RESUMO
AIMS/HYPOTHESIS: South Asians have a higher risk of developing type 2 diabetes than Europeans. The underlying cause of this excess risk is still poorly understood but might be related to differences in the regulation of energy/nutrient-sensing pathways in metabolic tissues and subsequent changes in whole-body substrate metabolism. In this study, we investigated the whole-body and skeletal muscle metabolic adaptations to short-term energy restriction in South Asian and European volunteers. METHODS: Twenty-four middle-aged overweight South Asian and European men underwent a two-step hyperinsulinaemic-euglycaemic clamp, with skeletal muscle biopsies and indirect calorimetry before and after an 8 day diet very low in energy (very low calorie diet [VLCD]). Abdominal fat distribution and hepatic triacylglycerol content were assessed using MRI and MR spectroscopy. RESULTS: South Asian men had higher hepatic triacylglycerol content than European men, and exhibited elevated clamp insulin levels that probably reflect a lower insulin clearance rate. Despite higher insulin levels, endogenous glucose production rate was similar and glucose disposal rate (Rd) and nonoxidative glucose disposal rate (NOGD) were significantly lower in South Asian than European men, indicating impaired whole-body insulin sensitivity. Energy restriction decreased abdominal fat mass and hepatic triacylglycerol content in both groups. However, the shift induced by energy restriction from glucose towards lipid oxidation observed in European men was impaired in South Asian men, indicating whole-body metabolic inflexibility. Remarkably, although energy restriction improved hepatic insulin sensitivity in both groups, Rd improved only in South Asian men owing to higher NOGD. At the molecular level, an increase in insulin-induced activation of the skeletal muscle mTOR pathway was found in South Asian men, showing that skeletal muscle energy/nutrient-sensing pathways were differentially affected by energy restriction. CONCLUSIONS/INTERPRETATION: We conclude that South Asian men exhibit a different metabolic adaptation to short-term energy restriction than European men. TRIAL REGISTRATION: Dutch trial registry ( www.trialregister.nl ), trial number NTR 2473.
Assuntos
Adaptação Fisiológica/fisiologia , Povo Asiático , Restrição Calórica , Sobrepeso/dietoterapia , Sobrepeso/etnologia , Sobrepeso/metabolismo , População Branca , Proteínas Quinases Ativadas por AMP/metabolismo , Adulto , Ásia/etnologia , Restrição Calórica/etnologia , Humanos , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Países Baixos , Transdução de SinaisRESUMO
Macrophage markers in skeletal muscle of obese subjects are elevated and inversely relate to insulin sensitivity. The present study aimed to investigate whether short-term high-fat high-calorie (HFHC) diet already increases macrophage markers and affects glucose metabolism in skeletal muscle of healthy lean subjects. Muscle biopsies were obtained from 24 healthy lean young men before and after a 5-day HFHC-diet. mRNA expression levels of relevant genes in muscle and glucose, insulin, C-peptide and cholesteryl ester transfer protein (CETP) levels in plasma were measured. In addition, we assessed hepatic triacylglycerol ('triglyceride') (HTG) content by magnetic resonance spectroscopy and subcutaneous white adipose tissue (sWAT) biopsies were analysed histologically from a subset of subjects (n=8). A 5-day HFHC-diet markedly increased skeletal muscle mRNA expression of the general macrophage markers CD68 (3.7-fold, P<0.01) and CD14 (3.2-fold, P<0.01), as well as the M1 macrophage markers MARCO (11.2-fold, P<0.05), CD11c (1.8-fold, P<0.05) and MRC1 (1.7-fold, P<0.05). This was accompanied by down-regulation of SLC2A4 and GYS1 mRNA expression, and elevated plasma glucose (+4%, P<0.001) and insulin (+55%, P<0.001) levels together with homoeostasis model assessment of insulin resistance (HOMA-IR) (+48%, P<0.001), suggesting development of insulin resistance (IR). Furthermore, the HFHC-diet markedly increased HTG (+118%, P<0.001) and plasma CETP levels (+21%, P<0.001), a marker of liver macrophage content, whereas sWAT macrophage content remained unchanged. In conclusion, short-term HFHC-diet increases expression of macrophage markers in skeletal muscle of healthy men accompanied by reduced markers of insulin signalling and development of IR. Therefore, recruitment of macrophages into muscle may be an early event in development of IR in response to short-term HFHC-feeding.
