altering adipocyte differentiation or other means, holds promise for interventions that can be helpful in human disease, particularly cardiometabolic disorders associated with the world wide explosion of obesity.
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BACKGROUND AND AIMS: L-glutamine is an efficacious glucagon-like peptide (GLP)-1 secretagogue in vitro. When administered with a meal, glutamine increases GLP-1 and insulin excursions and reduces postprandial glycaemia in type 2 diabetes patients. The aim of the study was to assess the efficacy and safety of daily glutamine supplementation with or without the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin in well-controlled type 2 diabetes patients. METHODS: Type 2 diabetes patients treated with metformin (nâ=â13, 9 men) with baseline glycated hemoglobin (HbA1c) 7.1±0.3% (54±4 mmol/mol) received glutamine (15 g bd)+ sitagliptin (100 mg/d) or glutamine (15 g bd) + placebo for 4 weeks in a randomized crossover study. RESULTS: HbA1c (Pâ=â0.007) and fructosamine (Pâ=â0.02) decreased modestly, without significant time-treatment interactions (both Pâ=â0.4). Blood urea increased (P<0.001) without a significant time-treatment interaction (Pâ=â0.8), but creatinine and estimated glomerular filtration rate (eGFR) were unchanged (P≥0.5). Red blood cells, hemoglobin, hematocrit, and albumin modestly decreased (P≤0.02), without significant time-treatment interactions (P≥0.4). Body weight and plasma electrolytes remained unchanged (P≥0.2). CONCLUSIONS: Daily oral supplementation of glutamine with or without sitagliptin for 4 weeks decreased glycaemia in well-controlled type 2 diabetes patients, but was also associated with mild plasma volume expansion. TRIAL REGISTRATION: ClincalTrials.gov NCT00673894.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Glutamina/administração & dosagem , Glutamina/efeitos adversos , Hipoglicemiantes/administração & dosagem , Fosfato de Sitagliptina/administração & dosagem , Administração Oral , Idoso , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Esquema de Medicação , Quimioterapia Combinada , Feminino , Glutamina/uso terapêutico , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/administração & dosagem , Metformina/uso terapêutico , Pessoa de Meia-Idade , Volume Plasmático/efeitos dos fármacos , Fosfato de Sitagliptina/uso terapêutico , Resultado do TratamentoRESUMO
While adipogenesis is controlled by a cascade of transcription factors, the global gene expression profiles in the early phase of adipogenesis are not well defined. Using microarray analysis of gene expression in 3T3-L1 cells, we have identified evidence for the activity of 2,568 genes during the early phase of adipocyte differentiation. One of these, the ISL1 gene, was of interest since its expression was markedly upregulated 1 h after initiation of differentiation, with a subsequent rapid decline. Overexpression of ISL1 at early times during adipocyte differentiation but not at later times was found to profoundly inhibit differentiation. This was accompanied by moderate downregulation of peroxisome proliferator-activated receptor γ (PPARγ) levels, substantial downregulation of PPARγ downstream genes, and downregulation of bone morphogenetic protein 4 (BMP4) levels in preadipocytes. Readdition of BMP4 overcame the inhibitory effect of ISL1 on the expression of PPARγ but not aP2, a gene downstream of PPARγ, and BMP4 also partially rescued ISL1 inhibition of adipogenesis, an effect which is additive with rosiglitazone. These results suggest that ISL1 is intimately involved in early regulation of adipogenesis, modulating PPARγ expression and activity via BMP4-dependent and -independent mechanisms. Our time course gene expression survey sets the stage for further studies to explore other early and immediate regulators.
