RESUMO
Lipodystrophies have been recognized since at least the nineteenth century and, despite their rarity, tended to attract considerable medical attention because of the severity and somewhat paradoxical nature of the associated metabolic disease that so closely mimics that of obesity. Within the last 20 yr most of the monogenic subtypes have been characterized, facilitating family genetic screening and earlier disease detection as well as providing important insights into adipocyte biology and the systemic consequences of impaired adipocyte function. Even more recently, compelling genetic studies have suggested that subtle partial lipodystrophy is likely to be a major factor in prevalent insulin-resistant type 2 diabetes mellitus (T2DM), justifying the longstanding interest in these disorders. This progress has also underpinned novel approaches to treatment that, in at least some patients, can be of considerable therapeutic benefit.
Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Dislipidemias/metabolismo , Lipodistrofia/metabolismo , Obesidade/metabolismo , Animais , Humanos , Resistência à Insulina/fisiologiaRESUMO
It has been shown using proton magnetic resonance spectroscopy (1H MRS) that, in a group of females, whole-body insulin resistance was more closely related to accumulation of saturated intramyocellular lipid (IMCL) than to IMCL concentration alone. This has not been investigated in males. We investigated whether age- and body mass index-matched healthy males differ from the previously reported females in IMCL composition (measured as CH2:CH3) and IMCL concentration (measured as CH3), and in their associations with insulin resistance. We ask whether saturated IMCL accumulation is more strongly associated with insulin resistance than other ectopic and adipose tissue lipid pools and remains a significant predictor when these other pools are taken into account. In this group of males, who had similar overall insulin sensitivity to the females, IMCL was similar between sexes. The males demonstrated similar and even stronger associations of IMCL with insulin resistance, supporting the idea that a marker reflecting the accumulation of saturated IMCL is more strongly associated with whole-body insulin resistance than IMCL concentration alone. However, this marker ceased to be a significant predictor of whole-body insulin resistance after consideration of other lipid pools, which implies that this measure carries no more information in practice than the other predictors we found, such as intrahepatic lipid and visceral adipose tissue. As the marker of saturated IMCL accumulation appears to be related to these two predictors and has a much smaller dynamic range, this finding does not rule out a role for it in the pathogenesis of insulin resistance.
Assuntos
Resistência à Insulina , Metabolismo dos Lipídeos , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Ácidos Graxos/metabolismo , Tecido Adiposo/metabolismo , Espectroscopia de Ressonância MagnéticaRESUMO
BACKGROUND: Iron repletion augments exercise capacity in chronic heart failure (HF), but there is a lack of mechanistic data explaining how iron could augment exercise performance despite minimal changes in hemoglobin (Hb). Besides Hb, iron is an obligate component of mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine (PCr). Dynamic phosphorus magnetic resonance spectroscopy is a noninvasive tool that quantifies in vivo muscle energetics by measuring the kinetics of PCr recovery after exertion. We tested the hypothesis that intravenous iron repletion in chronic HF enhances skeletal muscle energetics as reflected by shorter PCr recovery half-times (PCr t1/2) on phosphorus magnetic resonance spectroscopy. METHODS: We enrolled 40 patients (50% anemic) with chronic HF, New York Heart Association class ≥II, left ventricular ejection fraction ≤45%, and iron deficiency (ferritin<100 µg/L or 100-300 µg/L with transferrin saturation <20%). Subjects underwent stratified (anemic versus nonanemic) randomization (1:1) to a single, double-blinded, total dose infusion of iron isomaltoside or saline placebo with end points reassessed early at 2 weeks posttreatment to minimize confounding from exercise adaptation. The primary end point was PCr t1/2 at 2 weeks. Secondary end points included ADP recovery half-time (ADP t1/2; energetic marker), iron status, symptoms, Hb, exercise capacity, and safety. RESULTS: In the total population, treatment groups were similar at baseline. At 2 weeks, iron isomaltoside improved PCr t1/2 (adjusted difference, -6.8 s; 95% CI, 11.5 to -2.1; P=0.006), ADP t1/2 (-5.3 s; 95% CI, -9.7 to -0.9; P=0.02), ferritin (304 ng/mL; 95% CI, 217-391; P<0.0001), transferrin saturation (6.8%; 95% CI, 2.7-10.8; P=0.002), New York Heart Association class (-0.23; 95% CI, -0.46 to -0.01; P=0.04), resting respiratory rate (-0.7 breaths/min; 95% CI, -1.2 to -0.2; P=0.009), and postexercise Borg dyspnea score (-2.0; 95% CI, -3.7 to -0.3; P=0.04), but not Hb (2.4 g/L; 95% CI, -3.5 to 8.4; P=0.41). Adverse events were similar between groups. In subgroup analyses, iron isomaltoside improved PCr t1/2 in anemic (-8.4 s; 95% CI, -16.7 to -0.2; P=0.04) and nonanemic (-5.2 s; 95% CI, -10.6 to 0.2; P=0.06) cohorts. CONCLUSIONS: In patients with chronic HF and iron deficiency, a total repletion dose of iron isomaltoside given at a single sitting is well tolerated and associated with faster skeletal muscle PCr t1/2 at 2 weeks, implying better mitochondrial function. Augmented skeletal muscle energetics might therefore be an important mechanism via which iron repletion confers benefits in chronic HF despite minimal Hb changes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005592-13/GB . Unique identifier: EudraCT 2012-005592-13.
Assuntos
Anemia Ferropriva/tratamento farmacológico , Dissacarídeos/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Tolerância ao Exercício/efeitos dos fármacos , Compostos Férricos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Hematínicos/uso terapêutico , Deficiências de Ferro , Músculo Esquelético/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Anemia Ferropriva/sangue , Anemia Ferropriva/diagnóstico , Biomarcadores/sangue , Dissacarídeos/efeitos adversos , Método Duplo-Cego , Feminino , Compostos Férricos/efeitos adversos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Hematínicos/efeitos adversos , Humanos , Ferro/sangue , Londres , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Fosfocreatina/metabolismo , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do TratamentoRESUMO
Skeletal muscle phosphorus-31 31 P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of 31 P MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how 31 P MRS methods can probe it. Here we consider basic signal-acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with 31 P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near-infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and 1 H MRS measurements) can help in the physiological/metabolic interpretation of 31 P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology.
RESUMO
Intramyocellular lipid (IMCL) accumulation has been linked to both insulin-resistant and insulin-sensitive (athletes) states. Biochemical analysis of intramuscular triglyceride composition is confounded by extramyocellular triglycerides in biopsy samples, and hence the specific composition of IMCLs is unknown in these states. 1H magnetic resonance spectroscopy (MRS) can be used to overcome this problem. Thus, we used a recently validated 1H MRS method to compare the compositional saturation index (CH2:CH3) and concentration independent of the composition (CH3) of IMCLs in the soleus and tibialis anterior muscles of 16 female insulin-resistant lipodystrophic subjects with that of age- and gender-matched athletes (n = 14) and healthy controls (n = 41). The IMCL CH2:CH3 ratio was significantly higher in both muscles of the lipodystrophic subjects compared with controls but was similar in athletes and controls. IMCL CH2:CH3 was dependent on the IMCL concentration in the controls and, after adjusting the compositional index for quantity (CH2:CH3adj), could distinguish lipodystrophics from athletes. This CH2:CH3adj marker had a stronger relationship with insulin resistance than IMCL concentration alone and was inversely related to VO2max The association of insulin resistance with the accumulation of saturated IMCLs is consistent with a potential pathogenic role for saturated fat and the reported benefits of exercise and diet in insulin-resistant states.
Assuntos
Ácidos Graxos/metabolismo , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Adulto , Colina-Fosfato Citidililtransferase/genética , Exercício Físico/fisiologia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Insulina/metabolismo , Resistência à Insulina/genética , Lamina Tipo A/genética , Lipodistrofia/genética , Lipodistrofia/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Triglicerídeos/metabolismoRESUMO
Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action.