Assuntos
Insulina/sangue , Músculo Esquelético/metabolismo , Tecido Adiposo/metabolismo , Adulto , Biomarcadores/metabolismo , Glicemia , Peptídeo C/sangue , Proteínas de Transferência de Ésteres de Colesterol/sangue , Dieta Hiperlipídica , Humanos , Insulina/metabolismo , Resistência à Insulina , Fígado/metabolismo , Macrófagos/metabolismo , Masculino , Triglicerídeos/metabolismoRESUMO
OBJECTIVE: Cardiac ectopic fat depositions are thought to play a role in the pathogenesis of cardiovascular disease (CVD), the main cause of death in patients with type 2 diabetes. Diet-induced weight loss results in a decrease in cardiac ectopic fat stores, however if this is the same for surgically induced weight loss is less clear. Therefore, we assessed myocardial triglyceride (TG) content, pericardial fat and cardiac function in obese patients with insulin-dependent type 2 diabetes before and 16 weeks after Roux-en-Y gastric bypass (RYGB) surgery. PATIENTS: Ten obese patients with insulin-dependent type 2 diabetes [40% male, age 53·7 ± 8·9 years (mean ± SD)] scheduled to undergo RYGB surgery were included. MEASUREMENTS: Ectopic fat accumulation and cardiovascular function were assessed with magnetic resonance (MR) imaging and myocardial TG content with MR spectroscopy before and 16 weeks after RYGB surgery. RESULTS: Body mass index decreased from 41·3 ± 4·3 at baseline to 34·1 ± 2·8 kg/m(2) (P < 0·001) after 16 weeks. Glycemic control improved as well [HbA1c: 7·8 ± 1·1 to 6·8 ± 1·3% (62 ± 12 to 51 ± 14 mm) (P < 0·05)]. We did not observe an effect of the RYGB surgery on myocardial TG content, cardiac function or pulse wave velocity. There was a greater relative decrease in visceral (-35·5 ± 9·6%) as compared to subcutaneous fat volume (-25·0 ± 6·3%) and in paracardial (-17·3 ±17·2%) as compared to epicardial fat volume (-6·4 ± 6·0%). CONCLUSIONS: This study shows that surgical-induced weight loss leads to a larger decrease in paracardial than epicardial fat. Myocardial TG and cardiovascular function did not change.
Assuntos
Tecido Adiposo , Cirurgia Bariátrica , Fenômenos Fisiológicos Cardiovasculares , Diabetes Mellitus Tipo 2/cirurgia , Obesidade Mórbida/cirurgia , Pericárdio/metabolismo , Adolescente , Adulto , Coristoma , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/complicações , Obesidade Mórbida/fisiopatologia , Pericárdio/patologia , Análise de Onda de Pulso , Adulto JovemRESUMO
OBJECTIVE: To assess the association between aortic pulse wave velocity (PWV) as a marker of arterial stiffness and diffusion tensor imaging of brain white matter integrity in patients with type 1 diabetes using advanced magnetic resonance imaging (MRI) technology. METHODS: Forty-one patients with type 1 diabetes (23 men, mean age 44 ± 12 years, mean diabetes duration 24 ± 13 years) were included. Aortic PWV was assessed using through-plane velocity-encoded MRI. Brain diffusion tensor imaging (DTI) measurements were performed on 3-T MRI. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated for white and grey matter integrity. Pearson correlation and multivariable linear regression analyses including cardiovascular risk factors as covariates were assessed. RESULTS: Multivariable linear regression analyses revealed that aortic PWV is independently associated with white matter integrity FA (ß = -0.777, p = 0.008) in patients with type 1 diabetes. This effect was independent of age, gender, mean arterial pressure, body mass index, smoking, duration of diabetes and glycated haemoglobin levels. Aortic PWV was not significantly related to grey matter integrity. CONCLUSIONS: Our data suggest that aortic stiffness is independently associated with reduced white matter integrity in patients with type 1 diabetes. KEY POINTS: Aortic stiffness is associated with brain injury. Aortic stiffness exposes small vessels to high pressure fluctuations and flow. Aortic stiffness is associated with microvascular brain injury in diabetes. This suggests a vascular contribution to early subtle microstructural deficits.