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Adipogenia , Proteína Morfogenética Óssea 4/genética , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , PPAR gama/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Sequência de Bases , Proteína Morfogenética Óssea 4/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Regulação da Expressão Gênica , Camundongos , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , PPAR gama/antagonistas & inibidores , Rosiglitazona , Tiazolidinedionas/farmacologiaRESUMO
Human adiposity has long been associated with insulin resistance and increased cardiovascular risk, and abdominal adiposity is considered particularly adverse. Intra-abdominal fat is associated with insulin resistance, possibly mediated by greater lipolytic activity, lower adiponectin levels, resistance to leptin, and increased inflammatory cytokines, although the latter contribution is less clear. Liver lipid is also closely associated with, and likely to be an important contributor to, insulin resistance, but it may also be in part the consequence of the lipogenic pathway of insulin action being up-regulated by hyperinsulinemia and unimpaired signaling. Again, intramyocellular triglyceride is associated with muscle insulin resistance, but anomalies include higher intramyocellular triglyceride in insulin-sensitive athletes and women (vs men). Such issues could be explained if the "culprits" were active lipid moieties such as diacylglycerol and ceramide species, dependent more on lipid metabolism and partitioning than triglyceride amount. Subcutaneous fat, especially gluteofemoral, appears metabolically protective, illustrated by insulin resistance and dyslipidemia in patients with lipodystrophy. However, some studies suggest that deep sc abdominal fat may have adverse properties. Pericardial and perivascular fat relate to atheromatous disease, but not clearly to insulin resistance. There has been recent interest in recognizable brown adipose tissue in adult humans and its possible augmentation by a hormone, irisin, from exercising muscle. Brown adipose tissue is metabolically active, oxidizes fatty acids, and generates heat but, because of its small and variable quantities, its metabolic importance in humans under usual living conditions is still unclear. Further understanding of specific roles of different lipid depots may help new approaches to control obesity and its metabolic sequelae.
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Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adiposidade , Resistência à Insulina , Metabolismo dos Lipídeos , Obesidade/metabolismo , Obesidade/patologia , Animais , Humanos , Especificidade de ÓrgãosRESUMO
Impaired glucagon-like peptide (GLP-1) secretion or response may contribute to ineffective insulin release in type 2 diabetes. The conditionally essential amino acid glutamine stimulates GLP-1 secretion in vitro and in vivo. In a randomized, crossover study, we evaluated the effect of oral glutamine, with or without sitagliptin (SIT), on postprandial glycemia and GLP-1 concentration in 15 type 2 diabetes patients (glycated hemoglobin 6.5 ± 0.6%). Participants ingested a low-fat meal (5% fat) after receiving either water (control), 30 g l-glutamine (Gln-30), 15 g L-glutamine (Gln-15), 100 mg SIT, or 100 mg SIT and 15 g L-glutamine (SIT+Gln-15). Studies were conducted 1-2 wk apart. Blood was collected at baseline and postprandially for 180 min for measurement of circulating glucose, insulin, C-peptide, glucagon, and total and active GLP-1. Gln-30 and SIT+Gln-15 reduced the early (t = 0-60 min) postprandial glycemic response compared with control. All Gln treatments enhanced the postprandial insulin response from t = 60-180 min but had no effect on the C-peptide response compared with control. The postprandial glucagon concentration was increased by Gln-30 and Gln-15 compared with control, but the insulin:glucagon ratio was not affected by any treatment. In contrast to Gln-30, which tended to increase the total GLP-1 AUC, SIT tended to decrease the total GLP-1 AUC relative to control (both P = 0.03). Gln-30 and SIT increased the active GLP-1 AUC compared with control (P = 0.008 and P = 0.01, respectively). In summary, Gln-30 decreased the early postprandial glucose response, enhanced late postprandial insulinemia, and augmented postprandial active GLP-1 responses compared with control. These findings suggest that glutamine may be a novel agent for stimulating GLP-1 concentration and limiting postprandial glycemia in type 2 diabetes.
