RESUMO
The authors regret that Alexandra Bargiota's name was spelt incorrectly in the author list. The details given in this correction are correct.
RESUMO
In this study, the regional adipose tissue-adiponectin (AT-ADN) and adiponectin receptor (R1 and R2) expression and their relation with metabolic parameters, circulating and AT-derived cytokine expressions were compared. Paired subcutaneous adipose tissue (SCAT) and visceral adipose tissue (VAT) were taken from 18 lean and 39 obese humans, AT-mRNA expression of adipokines analysed by RT-PCR and corresponding serum levels by enzyme-linked immunosorbent assay (ELISA). R1 and R2 adipocyte expression was compared with 17 other human tissues. ADN-gene expression was lower in VAT than SCAT [mean (SD) 1.54 (1.1) vs. 2.84 (0.87); p < 0.001], and lower in obese subjects (VAT : p = 0.01;SCAT : p < 0.001). SCAT-ADN correlated positively with serum ADN (r = 0.33;p = 0.036) but not VAT-ADN. AT expressions of ADN and macrophage migration inhibiting factor (MMIF), IL18 and cluster of differentiation factor 14 (CD14) in both depots showed inverse correlations. R1 and R2 were expressed ubiquitously and R2 highest in SCAT, and this is much higher (x100) than R1 (x100). R expression was similar in lean and obese subjects and unrelated to the metabolic syndrome, however, receptors correlated with VAT-MMIF (R 1: r = 0.4;p = 0.008;R 2: r = 0.35,p = 0.02) and SCAT-MMIF expression (R 2: r = 0.43;p = 0.004). Unlike ADN, its receptors are expressed in many human tissues. Human R2 expression is not highest in the liver but in AT where it is associated with MMIF expression. The adiponectin-dependent insulin-sensitizing action of thiazolidinediones is thus probably to differ amongst species with weaker effects on the human liver.
Assuntos
Gordura Intra-Abdominal/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Receptores de Adiponectina/metabolismo , Gordura Subcutânea/metabolismo , Adiponectina/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , MasculinoRESUMO
BACKGROUND: Apart from their role in insulin secretion and glucose homeostasis, the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) exert a number of extra-pancreatic effects which in the case of GIP remain largely unknown. DESIGN/PATIENTS: Six obese male patients with diet-controlled type 2 diabetes (T2DM) and six healthy lean male subjects were studied. The protocol included four experiments for each participant that were carried out in randomized order and included: GLP-1 infusion at a rate of 1 pmol/kg/min for 4 h, GIP at a rate of 2 pmol/kg/min, GLP-1 (at 1 pmol/kg/min) with GIP (at 2 pmol/kg/min), and placebo infusion for 4 h. Energy expenditure (EE) was measured throughout with indirect calorimetry and subjects were given a series of visual analogue scales to rate hourly their hunger, fullness, urge to eat and prospective consumption of food. Immediately following termination of the infusions all subjects were offered a free choice buffet lunch and total calorie and macronutrient intake was calculated. RESULTS: During GIP infusion there was a trend for healthy subjects to report higher hunger scores and a reduction in EE only when compared with placebo. These parameters remained unchanged in patients with T2DM. Ad libitum energy intake after all four infusions was the same in both groups. CONCLUSION: We report here for the first time that GIP infusion may impact on resting EE and subjective appetite sensations in normal weight healthy subjects and further studies with larger numbers of subjects are required to help define more conclusively the precise role of GIP in energy balance in humans.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/psicologia , Metabolismo Energético/efeitos dos fármacos , Polipeptídeo Inibidor Gástrico/administração & dosagem , Administração Tópica , Adulto , Apetite/efeitos dos fármacos , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Inibidor Gástrico/síntese química , Humanos , Masculino , Pessoa de Meia-Idade , Paladar/efeitos dos fármacosRESUMO
BACKGROUND: Adults with growth hormone deficiency (AGHD) have an adverse body composition with an increased prevalence of obesity. It is not known whether growth hormone replacement (GHR) results in alterations in energy intake (EI) and/or energy expenditure (EE). The aim of the study was to investigate the effects of GHR on EI and EE. MATERIALS AND METHODS: Nineteen hypopituitary adults (14 males, 5 females, mean age 46.2 years) with severe GHD (peak GH response to glucagon Assuntos