Assuntos
Colina-Fosfato Citidililtransferase/genética , Fígado Gorduroso/genética , Lipodistrofia/congênito , Lipodistrofia/genética , Fosfatidilcolinas/química , Células 3T3-L1 , Tecido Adiposo/metabolismo , Adolescente , Alelos , Animais , Criança , HDL-Colesterol/química , Colina-Fosfato Citidililtransferase/metabolismo , Biologia Computacional , Fígado Gorduroso/metabolismo , Feminino , Glicerofosfolipídeos/química , Humanos , Insulina/química , Lipídeos/química , Lipodistrofia/metabolismo , Camundongos , Mutação , Fenótipo , Distribuição TecidualRESUMO
BACKGROUND: Individuals of black African ethnicity tend to have less visceral adipose tissue (VAT) but more subcutaneous-abdominal adipose tissue (SCAT) than white Caucasians. However, it is unclear whether such distribution of abdominal fat is beneficial for metabolic disease risk in black individuals. Here we compared the associations between these specific abdominal fat depots, insulin sensitivity and metabolic syndrome risk. METHODS: A cross-sectional analysis of 76 black South African young adults (36 men; 40 women) aged 18-19 years participating in the Birth to Twenty Cohort Study had VAT and SCAT measured by MRI. The metabolic syndrome traits (blood pressure, lipid profile, fasting glucose and insulin) were measured and the values were combined into a metabolic syndrome risk score. Fasting glucose and insulin were used to derive the HOMA-index of insulin resistance (HOMA-IR). RESULTS: Compared to men, women had greater VAT (mean: 16.6 vs. 12.5 cm(2)) and SCAT (median 164.0 vs. 59.9 cm(2)). In men, SCAT (r = 0.50) was more strongly correlated to the metabolic syndrome score (MetS) than was VAT (r = 0.23), and was associated with both MetS (P = 0.001) and HOMA-IR (P = 0.001) after adjustment for VAT and total fat mass. In women, both abdominal fat compartments showed comparable positive correlations with MetS (r = 0.26 to 0.31), although these trends were weaker than in men. CONCLUSIONS: In young black South African adults, SCAT appears to be more relevant than VAT to metabolic syndrome traits.
Assuntos
Gordura Abdominal/metabolismo , População Negra/estatística & dados numéricos , Resistência à Insulina/fisiologia , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Gordura Abdominal/fisiopatologia , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Insulina/sangue , Lipídeos/sangue , Masculino , Síndrome Metabólica/fisiopatologia , Fatores de Risco , Fatores Sexuais , África do Sul/epidemiologia , População Branca , Adulto JovemRESUMO
CONTEXT: Glucokinase (GCK) phosphorylates and thereby "traps" glucose in cells, thus serving as a gatekeeper for cellular glucose metabolism, particularly in hepatocytes and pancreatic beta cells. In humans, activating GCK mutations cause familial hyperinsulinaemic hypoglycaemia (GCK-HH), leading to keen interest in the potential of small-molecule glucokinase activators (GKAs) as treatments for diabetes mellitus. Many such agents have been developed; however, observation of side effects including hypertriglyceridaemia and hepatic steatosis has delayed their clinical development. OBJECTIVE: To describe the clinical presentation and metabolic profiles of affected family members in a kindred with familial hyperinsulinism of adult presentation due to a known activating mutation in GCK. DESIGN: Clinical, biochemical and metabolic assessment, and GCK sequencing in affected family members. RESULTS: In the 60-year-old female proband, hyperinsulinaemic hypoglycaemia (blood glucose 2·1 mmol/mol, insulin 18 pm) was confirmed following 34 h of fasting; however, abdominal computed tomography (CT), pancreatic MRI, endoscopic ultrasound, octreotide scintigraphy and selective arterial calcium stimulation failed to localize an insulinoma. A prolonged OGTT revealed fasting hypoglycaemia that was exacerbated after glucose challenge, consistent with dysregulated glucose-stimulated insulin release. A heterozygous activating mutation, p.Val389Leu, in the glucokinase gene (GCK) was found in the proband and four other family members. Of these, two had been investigated elsewhere for recurrent hypoglycaemia in adulthood, while the other two adult relatives were asymptomatic despite profound hypoglycaemia. All three of the available family members with the p.Val389Leu mutation had normal serum lipid profiles, normal rates of fasting hepatic de novo lipogenesis and had hepatic triglyceride levels commensurate with their degree of adiposity. CONCLUSION: Activating GCK mutations may present in late adulthood with hyperinsulinaemic hypoglycaemia and should be considered even in older patients being investigated for insulinoma. Normal circulating lipids, rates of hepatic de novo lipogenesis and appropriate hepatic triglyceride content for degree of adiposity in the patients we describe suggest that even lifelong GCK activation in isolation is insufficient to produce fatty liver and metabolic dyslipidaemia.