Assuntos
Aorta Torácica/fisiopatologia , Encefalopatias/diagnóstico , Diabetes Mellitus Tipo 1/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Rigidez Vascular , Substância Branca/patologia , Adulto , Anisotropia , Aorta Torácica/patologia , Encefalopatias/etiologia , Encefalopatias/fisiopatologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/diagnóstico , Feminino , Humanos , Masculino , Análise de Onda de Pulso , Estudos RetrospectivosRESUMO
PURPOSE: To prospectively assess the effects of an exercise intervention on organ-specific fat accumulation and cardiac function in type 2 diabetes mellitus. MATERIALS AND METHODS: Written informed consent was obtained from all participants, and the study protocol was approved by the medical ethics committee. The study followed 12 patients with type 2 diabetes mellitus (seven men; mean age, 46 years ± 2 [standard error]) before and after 6 months of moderate-intensity exercise, followed by a high-altitude trekking expedition with exercise of long duration. Abdominal, epicardial, and paracardial fat volume were measured by using magnetic resonance (MR) imaging. Cardiac function was quantified with cardiac MR, and images were analyzed by a researcher who was supervised by a senior researcher (4 and 21 years of respective experience in cardiac MR). Hepatic, myocardial, and intramyocellular triglyceride (TG) content relative to water were measured with proton MR spectroscopy at 1.5 and 7 T. Two-tailed paired t tests were used for statistical analysis. RESULTS: Exercise reduced visceral abdominal fat volume from 348 mL ± 57 to 219 mL ± 33 (P < .01), and subcutaneous abdominal fat volume remained unchanged (P = .9). Exercise decreased hepatic TG content from 6.8% ± 2.3 to 4.6% ± 1.6 (P < .01) and paracardial fat volume from 4.6 mL ± 0.9 to 3.7 mL ± 0.8 (P = .02). Exercise did not change epicardial fat volume (P = .9), myocardial TG content (P = .9), intramyocellular lipid content (P = .3), or cardiac function (P = .5). CONCLUSION: A 6-month exercise intervention in type 2 diabetes mellitus decreased hepatic TG content and visceral abdominal and paracardial fat volume, which are associated with increased cardiovascular risk, but cardiac function was unaffected. Tissue-specific exercise-induced changes in body fat distribution in type 2 diabetes mellitus were demonstrated in this study.
Assuntos
Tecido Adiposo/patologia , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Exercício Físico/fisiologia , Imageamento por Ressonância Magnética/métodos , Feminino , Testes de Função Cardíaca , Humanos , Gordura Intra-Abdominal/patologia , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Resistência Física/fisiologia , Estudos Prospectivos , Fatores de Risco , Triglicerídeos/análiseRESUMO
Several case reports have described hypopituitarism following orthohantavirus infection, mostly following Puumala virus. The pathogenesis of this seemingly rare complication of orthohantavirus infection remains unknown. This review explores the possible pathophysiological mechanisms of pituitary damage due to orthohantavirus infection. In only three out of the 28 reported cases, hypopituitarism was detected during active infection. In the remaining cases, detection of pituitary damage was delayed, varying from two months up to thirteen months post-infection. In these cases, hypopituitarism remained undetected during the acute phase of infection or only occurred weeks to months post infection. Both ischemic and hemorrhagic damage of the pituitary gland have been detected in radiographic imaging and post-mortem studies in the studied case reports series. Ischemic damage could be caused by hypotension and/or vasospasms during the acute phase of hemorrhagic fever with renal syndrome (HFRS) while hemorrhage could be caused by thrombocytopenia, thrombopathy, and other known causes of coagulation disorders during orthohantavirus infection. Also, hypophysitis due to the presence of auto-antibodies have been suggested in the literature. In conclusion, a significant number of case reports and series describe hypopituitarism after orthohantavirus infection. In most cases hypopituitarism was diagnosed with a delay and therefore could very well be underreported. Clinicians should be aware of this potential endocrine complication, with substantial morbidity, and if unrecognized, significant mortality.