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Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/sangue , Glutamina/farmacologia , Administração Oral , Idoso , Glicemia/metabolismo , Peptídeo C/sangue , Estudos Cross-Over , Feminino , Esvaziamento Gástrico/efeitos dos fármacos , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glutamina/administração & dosagem , Glutamina/efeitos adversos , Humanos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Pirazinas/administração & dosagem , Fosfato de Sitagliptina , Triazóis/administração & dosagemRESUMO
OBJECTIVE: Visceral adipose tissue (VAT) is more closely linked to insulin resistance than subcutaneous adipose tissue (SAT). We conducted a quantitative analysis of the secretomes of VAT and SAT to identify differences in adipokine secretion that account for the adverse metabolic consequences of VAT. RESEARCH DESIGN AND METHODS: We used lectin affinity chromatography followed by comparison of isotope-labeled amino acid incorporation rates to quantitate relative differences in the secretomes of VAT and SAT explants. Because adipose tissue is composed of multiple cell types, which may contribute to depot-specific differences in secretion, we isolated preadipocytes and microvascular endothelial cells (MVECs) and compared their secretomes to those from whole adipose tissue. RESULTS: Although there were no discrete depot-specific differences in the secretomes from whole adipose tissue, preadipocytes, or MVECS, VAT exhibited an overall higher level of protein secretion than SAT. More proteins were secreted in twofold greater abundance from VAT explants compared with SAT explants (59% versus 21%), preadipocytes (68% versus 0%), and MVECs (62% versus 15%). The number of proteins in the whole adipose tissue secretome was greater than the sum of its cellular constituents. Finally, almost 50% of the adipose tissue secretome was composed of factors with a role in angiogenesis. CONCLUSIONS: VAT has a higher secretory capacity than SAT, and this difference is an intrinsic feature of its cellular components. In view of the number of angiogenic factors in the adipose tissue secretome, we propose that VAT represents a more readily expandable tissue depot.
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Tecido Adiposo/fisiologia , Endotélio Vascular/fisiologia , Resistência à Insulina/fisiologia , Gordura Intra-Abdominal/fisiologia , Gordura Subcutânea/fisiologia , Adipócitos/citologia , Adipócitos/fisiologia , Aminoácidos/metabolismo , Animais , Meios de Cultura , Endotélio Vascular/citologia , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Microcirculação/fisiologia , Fragmentos de Peptídeos/isolamento & purificação , Peptídeos/isolamento & purificação , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Proteínas/isolamento & purificação , Proteínas/metabolismoRESUMO
BACKGROUND & AIMS: Chronic hepatitis C (CHC) is associated with insulin resistance (IR), liver steatosis (genotype 3), and increased diabetes risk. The site and mechanisms of IR are unclear. METHODS: We compared cross-sectionally 29 nonobese, normoglycemic males with CHC (genotypes 1 and 3) to 15 adiposity and age-matched controls using a 2-step hyperinsulinemic-euglycemic clamp with [6,6-(2)H(2)] glucose to assess insulin sensitivity in liver and peripheral tissues and (1)H-magnetic resonance spectroscopy to evaluate liver and intramyocellular lipid. Insulin secretion was assessed after intravenous glucose. RESULTS: Insulin secretion was not impaired in CHC. Peripheral insulin sensitivity was 35% higher in controls vs CHC (P < .001) during high-dose (264.3 +/- 25 [standard error] mU/L) insulin (P < .001); this was negatively associated with viral load (R(2) = .12; P = .05) and subcutaneous fat (R(2) = .41; P < .001). IR was similar in both genotypes despite 3-fold increased hepatic fat in genotype 3 (P < .001). Hepatic glucose production (P = .25) and nonesterified free fatty acid (P = .84) suppression with insulin were not different between CHC and controls inferring no adipocyte IR, and suggesting IR is mainly in muscle. In CHC, intramyocellular lipid was nonsignificantly increased but levels of glucagon (73.8 +/- 3.6 vs 52.8 +/- 3.1 ng/mL; P < .001), soluble tumor necrosis factor receptor 2 (3.1 +/- 0.1 vs 2.3 +/- 0.1 ng/mL; P < .001), and Lipocalin-2 (36.4 +/- 2.9 vs 19.6 +/- 1.6 ng/mL; P < .001) were elevated. CONCLUSIONS: CHC represents a unique infective/inflammatory model of IR, which is predominantly in muscle, correlates with subcutaneous, not visceral, adiposity, and is independent of liver fat.