Assuntos
Glucoquinase/genética , Heterozigoto , Hiperinsulinismo/genética , Adulto , Idoso , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Análise de Sequência de DNARESUMO
Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.
Assuntos
Dislipidemias/etiologia , Fígado Gorduroso/etiologia , Resistência à Insulina , Receptor de Insulina/fisiologia , Adolescente , Adulto , Ácidos Graxos não Esterificados/sangue , Feminino , Teste de Tolerância a Glucose , Humanos , Lipoproteínas VLDL/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas c-akt/genética , Receptor de Insulina/genética , Transdução de SinaisRESUMO
PURPOSE: In resistance to thyroid hormone due to mutations in thyroid hormone receptor ß, peripheral tissues are variably refractory to the action of circulating thyroid hormones. We evaluated parameters contributing to atherosclerotic risk in this disorder. METHODS: We measured low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), nonesterified fatty acids (NEFA), intrahepatic lipid (IHL) and intramyocellular lipid (IMCL), Homeostasis-model assessment of insulin resistance (HOMA-IR), augmentation index (AIx) and pulse wave velocity (PWV), flow-mediated dilatation, and carotid intima-media thickness (cIMT) in an unselected, genetically confirmed cohort of adult RTHß patients (nâ =â 27-77) and compared these with measurements in healthy subjects (up to nâ =â 100) and thyrotoxic patients (nâ =â 40). RESULTS: Resistance to thyroid hormone beta (RTHß) patients exhibited higher LDL-C (Pâ =â 0.008) and TG (Pâ =â 0.002) and lower HDL-C concentrations (Pâ =â 0.015â ×â 10-2) than control subjects, with LDL-C being higher than in thyrotoxic patients with comparable hyperthyroxinemia. Proprotein convertase subtilisin/kexin 9 (Pâ =â 0.002) and apolipoprotein B (Pâ =â 0.0009) levels were reduced in thyrotoxic patients but not lower in RTHß patients or control subjects. Intrahepatic lipid (Pâ =â 0.02â ×â 10-4), IMCL (Pâ =â 0.002), HOMA-IR (Pâ =â 0.01â ×â 10-2), and NEFA (Pâ =â 0.04â ×â 10-6) were significantly higher in RTHß patients than control subjects. Flow-mediated dilatation was increased (Pâ =â 0.04) but cIMT (Pâ =â 0.71), PWV Pâ =â 0.81), and AIx (Pâ =â 0.95) were unaltered in RTHß patients. CONCLUSIONS: We have documented mixed dyslipidemia with hepatic and IMCL accumulation in RTHß, suggesting that surveillance for these metabolic abnormalities is warranted. How they combine with enhanced endothelial function and unaltered vessel wall thickness and compliance to determine overall cardiometabolic risk in this disorder remains to be defined.