Ingestão de Energia/efeitos dos fármacos
, Metabolismo Energético/efeitos dos fármacos
, Transtornos do Crescimento/tratamento farmacológico
, Hormônio do Crescimento/deficiência
, Hormônio do Crescimento/uso terapêutico
, Adulto
, Composição Corporal
, Feminino
, Transtornos do Crescimento/metabolismo
, Hormônio do Crescimento/farmacologia
, Humanos
, Masculino
, Pessoa de Meia-Idade
, Obesidade/complicações
, Fatores de Risco
, Resultado do Tratamento
RESUMO
BACKGROUND: Ghrelin is a gut-brain peptide that powerfully stimulates appetite and growth hormone secretion and is also known to directly regulate osteoblast cell function in vitro and in animal models. Little is known about the effects of ghrelin on bone turnover in humans. As the stomach is the main site of ghrelin synthesis, gastrectomy patients are deficient in ghrelin; they are also prone to osteopenia and osteomalacia. HYPOTHESIS: Ghrelin may play a role in bone regulation in humans; ghrelin deficiency following gastrectomy is associated with the disrupted regulation of bone turnover seen in these subjects. SUBJECTS AND METHODS: In a randomised, double-blind, placebo-controlled study 8 healthy controls and 8 post-gastrectomy subjects were infused with intravenous ghrelin (5 pmol/kg/min) or saline over 240 min on different days. Subjects were given a fixed energy meal during the infusion. Ghrelin, GH, type-1 collagen beta C-telopeptide (betaCTX), a marker of bone resorption, and procollagen type-1 amino-terminal propeptide (P1NP), a marker of bone formation, were measured. RESULTS: Fasting ghrelin was significantly lower in the gastrectomy group during the saline infusion (226.1+/-62.0 vs. 762+/-71.1 ng/l p<0.001). Growth hormone was significantly higher at 90 min after the ghrelin infusion, compared to saline in both healthy controls (61.1+/-8.8 vs. 1.4+/-0.6 mIU/l p<0.001) and gastrectomy subjects (61.1+/-11.8 vs. 0.9+/-0.2 mIU/l p<0.001) confirming the ghrelin was bioactive. Gastrectomy subjects were significantly older and had significantly higher plasma betaCTX than healthy controls at all time points (ANOVA p=0.009). After adjustment for age and BMI ghrelin was found to be a significant predictor of baseline plasma betaCTX and was inversely correlated with baseline plasma betaCTX (beta=-0.54 p=0.03 R2=26%). However, there was no significant effect of the ghrelin infusion on plasma betaCTX or P1NP in either subject group. CONCLUSIONS: Ghrelin infusion has no acute effect on markers of bone turnover in healthy controls and post-gastrectomy subjects, but is inversely correlated with bone resorption.
Assuntos
Remodelação Óssea/fisiologia , Gastrectomia , Hormônios Peptídicos/metabolismo , Adulto , Idoso , Colágeno Tipo I/sangue , Método Duplo-Cego , Feminino , Grelina , Hormônio do Crescimento Humano/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Peptídeos/sangue , Pró-Colágeno/sangueRESUMO
There is a growing worldwide epidemic of obesity. Obese people have a higher incidence of type 2 diabetes and cardiovascular disease, and hence present increasing social, financial and health burdens. Weight loss is always difficult to achieve through lifestyle changes alone, and currently licensed anti-obesity drug treatments, such as orlistat and sibutramine, if tolerated, only achieve modest weight loss. Therefore, there is a need to identify more potent pharmacological targets. In the last 10 years, discoveries of new hormones such as leptin and ghrelin, together with greater understanding of previously described hormones such as cholecystokinin (CCK), pancreatic polypeptide (PP), peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), have led to a rapid increase in our knowledge of the regulation of energy balance. Among the most important factors, controlling appetite and satiety are peptide hormones released from the gut. In this paper, we provide a full up-to-date overview of the current state of knowledge of this field, together with the potential of these peptides as drugs, or as other therapeutic targets, in the treatment of obesity. Finally, we propose an integrated model to describe the complex interplay of these hormones in the broader physiology of energy balance.