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Glicemia/metabolismo , Hepatite C Crônica/fisiopatologia , Resistência à Insulina , Insulina/sangue , Fígado/fisiopatologia , Músculo Esquelético/fisiopatologia , Proteínas de Fase Aguda , Adiposidade , Adulto , Austrália , Biomarcadores/sangue , Estudos de Casos e Controles , China , Estudos Transversais , Inglaterra , Genótipo , Glucagon/sangue , Técnica Clamp de Glucose , Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/diagnóstico , Humanos , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/fisiopatologia , Lipocalina-2 , Lipocalinas/sangue , Fígado/metabolismo , Fígado/virologia , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/virologia , Proteínas Proto-Oncogênicas/sangue , RNA Viral/sangue , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Gordura Subcutânea/metabolismo , Gordura Subcutânea/fisiopatologia , Fatores de Tempo , Carga ViralRESUMO
Type 2 diabetes mellitus (T2D) is predicted by central obesity and circulating adipokines regulating inflammation. We hypothesized that visceral adipose tissue (VAT) in T2D expresses greater levels of proinflammatory molecules. Paired samples of subcutaneous (SAT) and VAT were excised at elective surgery (n = 16, 6 with T2D, n = 8 age- and gender- matched controls). Metabolic parameters were measured in the fasted state: body composition by dual-energy X-ray absorptiometry and insulin action by hyperinsulinemic-euglycemic clamp. Adipose tissue mRNA gene expression was measured by quantitative reverse transcriptase-PCR. Subjects with T2D had higher VAT expression of molecules regulating inflammation (tumor necrosis factor-alpha (TNFalpha), macrophage inflammatory protein (MIP), interleukin-8 (IL-8)). Fasting glucose related to VAT expression of TNFalpha, MIP, serum amyloid A (SAA), IL-1alpha, IL-1beta, IL-8, and IL-8 receptor. Abdominal fat mass was related to VAT expression of MIP, SAA, cAMP response element-binding protein (CREBP), IL-1beta, and IL-8. Insulin action related inversely to VAT complement C3 expression only. There were depot-specific differences in expression of serum T2D predictors: VAT expressed higher levels of complement C3; SAT expressed higher levels of retinol-binding protein-4 (RBP4), adiponectin, and leptin. In summary, VAT in T2D expresses higher levels of adipokines involved in inflammation. VAT expression of these molecules is related to fasting glucose and insulin action. Increased production of these proinflammatory molecules by VAT may explain the links observed between visceral obesity, insulin resistance, and diabetes risk.
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Adipocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Gordura Subcutânea/metabolismo , Adulto , Idoso , Índice de Massa Corporal , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Diabetes Mellitus Tipo 2/genética , Feminino , Expressão Gênica , Humanos , Inflamação/genética , Inflamação/metabolismo , Resistência à Insulina/genética , Interleucina-8/genética , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Circunferência da CinturaRESUMO
BACKGROUND: FTO gene variants are linked to obesity. We tested for site-specific differences in FTO gene expression in subcutaneous and visceral adipose tissue (SAT and VAT, respectively) from individuals with and without type 2 diabetes mellitus (T2D) and the relationships between fasting glucose, in vivo insulin action, and measures of adiposity with FTO gene expression in adipose tissue. METHODS: Paired subcutaneous and visceral fat were excised at elective surgery in n = 16 subjects (six with T2D, age-matched). Metabolic parameters were measured in fasted state; body composition by dual-energy X-ray absorptiometry; and insulin action by hyperinsulinemic euglycemic clamp. Adipose tissue mRNA gene expression was determined by quantitative RT-PCR. RESULTS: Subjects with T2D had SAT and VAT FTO mRNA expression similar to controls. There was no depot specificity between SAT and VAT FTO mRNA expression. Insulin action did not relate to SAT or VAT FTO mRNA expression. SAT FTO mRNA expression was related to fasting glucose and waist circumference only. SAT and VAT FTO mRNA expression was not related to direct measures of total or central abdominal adiposity. SAT FTO mRNA expression was related to SAT tumor necrosis factor-alpha and nuclear factor-kappaB mRNA expression. CONCLUSIONS: FTO gene expression is not increased in SAT and VAT in T2D and does not relate to insulin action. The links between FTO and metabolic complications of diabetes require further elucidation.