Assuntos
Dislipidemias/epidemiologia , Hipercolesterolemia/epidemiologia , Resistência à Insulina , Lipídeos/análise , Mutação , Receptores beta dos Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Adulto , Biomarcadores/análise , Espessura Intima-Media Carotídea , Estudos de Casos e Controles , Dislipidemias/metabolismo , Dislipidemias/patologia , Feminino , Seguimentos , Humanos , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Masculino , Prognóstico , Reino Unido/epidemiologiaRESUMO
Large-scale aetiological studies of obesity and its pathological consequences require accurate measurements of adipose mass, distribution and subtype. Here, we compared the validity of three abdominal obesity assessment methods (dual-energy X-ray absorptiometry (DXA), ultrasound and anthropometry) against the gold-standard method of computed tomography (CT) in twenty-nine non-diseased middle-aged men (BMI 26.5 (sd 3.1) kg/m(2)) and women (BMI 25.5 (sd 3.2) kg/m(2)). Assessments of adipose mass (kg) and distribution (total subcutaneous (TSAT), superficial subcutaneous (SSAT), deep subcutaneous (DSAT) and visceral (VAT)) were obtained. Spearman's correlations were performed adjusted for age and sex. VAT area that was assessed using ultrasound (r 0.79; P < 0.0001) and waist circumference (r 0.85; P < 0.0001) correlated highly with VAT from CT, as did BMI (r 0.67; P < 0.0001) and DXA (r 0.70; P < 0.0001). DXA (r 0.72; P = 0.0004), BMI (r 0.71; P = 0.0003), waist circumference (r 0.86; P < 0.0001) and ultrasound (r 0.52; P = 0.015) were less strongly correlated with CT TSAT. None of the comparison measures of DSAT was strongly correlated with CT DSAT (all r approximately 0.50; P < 0.02). BMI (r 0.76; P < 0.0001), waist circumference (r 0.65; P = 0.002) and DXA (r 0.75; P < 0.0001) were all fairly strongly correlated with the CT measure of SSAT, whereas ultrasound yielded a weaker yet statistically significant correlation (r 0.48; P = 0.03). Compared with CT, visceral and subcutaneous adiposity can be assessed with reasonable validity using waist circumference and BMI, respectively. Ultrasound or DXA does not generally provide substantially better measures of these traits. Highly valid assessments of DSAT do not appear to be possible with surrogate measures. These findings may help guide the selection of measures for epidemiological studies of obesity.
Assuntos
Adiposidade , Índice de Massa Corporal , Diagnóstico por Imagem/métodos , Gordura Intra-Abdominal , Obesidade Abdominal/diagnóstico por imagem , Gordura Subcutânea , Circunferência da Cintura , Absorciometria de Fóton/métodos , Adulto , Antropometria , Feminino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estatísticas não Paramétricas , Gordura Subcutânea/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , UltrassonografiaRESUMO
Increased levels of IMCL (intramyocellular lipid) have been shown to be associated with reduced steady-state glucose infusion rates during a hyperinsulinaemic-euglycaemic clamp (M-value). The aim of the present study was to explore how IMCL levels relate to the insulin-mediated suppression of endogenous glucose production [hepatic SI (insulin sensitivity)] and increase in glucose disposal (peripheral SI). In the present study, 11 healthy young adults (7 male, 4 female; aged 21-31 years) undertook, in random order, an hyperinsulinaemic-euglycaemic clamp combined with stable glucose isotope enrichment to measure peripheral and hepatic SI, a 1H-MRS (proton-magnetic resonance spectroscopy) scan to determine IMCL levels and a DXA (dual-energy X-ray absorptiometry) scan to assess body composition. IMCL levels (range, 3.2-10.7) were associated with whole-body fat mass (r=0.787, P=0.004), fat mass corrected for height (r=0.822, P=0.002) and percentage of central fat mass (r=0.694, P=0.02), but were not related to whole-body FFM (fat-free mass; r=-0.472, P=0.1). IMCL levels correlated closely with the M-value (r=-0.727, P=0.01) and FFM-corrected peripheral SI (r=-0.675, P=0.02), but were not related to hepatic SI adjusted for body weight (r=0.08, P=0.8). The results of the present study suggest that IMCL accumulation may be a sensitive marker for attenuations in peripheral, but not hepatic, SI in normal populations. Given the close relationship of IMCL levels to whole-body and central abdominal fat mass, relative increases in the flux of lipids from adipose tissue to the intramyocellular compartment may be an integral part of the mechanisms underlying reductions in SI.