Assuntos
Regulação do Apetite/fisiologia , Metabolismo Energético/fisiologia , Hormônios Gastrointestinais/fisiologia , Obesidade/epidemiologia , Saciação/fisiologia , Colecistocinina/metabolismo , Colecistocinina/fisiologia , Hormônios Gastrointestinais/metabolismo , Grelina , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Peptídeos Semelhantes ao Glucagon/metabolismo , Peptídeos Semelhantes ao Glucagon/fisiologia , Humanos , Leptina/metabolismo , Leptina/fisiologia , Obesidade/etiologia , Oxintomodulina , Hormônios Peptídicos/metabolismo , Hormônios Peptídicos/fisiologia , Peptídeo YY/metabolismo , Peptídeo YY/fisiologiaRESUMO
AIMS: To determine the prevalence of overweight and obesity among patients with type 1 and type 2 diabetes mellitus attending a secondary care diabetes clinic in the United Kingdom, and to assess the impact of overweight and obesity on glycaemic control and cardiovascular risk factors in patients with type 2 diabetes. METHODS: 3637 patients with diabetes were identified from the hospital electronic diabetes register, 916 with type 1 diabetes (mean (SD) age 40.4 (15.1) years, 496 male) and 2721 with type 2 diabetes (mean (SD) age 62.5 (11.8) years, 1436 male). Data on body mass index (BMI), glycaemic control, lipid profiles, and blood pressure were extracted. RESULTS: Of patients with type 1 diabetes, 55.3% were overweight (BMI >or=25 kg/m(2)), 16.6% were obese (BMI >or=30 kg/m(2)), and 0.4% had morbid obesity (BMI >or=40 kg/m(2)). In contrast, 86% of patients with type 2 diabetes were overweight or obese, 52% were obese, and 8.1% had morbid obesity. Obese patients with type 2 diabetes were younger, had poorer glycaemic control, higher blood pressures, worse lipid profiles, and were more likely to be receiving antihypertensive and lipid lowering drugs compared with patients with BMI <30 kg/m(2). CONCLUSIONS: Obesity is the rule among patients attending this hospital diabetes clinic, with 86% of those with type 2 diabetes overweight or obese. Obesity is associated with significantly worse cardiovascular risk factors in this patient group, suggesting that more active interventions to control weight gain would be appropriate.
Assuntos
Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/complicações , Obesidade/complicações , Adulto , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/complicações , Ambulatório Hospitalar , Fatores de RiscoRESUMO
Insulin resistance has been proposed as the metabolic basis of atherogenesis. This hypothesis is based on the concept of the "insulin resistance syndrome," according to which insulin resistance is viewed as the primary abnormality that gives rise to dyslipidemia, essential hypertension, impaired glucose tolerance, and NIDDM. However, this hypothesis takes no account of the well-established and central role of vascular endothelium in the atherogenic process. Although endothelial injury is an early and prominent feature of atherogenesis, relatively little attention has been given to its metabolic consequences. In subjects with NIDDM, we have shown that endothelial dysfunction is associated with insulin resistance, raising the question of whether this relationship could be causal. In this article, we review the factors that are considered to be responsible for the development of endothelial dysfunction during atherogenesis, together with the metabolic consequences of endothelial dysfunction. While dysfunction of the endothelium in large and medium-sized arteries plays a central role in atherogenesis, we argue that dysfunction of peripheral vascular endothelium, at arteriolar and capillary level, plays the primary role in the pathogenesis of both insulin resistance and the associated features of the insulin resistance syndrome. We propose that the insulin resistance syndrome, together with many aspects of atherogenesis, can be viewed as the diverse consequences of endothelial dysfunction in different vascular beds. This new and testable hypothesis accounts for both the endothelial and metabolic abnormalities associated with atherogenesis.
Assuntos
Arteriosclerose/etiologia , Endotélio Vascular/fisiopatologia , Resistência à Insulina , Insulina/fisiologia , Animais , Arteriosclerose/fisiopatologia , Humanos , Hipercolesterolemia/fisiopatologia , Fumar/fisiopatologiaRESUMO
The physiological significance of changes in uncoupling protein-2 (UCP-2) gene expression is controversial. In this study we investigated the biochemical and functional correlates of UCP-2 gene expression in sc abdominal adipose tissue in humans in vivo. UCP-2 messenger ribonucleic acid expression was quantified by nuclease protection in adipose tissue from lean and obese humans in both the fasting and postprandial states. Plasma fatty acids, insulin, and leptin were all determined in paired samples from the superficial epigastric vein and radial artery, and local production rates were calculated from 133Xe washout. In the fasting state UCP-2 expression correlated inversely with body mass index (r = -0.45; P = 0.026), percent body fat (r = -0.41; P = 0.05), plasma insulin (r = -0.47; P = 0.02), epigastric venous fatty acids (r = -0.45; P = 0.04), and leptin (r = -0.50; P = 0.018). UCP-2 expression remained inversely related with plasma leptin after controlling for percent body (r = -0.45; P = 0.038). At 2 or 4 h postprandially, there were no significant relationships between UCP-2 expression and biochemical parameters. In conclusion, 1) UCP-2 messenger ribonucleic acid expression in sc adipose tissue is inversely related to adiposity and independently linked to local plasma leptin levels; and 2) UCP-2 expression is not acutely regulated by food intake, insulin, or fatty acids. Reduced UCP-2 expression may be a maladaptive response to sustained energy surplus and could contribute to the pathogenesis and maintenance of obesity.