Assuntos
Febre Hemorrágica com Síndrome Renal/complicações , Hipopituitarismo/etiologia , Orthohantavírus/patogenicidade , Febre Hemorrágica com Síndrome Renal/diagnóstico , Febre Hemorrágica com Síndrome Renal/patologia , Febre Hemorrágica com Síndrome Renal/fisiopatologia , Humanos , Hipopituitarismo/diagnóstico , Hipopituitarismo/patologia , Hipopituitarismo/fisiopatologia , Hipófise/patologia , Hipófise/fisiopatologia , Virus Puumala/patogenicidadeRESUMO
BACKGROUND/OBJECTIVES: Endocannabinoids (ECs) are associated with obesity and ectopic fat accumulation, both of which play a role in the development of cardiovascular disease (CVD) in type 2 diabetes (T2D). The effect of prolonged caloric restriction on ECs in relation to fat distribution and cardiac function is still unknown. Therefore, our aim was to investigate this relationship in obese T2D patients with coronary artery disease (CAD). SUBJECTS/METHODS: In a prospective intervention study, obese T2D patients with CAD (n = 27) followed a 16 week very low calorie diet (VLCD; 450-1000 kcal/day). Cardiac function and fat accumulation were assessed with MRI and spectroscopy. Plasma levels of lipid species, including ECs, were measured using liquid chromatography-mass spectrometry. RESULTS: VLCD decreased plasma levels of virtually all measured lipid species of the class of N-acylethanolamines including the EC anandamide (AEA; -15%, p = 0.016), without decreasing monoacylglycerols including the EC 2-arachidonoylglycerol (2-AG). Baseline plasma AEA levels strongly correlated with the volume of subcutaneous white adipose tissue (SAT; R2 = 0.44, p < 0.001). VLCD decreased the volume of SAT (-53%, p < 0.001), visceral white adipose tissue (VAT) (-52%, p < 0.001), epicardial white adipose tissue (-15%, p < 0.001) and paracardial white adipose tissue (-28%, p < 0.001). VLCD also decreased hepatic (-86%, p < 0.001) and myocardial (-33%, p < 0.001) fat content. These effects were accompanied by an increased left ventricular ejection fraction (54.8 ± 8.7-56.2 ± 7.9%, p = 0.016). CONCLUSIONS: Caloric restriction in T2D patients with CAD decreases AEA levels, but not 2-AG levels, which is paralleled by decreased lipid accumulation in adipose tissue, liver and heart, and improved cardiovascular function. Interestingly, baseline AEA levels strongly correlated with SAT volume. We anticipate that dietary interventions are worthwhile strategies in advanced T2D, and that reduction in AEA may contribute to the improved cardiometabolic phenotype induced by weight loss.
Assuntos
Tecido Adiposo/metabolismo , Restrição Calórica , Doença da Artéria Coronariana/dietoterapia , Diabetes Mellitus Tipo 2/dietoterapia , Dieta Redutora , Endocanabinoides/sangue , Função Ventricular Esquerda , Idoso , Ácidos Araquidônicos/sangue , Distribuição da Gordura Corporal , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Ingestão de Energia , Etanolaminas/sangue , Feminino , Glicerídeos/sangue , Coração/fisiopatologia , Humanos , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Obesidade/sangue , Obesidade/complicações , Obesidade/dietoterapia , Obesidade/metabolismo , Alcamidas Poli-Insaturadas/sangue , Estudos Prospectivos , Redução de Peso/fisiologiaRESUMO
South Asians (SAs) develop type 2 diabetes at a younger age and lower BMI compared with Caucasians (Cs). The underlying cause is still poorly understood but might result from an innate inability to adapt to the Westernized diet. This study aimed to compare the metabolic adaptation to a high-fat, high-calorie (HFHC) diet between both ethnicities. Twelve healthy, young lean male SAs and 12 matched Cs underwent a two-step hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies and indirect calorimetry before and after a 5-day HFHC diet. Hepatic triglyceride content (HTG) and abdominal fat distribution were assessed using magnetic resonance imaging and spectroscopy. At baseline, SAs had higher insulin clamp levels than Cs, indicating reduced insulin clearance rate. Despite the higher insulin levels, endogenous glucose production was comparable between groups, suggesting lower hepatic insulin sensitivity in SAs. Furthermore, a 5-day HFHC diet decreased the insulin-stimulated (nonoxidative) glucose disposal rate only in SA. In skeletal muscle, no significant differences were found between groups in insulin/mammalian target of rapamycin signaling, metabolic gene expression, and mitochondrial respiratory chain content. Furthermore, no differences in (mobilization of) HTG and abdominal fat were detected. We conclude that HFHC feeding rapidly induces insulin resistance only in SAs. Thus, distinct adaptation to Western food may partly explain their propensity to develop type 2 diabetes.