Assuntos
Glicemia/biossíntese , Insulina/metabolismo , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Absorciometria de Fóton , Tecido Adiposo/metabolismo , Adulto , Composição Corporal , Índice de Massa Corporal , Feminino , Técnica Clamp de Glucose , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND: While there are compelling observational data confirming that individuals who exercise are healthier, the efficacy of aerobic exercise interventions to reduce metabolic risk and improve insulin sensitivity in older people has not been fully elucidated. Furthermore, while low birth weight has been shown to predict adverse health outcomes later in life, its influence on the response to aerobic exercise is unknown. Our primary objective is to assess the efficacy of a fully supervised twelve week aerobic exercise intervention in reducing clustered metabolic risk in healthy older adults. A secondary objective is to determine the influence of low birth weight on the response to exercise in this group. METHODS/DESIGN: We aim to recruit 100 participants born between 1931-1939, from the Hertfordshire Cohort Study and randomly assign them to no intervention or to 36 fully supervised one hour sessions on a cycle ergometer, over twelve weeks. Each participant will undergo detailed anthropometric and metabolic assessment pre- and post-intervention, including muscle biopsy, magnetic resonance imaging and spectroscopy, objective measurement of physical activity and sub-maximal fitness testing. DISCUSSION: Given the extensive phenotypic characterization, this study will provide valuable insights into the mechanisms underlying the beneficial effects of aerobic exercise as well as the efficacy, feasibility and safety of such interventions in this age group. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN60986572.
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BACKGROUND: The rising prevalence of obesity has made hepatic steatosis an increasingly common issue. Ultrasound is generally used in clinical practice to assess steatosis, but its accuracy has been inconsistent across studies. We aimed to determine the validity of ultrasound to diagnose hepatic steatosis when compared to the criterion method proton magnetic resonance spectroscopy (MRS) in older individuals. METHODS: A total of 72 healthy white European individuals (n = 42 men; n = 30 women aged 67-76 years) participating in the Hertfordshire Birth Cohort Physical Activity trial had hepatic steatosis assessed by ultrasound and MRS. The ultrasound scans were graded as normal, mild, moderate and severe steatosis, while hepatic fat content above 5.5% by MRS was used as a cut-off for steatosis. RESULTS: 18 participants (25%) had a level of hepatic fat measured by MRS consistent with diagnosis of steatosis. The sensitivity and specificity of ultrasound in diagnosing hepatic steatosis (mild/moderate/severe vs normal) were 96% (95% CI: 87-99.6%) and 94% (95% CI: 73-100%) respectively, although overlap in MRS hepatic fat content was observed between the ultrasound categories. CONCLUSIONS: Ultrasound is a valid method for detecting the presence or absence of hepatic steatosis in older adults and can be used as an alternative tool in both clinical investigations and epidemiological studies, when other imaging techniques are not feasible.
Assuntos
Fígado Gorduroso/diagnóstico por imagem , Fígado/diagnóstico por imagem , Espectroscopia de Prótons por Ressonância Magnética , Ultrassonografia , Tecido Adiposo/diagnóstico por imagem , Tecido Adiposo/metabolismo , Idoso , Fígado Gorduroso/metabolismo , Feminino , Humanos , Fígado/metabolismo , Imageamento por Ressonância Magnética , Masculino , Variações Dependentes do Observador , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
Intramyocellular lipid (IMCL) is of particular metabolic interest, but despite many proton magnetic resonance spectroscopy (1H MRS) studies reporting IMCL content measured by the methylene (CH2) resonance signal, little is known about its composition. Here we validated IMCL CH3:CH2 ratio as a compositional marker using 1H MRS at short echo time, and investigated IMCL content and composition during a 28-hour fast in 24 healthy males. Increases in IMCL CH2 relative to the creatine and phosphocreatine resonance (Cr) at 3.0 ppm (an internal standard) correlated with circulating free fatty acid (FA) concentrations, supporting the concept of increased FA influx into IMCL. Significant decreases in IMCL CH3:CH2 ratio indicated a less unsaturated IMCL pool after fasting, and this compositional change related inversely to IMCL baseline composition, suggesting a selective efflux of unsaturated shorter-chain FA from the IMCL pool. This novel in vivo evidence reveals IMCL turnover during extended fasting, consistent with the concept of a flexible, responsive myocellular lipid store. There were also differences between soleus and tibialis anterior in basal IMCL composition and in response to fasting. We discuss the potential of this marker for providing insights into normal physiology and mechanisms of disease.