Assuntos
Tecido Adiposo/fisiologia , Regulação da Expressão Gênica , Proteínas de Membrana Transportadoras , Proteínas Mitocondriais , Proteínas/genética , Tecido Adiposo/irrigação sanguínea , Adulto , Índice de Massa Corporal , Jejum , Ácidos Graxos não Esterificados/sangue , Feminino , Humanos , Insulina/sangue , Canais Iônicos , Leptina/sangue , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Fluxo Sanguíneo Regional , Transcrição Gênica , Desacopladores , Proteína Desacopladora 2RESUMO
Both insulin resistance and insulin concentrations correlate with blood pressure in nondiabetic subjects, but there is no consensus on these relations in subjects with non-insulin-dependent diabetes, perhaps because of the use of nonspecific insulin assays and clinic blood pressure measurement. Therefore, we have investigated the relation between ambulatory blood pressure, insulin sensitivity (measured by an insulin sensitivity test), and levels of insulin and its principal precursors, measured by specific assays, in 24 subjects with non-insulin-dependent diabetes. Insulin sensitivity (glucose metabolic clearance rate) correlated strongly with mean 24-hour ambulatory systolic blood pressure (r = -.650, P < .001). In contrast, there was no relation between this blood pressure index and fasting levels of insulin (r = .096, P = NS) or all insulin-like molecules (r = .077, P = NS). Dichotomized on 24-hour ambulatory systolic blood pressure levels, the hypertensive group was more insulin resistant than the normotensive group (metabolic clearance rate, 3.6 [0.7] versus 6.5 [3.0] mL.kg-1.min-1, P = .006), whereas there was no difference in insulin or proinsulin concentrations among the groups. In multiple regression analysis, insulin sensitivity was the major determinant of blood pressure. We conclude that in subjects with non-insulin-dependent diabetes mellitus, blood pressure is related to insulin sensitivity but not to fasting levels of insulin, suggesting that hyperinsulinemia is probably not the mediator of this relation.
Assuntos
Pressão Sanguínea , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Resistência à Insulina , Insulina/sangue , Proinsulina/sangue , Assistência Ambulatorial , Determinação da Pressão Arterial/métodos , Feminino , Glucose/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização FisiológicaRESUMO
Insulin resistance and increased erythrocyte Na+/Li+ countertransport activity are well documented in subjects with essential hypertension, raising the question whether compensatory hyperinsulinaemia might be responsible for activating Na+/Li+ countertransport. We measured Na+/Li+ countertransport in 63 non-nephropathic non-insulin-dependent diabetic subjects (36 hypertensive, 27 normotensive), finding no correlation with fasting levels of insulin (r = 0.074, P = 0.28), despite using a sensitive and specific insulin assay. In contrast, in 33 of the subjects in whom insulin sensitivity was measured, Na+/Li+ countertransport correlated significantly with the whole body glucose clearance rate (r = -0.37, P = 0.036). It is concluded that increased Na+/Li+ countertransport may be a cellular marker for insulin resistance, but that hyperinsulinaemia is not likely to be the factor which mediates this relation.