Assuntos
Diabetes Mellitus Tipo 2/genética , Gordura Intra-Abdominal/fisiopatologia , Obesidade/genética , Proteínas/metabolismo , Gordura Subcutânea/fisiopatologia , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Comorbidade , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Regulação da Expressão Gênica/fisiologia , Técnica Clamp de Glucose , Humanos , Insulina/metabolismo , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/fisiologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Obesidade/epidemiologia , Gordura Subcutânea/metabolismo , Circunferência da CinturaRESUMO
UNLABELLED: Several circulating cytokines are increased with obesity and may combine with the influence of visceral fat to generate insulin resistance, inflammation, and fibrosis in nonalcoholic fatty liver disease (NAFLD). Little information exists in NAFLD about three recently recognized tissue-derived cytokines that are all lipid-binding and involved in inflammation, namely adipocyte fatty acid-binding protein (AFABP), lipocalin-2, and retinol-binding protein 4 (RBP4). We examined the association of these three peptides with hepatic steatosis, inflammation, and fibrosis plus indices of adiposity, insulin resistance, and dyslipidaemia in 100 subjects with NAFLD and 129 matched controls. Levels of AFABP and lipocalin-2, but not RBP4, were significantly elevated in NAFLD versus control (AFABP, 33.5 +/- 14.4 versus 23.1 +/- 12.1 ng/mL [P < 0.001]; lipocalin-2, 63.2 +/- 26 versus 48.6 +/- 20 ng/mL [P < 0.001]) and correlated with indices of adiposity. AFABP correlated with indices of subcutaneous rather than visceral fat. AFABP alone distinguished steatohepatitis from simple steatosis (P= 0.02). Elevated AFABP independently predicted increasing inflammation and fibrosis, even when insulin resistance and visceral fat were considered; this applied to lobular inflammation and ballooning (odds ratio 1.4, confidence interval 1.0-1.8) and fibrosis stage (odds ratio 1.3, confidence interval 1.0-1.7) (P < or = 0.05 for all). None of the cytokines correlated with steatosis grade. AFABP levels correlated with insulin resistance (homeostasis model assessment of insulin resistance) in controls and NAFLD, whereas lipocalin-2 and RBP4 only correlated positively with insulin resistance in controls. CONCLUSION: Circulating AFABP, produced by adipocytes and macrophages, and lipocalin-2, produced by multiple tissues, are elevated and may contribute to the metabolic syndrome in NAFLD. AFABP levels, which correlate with subcutaneous, but not visceral fat, independently predict inflammation and fibrosis in NAFLD and may have a direct pathogenic link to disease progression.