Assuntos
Jejum , Ácidos Graxos/metabolismo , Lipólise/fisiologia , Músculo Esquelético/metabolismo , Adolescente , Adulto , Ácidos Graxos/química , Voluntários Saudáveis , Humanos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-IdadeRESUMO
Context: The activating p.Glu17Lys mutation in AKT2, a kinase mediating many of insulin's metabolic actions, causes hypoinsulinemic hypoglycemia and left-sided hemihypertrophy. The wider metabolic profile and longer-term natural history of the condition has not yet been reported. Objective: To characterize the metabolic and cellular consequences of the AKT2 p.Glu17Lys mutation in two previously reported males at the age of 17 years. Design and Intervention: Body composition analysis using dual-energy X-ray absorptiometry, overnight profiling of plasma glucose, insulin, and fatty acids, oral glucose tolerance testing, and magnetic resonance spectroscopy to determine hepatic triglyceride content was undertaken. Hepatic de novo lipogenesis was quantified using deuterium incorporation into palmitate. Signaling in dermal fibroblasts was studied ex vivo. Results: Both patients had 37% adiposity. One developed hypoglycemia after 2 hours of overnight fasting with concomitant suppression of plasma fatty acids and ketones, whereas the other maintained euglycemia with an increase in free fatty acids. Blood glucose excursions after oral glucose were normal in both patients, albeit with low plasma insulin concentrations. In both patients, plasma triglyceride concentration, hepatic triglyceride content, and fasting hepatic de novo lipogenesis were normal. Dermal fibroblasts of one proband showed low-level constitutive phosphorylation of AKT and some downstream substrates, but no increased cell proliferation rate. Conclusions: The p.Glu17Lys mutation of AKT2 confers low-level constitutive activity upon the kinase and produces hypoglycemia with suppressed fatty acid release from adipose tissue, but not fatty liver, hypertriglyceridemia, or elevated hepatic de novo lipogenesis. Hypoglycemia may spontaneously remit.
Assuntos
Tecido Adiposo/diagnóstico por imagem , Hipoglicemia/genética , Proteínas Proto-Oncogênicas c-akt/genética , Absorciometria de Fóton , Adolescente , Composição Corporal/genética , Ácidos Graxos/metabolismo , Fígado Gorduroso , Humanos , Hipoglicemia/metabolismo , Lipogênese/genética , Masculino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Triglicerídeos/metabolismoRESUMO
[This corrects the article on p. 426 in vol. 8, PMID: 28955291.].
RESUMO
Traumatic brain injury (TBI) triggers a series of complex pathophysiological processes. These include abnormalities in brain energy metabolism; consequent to reduced tissue pO2 arising from ischemia or abnormal tissue oxygen diffusion, or due to a failure of mitochondrial function. In vivo magnetic resonance spectroscopy (MRS) allows non-invasive interrogation of brain tissue metabolism in patients with acute brain injury. Nuclei with "spin," e.g., 1H, 31P, and 13C, are detectable using MRS and are found in metabolites at various stages of energy metabolism, possessing unique signatures due to their chemical shift or spin-spin interactions (J-coupling). The most commonly used clinical MRS technique, 1H MRS, uses the great abundance of hydrogen atoms within molecules in brain tissue. Spectra acquired with longer echo-times include N-acetylaspartate (NAA), creatine, and choline. NAA, a marker of neuronal mitochondrial activity related to adenosine triphosphate (ATP), is reported to be lower in patients with TBI than healthy controls, and the ratio of NAA/creatine at early time points may correlate with clinical outcome. 1H MRS acquired with shorter echo times produces a more complex spectrum, allowing detection of a wider range of metabolites.31 P MRS detects high-energy phosphate species, which are the end products of cellular respiration: ATP and phosphocreatine (PCr). ATP is the principal form of chemical energy in living organisms, and PCr is regarded as a readily mobilized reserve for its replenishment during periods of high utilization. The ratios of high-energy phosphates are thought to represent a balance between energy generation, reserve and use in the brain. In addition, the chemical shift difference between inorganic phosphate and PCr enables calculation of intracellular pH.13 C MRS detects the 13C isotope of carbon in brain metabolites. As the natural abundance of 13C is low (1.1%), 13C MRS is typically performed following administration of 13C-enriched substrates, which permits tracking of the metabolic fate of the infused 13C in the brain over time, and calculation of metabolic rates in a range of biochemical pathways, including glycolysis, the tricarboxylic acid cycle, and glutamate-glutamine cycling. The advent of new hyperpolarization techniques to transiently boost signal in 13C-enriched MRS in vivo studies shows promise in this field, and further developments are expected.