Assuntos
Antiporters/análise , Diabetes Mellitus Tipo 2/metabolismo , Hipertensão/metabolismo , Resistência à Insulina , Idoso , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Ensaio de Imunoadsorção Enzimática , Eritrócitos/metabolismo , Feminino , Humanos , Hiperinsulinismo/metabolismo , Hipertensão/complicações , Hipertensão/fisiopatologia , Transporte de Íons , Lítio/sangue , Masculino , Pessoa de Meia-Idade , Potássio/sangueRESUMO
Microalbuminuria in both insulin-dependent (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) is a marker for insulin resistance. Microalbuminuria is also associated with hypertension, itself an insulin-resistant state. Therefore, in order to examine the independent relationships of microalbuminuria with blood pressure and insulin resistance, we measured ambulatory blood pressure (Takeda TM-2420), insulin resistance (modified Harano method), and urinary albumin excretion rate (overnight urine collection) in 36 subjects with NIDDM. Albumin excretion correlated with 24-h systolic blood pressure (r = 0.49, p = 0.003), and insulin sensitivity (r = -0.39, p = 0.007). Microalbuminuric subjects had reduced insulin sensitivity compared with normoalbuminuric subjects [Mean (SD) 2.95 (0.33) versus 4.67 (0.56) ml.kg-1.min-1; p = 0.013]. In multivariate analysis including ambulatory blood pressure and insulin resistance, urinary albumin excretion was associated primarily with insulin resistance, with smaller contributions from glycated hemoglobin and male gender. These data suggest that microalbuminuria in NIDDM, although associated with hypertension, is also independently associated with insulin resistance.
Assuntos
Albuminúria , Pressão Sanguínea , Diabetes Mellitus Tipo 2/fisiopatologia , Resistência à Insulina , Glicemia/metabolismo , Monitorização Ambulatorial da Pressão Arterial , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/urina , Feminino , Hemoglobinas Glicadas/análise , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Caracteres Sexuais , SístoleRESUMO
Narcolepsy-cataplexy is characterised by orexin deficiency, sleep disturbance, obesity and dysautonomia. Ghrelin and obestatin affect both energy intake and sleep. Our aim was to investigate ghrelin, obestatin and metabolic/autonomic function in narcolepsy-cataplexy. Eight narcolepsy-cataplexy patients (seven CSF orexin-deficient) and eight matched controls were studied. The subjects had a fixed energy meal with serial blood samples and measurement of heart rate variability (HRV). Fasting plasma obestatin was more than threefold higher in narcolepsy subjects (narcolepsy 89.6 ± 16 pg/ml vs. control 24.9 ± 3 pg/ml, p < 0.001). There was no change in HRV total power, but post-prandial low-frequency (LF) power and high-frequency (HF) power were lower in the narcolepsy group [area under the curve (AUC): HF power narcolepsy 1.4 × 10(5) ± 0.2 × 10(5) vs. control 3.3 × 10(5) ± 0.6 × 10(5 )ms(2)/h, p < 0.001]. On multiple regression analyses, the only significant predictor of plasma obestatin was HF power, which was inversely correlated with obestatin (ß = -0.65 R (2) = 38 %, p = 0.009). Fasting and post-prandial plasma ghrelin were similar in both groups (narcolepsy 589.5 ± 88 pg/ml vs. control 686.9 ± 81 pg/ml, p = 0.5; post-prandial AUC-narcolepsy 161.3 ± 22 ng/ml/min vs. control 188.6 ± 62 ng/ml/min, p = 0.4). Only the narcolepsy group had significant suppression of plasma ghrelin after the meal (ANOVA, p = 0.004). In orexin-deficient narcolepsy, fasting plasma ghrelin is unaltered, and post-prandial suppression is preserved. Fasting plasma obestatin is increased and correlates with autonomic dysfunction. As obestatin affects NREM sleep, we suggest that increased plasma levels contribute to the disrupted sleep-state control in narcolepsy.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Grelina/sangue , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Narcolepsia/sangue , Neuropeptídeos/deficiência , Adulto , Jejum/sangue , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Masculino , Pessoa de Meia-Idade , Narcolepsia/fisiopatologia , Neuropeptídeos/sangue , Orexinas , Período Pós-PrandialRESUMO
OBJECTIVE: Short-term fasting is associated with increased GH pulsatility and mobilisation of fats, but underlying mechanisms are unclear. We studied ghrelin's role during fasting and the effects of exogenous ghrelin on lipid mobilisation. DESIGN: Randomised placebo-controlled study. METHODS: In this study, ten controls (body mass index (BMI) 23.3±3.2), ten morbidly obese subjects (BMI 50.1±10.6) and six post-gastrectomy subjects (BMI 25.2±1.0) were fasted for 36â h undergoing regular blood sampling. On a separate occasion, subjects were infused with either i.v. ghrelin (5 âpmol/kg per min) or saline over 270â min. RESULTS: Obese and post-gastrectomy subjects had lower ghrelin compared with controls (ANOVA, P=0.02) during the fast. Controls and gastrectomy subjects showed a similar increase in GH pulsatility, circulating non-esterified fatty acids (NEFA) and 3ß-hydroxybutyrate (3 HB). Obese subjects had an impaired GH response (P<0.001), reduced excursions of 3 HB (P=0.01) but no change in NEFA excursions (P=0.09) compared with controls. Ghrelin infusion increased GH, NEFA and ketone bodies (ANOVA, P<0.0001) in all the three groups, but GH response was impaired in the obese subjects (P=0.001). Ghrelin also induced a significant (ANOVA, P=0.004) biphasic NEFA response to meals in all the subjects. CONCLUSIONS: Despite low circulating ghrelin, gastrectomy subjects maintain a normal metabolic response to fasting, implying that ghrelin plays a minimal role. In contrast, infused ghrelin has significant effects on lipid mobilisation and induces a marked biphasic NEFA response to meals. Hence, ghrelin may play a significant role in meal-related substrate utilisation and metabolic flexibility.