Assuntos
Proteínas de Ligação a Ácido Graxo/sangue , Fígado Gorduroso/sangue , Fígado Gorduroso/complicações , Hepatite/sangue , Hepatite/etiologia , Lipocalinas/sangue , Cirrose Hepática/sangue , Cirrose Hepática/etiologia , Proteínas Proto-Oncogênicas/sangue , Proteínas de Fase Aguda , Adulto , Feminino , Humanos , Lipocalina-2 , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To investigate sprint-training effects on muscle metabolism during exercise in subjects with (type 1 diabetic group) and without (control group) type 1 diabetes. RESEARCH DESIGN AND METHODS: Eight subjects with type 1 diabetes and seven control subjects, matched for age, BMI, and maximum oxygen uptake (Vo(2peak)), undertook 7 weeks of sprint training. Pretraining, subjects cycled to exhaustion at 130% Vo(2peak). Posttraining subjects performed an identical test. Vastus lateralis biopsies at rest and immediately after exercise were assayed for metabolites, high-energy phosphates, and enzymes. Arterialized venous blood drawn at rest and after exercise was analyzed for lactate and [H(+)]. Respiratory measures were obtained on separate days during identical tests and during submaximal tests before and after training. RESULTS: Pretraining, maximal resting activities of hexokinase, citrate synthase, and pyruvate dehydrogenase did not differ between groups. Muscle lactate accumulation with exercise was higher in type 1 diabetic than nondiabetic subjects and corresponded to indexes of glycemia (A1C, fasting plasma glucose); however, glycogenolytic and glycolytic rates were similar. Posttraining, at rest, hexokinase activity increased in type 1 diabetic subjects; in both groups, citrate synthase activity increased and pyruvate dehydrogenase activity decreased; during submaximal exercise, fat oxidation was higher; and during intense exercise, peak ventilation and carbon dioxide output, plasma lactate and [H(+)], muscle lactate, glycogenolytic and glycolytic rates, and ATP degradation were lower in both groups. CONCLUSIONS: High-intensity exercise training was well tolerated, reduced metabolic destabilization (of lactate, H(+), glycogenolysis/glycolysis, and ATP) during intense exercise, and enhanced muscle oxidative metabolism in young adults with type 1 diabetes. The latter may have clinically important health benefits.
Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Consumo de Oxigênio/fisiologia , Adulto , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/fisiopatologia , Teste de Esforço , Feminino , Humanos , Masculino , Adulto JovemRESUMO
UNLABELLED: Visceral obesity is intimately associated with metabolic disease and adverse health outcomes. However, a direct association between increasing amounts of visceral fat and end-organ inflammation and scarring has not been demonstrated. We examined the association between visceral fat and liver inflammation in patients with nonalcoholic fatty liver disease (NAFLD) to delineate the importance of visceral fat to progressive steatohepatitis and hence the inflammatory pathogenesis of the metabolic syndrome. We undertook a cross-sectional, proof of concept study in 38 consecutive adults with NAFLD at a tertiary liver clinic. All subjects had a complete physical examination, anthropometric assessment, and fasting blood tests on the day of liver biopsy. Abdominal fat volumes were assessed by magnetic resonance imaging within 2 weeks of liver biopsy. The extent of hepatic inflammation and fibrosis augmented incrementally with increases in visceral fat (P < 0.01). For each 1% increase in visceral fat, the odds ratio for increasing liver inflammation and fibrosis was 2.4 (confidence interval [CI]: 1.3-4.2) and 3.5 (CI: 1.7-7.1), respectively. Visceral fat remained an independent predictor of advanced steatohepatitis (odds ratio [OR] 2.1, CI: 1.1-4.2, P = 0.05) and fibrosis (OR 2.9, CI: 1.4-6.3, P = 0.006) even when controlled for insulin resistance and hepatic steatosis. Interleukin-6 (IL-6) levels, which correlated with visceral fat, also independently predicted increasing liver inflammation. Visceral fat was associated with all components of the metabolic syndrome. CONCLUSION: Visceral fat is directly associated with liver inflammation and fibrosis independent of insulin resistance and hepatic steatosis. Visceral fat should therefore be a central target for future interventions in nonalcoholic steatohepatitis and indeed all metabolic disease.