RESUMO
Common genetic variants at the ARL15 locus are associated with plasma adiponectin, insulin and HDL cholesterol concentrations, obesity, and coronary atherosclerosis. The ARL15 gene encodes a small GTP-binding protein whose function is currently unknown. In this study adipocyte-autonomous roles for ARL15 were investigated using conditional knockdown of Arl15 in murine 3T3-L1 (pre)adipocytes. Arl15 knockdown in differentiated adipocytes impaired adiponectin secretion but not adipsin secretion or insulin action, while in preadipocytes it impaired adipogenesis. In differentiated adipocytes GFP-tagged ARL15 localized predominantly to the Golgi with lower levels detected at the plasma membrane and intracellular vesicles, suggesting involvement in intracellular trafficking. Sequencing of ARL15 in 375 severely insulin resistant patients identified four rare heterozygous variants, including an early nonsense mutation in a proband with femorogluteal lipodystrophy and non classical congenital adrenal hyperplasia, and an essential splice site mutation in a proband with partial lipodystrophy and a history of childhood yolk sac tumour. No nonsense or essential splice site mutations were found in 2,479 controls, while five such variants were found in the ExAC database. These findings provide evidence that ARL15 plays a role in adipocyte differentiation and adiponectin secretion, and raise the possibility that human ARL15 haploinsufficiency predisposes to lipodystrophy.
Assuntos
Fatores de Ribosilação do ADP/metabolismo , Adipócitos/metabolismo , Adipócitos/patologia , Adiponectina/metabolismo , Diferenciação Celular , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Células 3T3-L1 , Fatores de Ribosilação do ADP/genética , Adipogenia , Adulto , Animais , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Complexo de Golgi/metabolismo , Células HEK293 , Haploinsuficiência , Humanos , Resistência à Insulina , Lipodistrofia/genética , Lipodistrofia/metabolismo , Masculino , Síndrome Metabólica/genética , Camundongos , Pessoa de Meia-Idade , Transporte Proteico , Adulto JovemRESUMO
MFN2 encodes mitofusin 2, a membrane-bound mediator of mitochondrial membrane fusion and inter-organelle communication. MFN2 mutations cause axonal neuropathy, with associated lipodystrophy only occasionally noted, however homozygosity for the p.Arg707Trp mutation was recently associated with upper body adipose overgrowth. We describe similar massive adipose overgrowth with suppressed leptin expression in four further patients with biallelic MFN2 mutations and at least one p.Arg707Trp allele. Overgrown tissue was composed of normal-sized, UCP1-negative unilocular adipocytes, with mitochondrial network fragmentation, disorganised cristae, and increased autophagosomes. There was strong transcriptional evidence of mitochondrial stress signalling, increased protein synthesis, and suppression of signatures of cell death in affected tissue, whereas mitochondrial morphology and gene expression were normal in skin fibroblasts. These findings suggest that specific MFN2 mutations cause tissue-selective mitochondrial dysfunction with increased adipocyte proliferation and survival, confirm a novel form of excess adiposity with paradoxical suppression of leptin expression, and suggest potential targeted therapies.