Assuntos
Jejum/fisiologia , Gastrectomia , Grelina/fisiologia , Mobilização Lipídica/efeitos dos fármacos , Obesidade Mórbida/fisiopatologia , Adulto , Idoso , Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Feminino , Grelina/farmacologia , Humanos , Insulina/sangue , Corpos Cetônicos/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS/HYPOTHESIS: Familial partial lipodystrophy (FPLD) and obesity are both associated with increased risks of type 2 diabetes and cardiovascular disease. Although adipokines have been implicated, few data exist in subjects with FPLD; therefore we investigated a family with FPLD due to a lamin A/C mutation in order to determine how abnormalities of the plasma adipokine profile relate to insulin resistance and the metabolic syndrome. METHODS: Plasma levels of adiponectin, leptin, resistin, IL-1beta, IL-6 and TNF-alpha in 30 subjects (ten patients, 20 controls) were correlated with indices of metabolic syndrome. RESULTS: Compared with controls, FPLD patients had significantly lower plasma levels of adiponectin (3.7+/-1.0 in FDLP cases vs 7.1+/-0.72 mug/ml in controls, p=0.02), leptin (1.23+/-0.4 vs 9.0+/-1.3 ng/ml, p=0.002) and IL-6 (0.59+/-0.12 vs 1.04+/-0.17 pg/ml, p=0.047) and elevated TNF-alpha (34.8+/-8.1 vs 13.7+/-2.7 pg/ml, p=0.028), whereas IL-1beta and resistin were unchanged. In both groups, adiponectin levels were inversely correlated with body fat mass (controls, r=-0.44, p=0.036; FDLP, r=-0.67, p=0.025), insulin resistance (controls, r=-0.62, p=0.003; FDLP, r=-0.70, p=0.025) and other features of the metabolic syndrome. TNF-alpha concentrations were positively related to fat mass (controls, r=0.68, p=0.001; FDLP, r=0.64, p=0.048) and insulin resistance (controls, r=0.86, p=0.001; FDLP, r=0.75, p=0.013). IL-6, IL-1beta and resistin did not demonstrate any correlations with the metabolic syndrome in either group. CONCLUSIONS/INTERPRETATION: Low adiponectin and leptin and high TNF-alpha were identified as the major plasma adipokine abnormalities in FPLD, consistent with the hypothesis that low adiponectin and high TNF-alpha production may be mechanistically related, and perhaps responsible for the development of insulin resistance and cardiovascular disease in FPLD.