Assuntos
Fígado Gorduroso/diagnóstico , Hepatite/diagnóstico , Gordura Intra-Abdominal/patologia , Cirrose Hepática/diagnóstico , Abdome , Adulto , Estudos de Coortes , Estudos Transversais , Progressão da Doença , Feminino , Hepatite/sangue , Hepatite/complicações , Humanos , Interleucina-6/sangue , Cirrose Hepática/complicações , Imageamento por Ressonância Magnética , Masculino , Síndrome Metabólica/etiologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Gordura Subcutânea/patologiaRESUMO
OBJECTIVE: To examine differences in gene expression between visceral (VF) and subcutaneous fat (SF) to identity genes of potential importance in regulation of VF. METHODS AND PROCEDURES: We compared gene expression (by DNA array and quantitative PCR (qPCR)) in paired VF and SF adipose biopsies from 36 subjects (age 54 +/- 15 years, 15 men/21 women) with varying degrees of adiposity and insulin resistance, in chow and fat fed mice (+/- rosiglitazone treatment) and in c-Cbl(-/-) mice. Gene expression was also examined in 3T3-L1 preadipocytes during differentiation. RESULTS: A twofold difference or more was found between VF and SF in 1,343 probe sets, especially for genes related to development, cell differentiation, signal transduction, and receptor activity. Islet-1 (ISL1), a LIM-homeobox gene with important developmental and regulatory function in islet, neural, and cardiac tissue, not previously recognized in adipose tissue was virtually absent in SF but substantially expressed in VF. ISL1 expression correlated negatively with BMI (r = -0.37, P = 0.03), abdominal fat (by dual energy X-ray absorptiometry, r = -0.44, P = 0.02), and positively with circulating adiponectin (r = 0.33, P = 0.04). In diet-induced obese mice, expression was reduced in the presence or absence of rosiglitazone. Correspondingly, expression was increased in the c-Cbl(-/-) mouse, which is lean and insulin sensitive (IS). ISL1 expression was increased sevenfold in 3T3-L1 preadipocytes during early (day 1) differentiation and was reduced by day 2 differentiation. DISCUSSION: An important developmental and regulatory gene ISL1 is uniquely expressed in VF, probably in the preadipocyte. Our data suggest that ISL1 may be regulated by adiposity and its role in metabolic regulation merits further study.
Assuntos
Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Gordura Intra-Abdominal/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Adipócitos/patologia , Adiponectina/metabolismo , Adiposidade/genética , Adiposidade/fisiologia , Adulto , Idoso , Animais , Biópsia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Feminino , Humanos , Técnicas In Vitro , Gordura Intra-Abdominal/patologia , Proteínas com Homeodomínio LIM , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Gordura Subcutânea/metabolismo , Gordura Subcutânea/patologia , Fatores de TranscriçãoRESUMO
CONTEXT: Chronic pharmacological glucocorticoid (GC) use causes substantial morbidity from protein wasting. GH and androgens are anabolic agents that may potentially reverse GC-induced protein loss. OBJECTIVE: Our objective was to assess the effect of GH and dehydroepiandrosterone (DHEA) on protein metabolism in subjects on long-term GC therapy. DESIGN: This was an open, stepwise GH dose-finding study (study 1), followed by a randomized cross-over intervention study (study 2). SETTING: The studies were performed at a clinical research facility. PATIENTS AND INTERVENTION: In study 1, six subjects (age 69+/-4 yr) treated with long-term (>6 months) GCs (prednisone dose 8.3+/-0.8 mg/d) were studied before and after two sequential GH doses (0.8 and 1.6 mg/d) for 2 wk each. In study 2, 10 women (age 71+/-3 yr) treated with long-term GCs (prednisone dose 5.4+/-0.5 mg/d) were studied at baseline and after 2-wk treatment with GH 0.8 mg/d, DHEA 50 mg/d, or GH and DHEA (combination treatment). MAIN OUTCOME MEASURE: Changes in whole body protein metabolism were assessed using a 3-h primed constant infusion of 1-[13C]leucine, from which rates of leucine appearance, leucine oxidation, and leucine incorporation into protein were estimated. RESULTS: In study 1, GH 0.8 and 1.6 mg/d significantly reduced leucine oxidation by 19% (P=0.03) and 31% (P=0.02), and increased leucine incorporation into protein by 10% (P=0.13) and 19% (P=0.04), respectively. The lower GH dose did not cause hyperglycemia, whereas GH 1.6 mg/d resulted in fasting hyperglycemia in two of six subjects. In study 2, DHEA did not significantly change leucine metabolism alone or when combined with GH. Blood glucose was not affected by DHEA. CONCLUSION: GH, at a modest supraphysiological dose of 0.8 mg/d, induces protein anabolism in chronic GC users without causing diabetes. DHEA 50 mg/d does not enhance the effect of GH. GH may safely prevent or reverse protein loss induced by chronic GC therapy.
Assuntos
Desidroepiandrosterona/farmacologia , Hormônio do Crescimento/farmacologia , Prednisona/farmacologia , Proteínas/metabolismo , Idoso , Estudos Cross-Over , Metabolismo Energético/efeitos dos fármacos , Feminino , Glucose/metabolismo , Humanos , Leucina/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
The metabolic response to two different forms of high-intensity intermittent cycle exercise was investigated in young women. Subjects (8 trained and 8 untrained) performed two bouts of high-intensity intermittent exercise: short sprint (SS) (8-s sprint, 12-s recovery) and long sprint (LS) (24-s sprint, 36-s recovery) for 20 min on two separate occasions. Both workload and oxygen uptake were greater in the trained subjects but were not significantly different for SS and LS. Plasma glycerol concentrations significantly increased during exercise. Lactate concentrations rose over the 20 min and were higher for the trained women. Catecholamine concentration was also higher postexercise compared with preexercise for both groups. Both SS and LS produced similar metabolic response although both lactate and catecholamines were higher after the 24-s sprint. In conclusion, these results show that high-intensity intermittent exercise resulted in significant elevations in catecholamines that appear to be related to increased venous glycerol concentrations. The trained compared with the untrained women tended to show an earlier increase in plasma glycerol concentrations during high-intensity exercise.
Assuntos
Catecolaminas/sangue , Glicerol/sangue , Ácido Láctico/sangue , Resistência Física/fisiologia , Esforço Físico/fisiologia , Aptidão Física/fisiologia , Adulto , Teste de Esforço , Feminino , Humanos , MasculinoRESUMO
CONTEXT: High-dose glucocorticoids cause acute protein loss by increasing protein breakdown and oxidation. Whether lower glucocorticoid doses, typical of therapeutic use, induce sustained catabolism has not been studied. OBJECTIVE: Our objective was to assess the effect of acute and chronic therapeutic glucocorticoid doses on protein metabolism. DESIGN AND SETTING: We conducted an open longitudinal and a cross-sectional study at a clinical research facility. PATIENTS AND INTERVENTION: Ten healthy subjects were studied before and after a short course of prednisolone (5 and 10 mg/d sequentially for 7 d each). Twelve subjects with inactive polymyalgia rheumatica receiving chronic (>12 months) prednisone (mean = 5.0 +/- 0.8 mg/d) were compared with 12 age- and gender-matched normal subjects. MAIN OUTCOME MEASURE: Whole-body protein metabolism was assessed using a 3-h primed constant infusion of 1-[(13)C]leucine, from which rates of leucine appearance (leucine Ra, an index of protein breakdown), leucine oxidation (Lox, index of protein oxidation) and leucine incorporation into protein (LIP, index of protein synthesis) were estimated. RESULTS: Prednisolone induced an acute significant increase in Lox (P = 0.008) and a fall in LIP (P = 0.08) but did not affect leucine Ra. There was no significant difference between the effects of the 5- and 10-mg prednisolone doses on leucine metabolism. In subjects receiving chronic prednisone therapy, leucine Ra, Lox, and LIP were not significantly different from normal subjects. CONCLUSION: Glucocorticoids stimulate protein oxidation after acute but not chronic administration. This time-related change suggests that glucocorticoid-induced stimulation of protein oxidation does not persist but that a metabolic adaptation occurs to limit protein loss.