Assuntos
Adiponectina/sangue , Diabetes Mellitus Lipoatrófica/fisiopatologia , Resistência à Insulina/fisiologia , Laminina/genética , Fator de Necrose Tumoral alfa/análise , Adulto , Estudos de Casos e Controles , Diabetes Mellitus Lipoatrófica/sangue , Diabetes Mellitus Lipoatrófica/genética , Feminino , Homeostase , Humanos , Interleucina-1/sangue , Interleucina-6/sangue , Laminina/fisiologia , Leptina/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Obesidade/sangue , Obesidade/fisiopatologia , Resistina/sangueRESUMO
OBJECTIVE: The sympathetic nervous system may play a central role in the regulation of both lipolysis and leptin production. Therefore, we investigated the effect of intravenous infusions of the beta-adrenergic agonist isoprenaline on plasma concentrations of leptin and nonesterified fatty acids. DESIGN AND PATIENTS: Eight lean, healthy human volunteers, (4M:4F; median (interquartile range) age 36.5 (30.8-40.0) years; BMI 22.9 (20.1-29.2) kg.m-2; % body fat 24.5 (17.9-26.3)), were studied following an overnight fast. Intravenous infusion of isoprenaline was carried out for 3 h, followed by a 1 hour recovery phase. The isoprenaline infusion rates (0.5-3.5 micrograms.min-1) were titrated individually for each subject in order to achieve similar biological sympathetic responses based on heart rate (target heart rates were > 100 min-1 but < twice resting heart rate). MEASUREMENTS: Plasma leptin was determined using an in-house radioimmunoassay, nonesterified fatty acids estimated with an enzymatic colourimetric assay and insulin concentrations were assayed using a specific, two-site immunoenzymometric assay. RESULTS: Fasting preinfusion plasma leptin concentrations (6.3 (3.0-12.8) micrograms/l) correlated with percentage body fat measured by bioimpedance (r = 0.95; P < 0.001). Plasma leptin concentrations were rapidly suppressed by isoprenaline, with maximal suppression (20.5 (15.0-25.0)% of preinfusion levels (Wilcoxon rank sum test; P < 0.05)), observed after 2 h. In the recovery period, plasma leptin concentrations rapidly returned to preinfusion levels (postinfusion vs maximally suppressed leptin concentrations P < 0.05; vs preinfusion leptin concentrations P = NS). Plasma nonesterified fatty acids and insulin concentrations showed opposite changes to those observed with leptin. CONCLUSION: Plasma leptin concentrations are rapidly and reversibly suppressed by the infusion of isoprenaline in humans in vivo.
Assuntos
Agonistas Adrenérgicos beta/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Isoproterenol/administração & dosagem , Proteínas/análise , Agonistas Adrenérgicos beta/farmacologia , Adulto , Biomarcadores/sangue , Depressão Química , Feminino , Humanos , Infusões Intravenosas , Insulina/sangue , Isoproterenol/farmacologia , Leptina , Lipólise/efeitos dos fármacos , Masculino , Proteínas/efeitos dos fármacosRESUMO
The discovery of leptin has imparted great impetus to adipose tissue research by demonstrating a more active role for the adipocyte in energy regulation. Besides leptin, however, the adipose tissue also secretes a large number other signals. Cytokine signals, TNFalpha and IL-6, and components of the alternative pathway of complement influence peripheral fuel storage, mobilization and combustion, as well as energy homeostasis. In addition to the acute regulation of fuel metabolism, adipose tissue also influences steroid conversion and sexual maturation. In this way, adipose tissue is an active endocrine organ, influencing many aspects of fuel metabolism through a network of local and systemic signals, which interact with the established neuroendocrine regulators of adipose tissue. Thus, insulin, catecholamines and anterior pituitary endocrine axes interact at multiple levels with both cytokines and leptin. It may be proposed that the existence of this network of adipose tissue signalling pathways, arranged in an hierarchical fashion, constitutes a metabolic repertoire which enables the organism to adapt to a range of different metabolic challenges, including starvation, reproduction, times of physical activity, stress and infection, as well as short periods of gross energy excess. However, the occurrence of more prolonged periods of energy surplus, leading to obesity, is an unusual state in evolutionary terms, and the adipose tissue signalling repertoire, although sophisticated, adapts poorly to these conditions. Rather, the responses of the adipose tissue endocrine network to obesity are maladaptive, and lay the foundations of metabolic disease.
Assuntos
Tecido Adiposo/fisiologia , Glândulas Endócrinas/fisiologia , Comunicação Parácrina , Animais , Citocinas/fisiologia , Humanos , Leptina , Obesidade/fisiopatologia , Proteínas/fisiologia , Transdução de SinaisRESUMO
OBJECTIVES: To investigate the regulation of soluble adhesion molecules by tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and relationships with circulating cytokine receptors, in vivo, in type 1 diabetes. DESIGN: Cross-sectional study. SETTING: University hospital diabetes clinic. SUBJECTS: A total of 47 non-nephropathic, Caucasian type 1 diabetics and 39 nondiabetic controls. OUTCOME MEASURES: Plasma levels of TNF-alpha, IL-6, their soluble receptors and adhesion molecules intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin and von Willebrand factor (vWF), and risk factors for cardiovascular disease. RESULTS: Plasma concentrations of IL-6 were elevated in diabetic patients compared with controls [median (interquartiles) 1.28 (0.89-2.65) vs. 0.66 (0.45-1.73) pg mL(-1): P=0.016], and in these patients IL-6 and soluble IL-6 receptor (sIL-6R) levels correlated with concentrations of sICAM-1 (r = 0.41, P = 0.012 and r = 0.31, P = 0.04, respectively). Tumour necrosis factor-alpha soluble receptor-2 (sTN-FRII), but not TNF-alpha or tumour necrosis factor soluble receptor-1 (sTNFRI), was elevated in diabetic subjects (P = 0.027). Plasma TNF-alpha levels correlated with sVCAM-1 (r = 0.39, P = 0.008), triglycerides (r = 0.36, P = 0.02 1) and diastolic blood pressure (r = 0.35; P = 0.024). Both sTNFRI and sTNFRII correlated with blood pressure (r = 0.46, P = 0.002; r = 0.32, P = 0.034) and triglycerides (r = 0.33, P = 0.033; r = 0.29, P = 0.05). In contrast, HDL-cholesterol and triglyceride were related to sE-selectin (r = -0.45 and +0.45; both P < 0.001). Neither sE-selectin nor vWF were related to cytokine concentrations. Finally, both TNF-alpha and sIL-6R correlated sTNFRI and RII (r = 0.44-0.49, P < 0.001). None of these interactions were apparent in control subjects. CONCLUSIONS: (i) IL-6, through effects on sICAM-1, and TNF-alpha via effects on sVCAM-1, may promote vascular adhesion; (ii) plasma levels of TNF-alpha are associated with dyslipidaemia and increased blood pressure, adding to vascular disease risk; (iii) the actions of both cytokines are probably modified by altered production of soluble receptors in diabetic subjects.
Assuntos
Doenças Cardiovasculares/sangue , Moléculas de Adesão Celular/sangue , Citocinas/sangue , Diabetes Mellitus Tipo 1/sangue , Receptores de Citocinas/sangue , Adulto , Doenças Cardiovasculares/etiologia , Estudos Transversais , Selectina E/sangue , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fator de Necrose Tumoral alfa/análise , Molécula 1 de Adesão de Célula Vascular/sangue , Fator de von Willebrand/análiseRESUMO
AIMS: To examine the hypothesis that increased susceptibility of low density lipoproteins (LDL) to oxidation predisposes to endothelial dysfunction in patients with Type 1 diabetes mellitus. METHODS: A cross-sectional study of 46 non-nephropathic diabetic and 39 control subjects and in the diabetic patients, a 3-month duration, randomized, placebo-controlled double-blind trial of vitamin E 500 U/day. Flow-mediated vasodilatation (FMD) was measured in the forearm by high resolution ultrasound. LDL oxidation by Cu2+ was measured in vitro. RESULTS: Diabetic patients had greater basal and reactive forearm blood flow (geometric mean (SD%) flow (ml/min) 110.15 (19.19%) vs. 74.99 (23.17%); P=0.045, and 344.35 (20.84%) vs. 205.17 (21.48%); P=0.007), compared with controls, but there was no difference in FMD (median (interquartile range) 0.00 (-0.01-0.02) vs. 0.02 (-0.01-0.02) cm2; P=0.78). Diabetic LDL oxidation lag time correlated with postdilatation brachial artery area (r= 0.32; P=0.05) but not with FMD. Lag-times and total LDL oxidation by Cu2+, lipoprotein and vitamin E concentrations were similar in diabetic and control groups. Antibody titres to oxidized LDL (oxLDL) were higher in non-diabetic than diabetic subjects, and were unrelated to FMD. In diabetic patients, vitamin E increased mean (SD) plasma vitamin E levels (24.0 (6.5) to 47.5 (7.5) gmol/l; P=0.0006) and resulted in increased FMD (delta 0.00 (-0.02-0.01) vs. 0.01 (0.01-0.02)) cm2; P=0.0036), but no changes in LDL Cu2+ oxidation profiles were observed. CONCLUSIONS: FMD is no different in Type 1 diabetic and non-diabetic subjects and nor are indices of lipid peroxidation and in vitro LDL oxidation although levels of antibody to oxLDL are lower in diabetes. Vitamin E supplementation increases plasma vitamin E levels and may enhance FMD in diabetes but, in the absence of changes in LDL oxidation, this may not be mediated by reduced oxidation of LDL.