Assuntos
Povo Asiático , Dieta Hiperlipídica , Dieta/etnologia , Resistência à Insulina/etnologia , Metabolismo dos Lipídeos/fisiologia , População Branca , Adulto , Glicemia/metabolismo , Técnica Clamp de Glucose , Humanos , Resistência à Insulina/fisiologia , Fígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Triglicerídeos/metabolismoRESUMO
Diabetes mellitus type 1 (DM1) is associated with aortic stiffening and left ventricular (LV) diastolic dysfunction, however the relationship between aortic stiffness and LV diastolic dysfunction in DM1 patients is still largely unknown. The purpose of this study was to evaluate whether an increased aortic stiffness, expressed by increased aortic pulse wave velocity (PWV), is associated with subclinical LV diastolic dysfunction and decreased left atrial (LA) compliance as assessed with speckle tracking strain analysis in patients with DM1. Aortic PWV was assessed with cardiovascular magnetic resonance in 41 DM1 patients. Patients underwent echocardiography for assessment of conventional LV diastolic function indices and LV and LA longitudinal strain and strain rate (SR) assessed with speckle tracking strain analysis. LV SR during the isovolumic relaxation period (SRIVR) and LA strain were recorded and the E-wave velocity to SRIVR velocity ratio (E/SRIVR) was calculated. Independent samples t test and multivariate linear regression analyses were used for statistical analyses. Aortic PWV significantly correlated with SRIVR (ß = -0.71, p < 0.001), E/SRIVR (ß = 0.61, p = 0.002) and LA strain (ß = -0.47, p = 0.014), but not with conventional echocardiographic markers of diastolic function (all p > 0.10). In DM1 patients, aortic stiffness is inversely associated with sensitive markers of LV diastolic function and decrease in LA compliance as measured with echocardiographic speckle tracking strain analysis.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Ecocardiografia Doppler , Imageamento por Ressonância Magnética , Contração Miocárdica , Rigidez Vascular , Disfunção Ventricular Esquerda/diagnóstico , Função Ventricular Esquerda , Adulto , Idoso , Função do Átrio Esquerdo , Distribuição de Qui-Quadrado , Complacência (Medida de Distensibilidade) , Estudos Transversais , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Análise de Onda de Pulso , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
OBJECTIVES: Magnetic resonance imaging (MRI) of the vessel wall enables determination of luminal area, vessel wall thickness, and atherosclerotic plaque characteristics. For clinical application, high spatial resolution, derived from optimal signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), is paramount. Vessel wall MRI is expected to benefit from higher magnetic field strength. Therefore, the purposes of the present study were to develop an ultrahigh-field 7-T MRI hardware and protocols for vessel wall imaging of the carotid artery and to compare quantitative parameters of vessel wall morphology and image quality between 3-T and 7-T MRI. MATERIAL AND METHODS: Eighteen volunteers (11 men and 7 women; mean [SD] age, 29 [7] years) underwent MRI examinations at 7 T (using a custom-built surface transmit/receive coil of 15-cm diameter) and at 3 T (using a commercial phased-array coil with 2 flexible oval elements, 14 × 17 cm each). Magnetic resonance imaging of the left common carotid artery vessel wall was performed at 7 T with identical in-plane resolution as that of 3-T MRI (0.46 × 0.46 mm), providing transverse T1- and T2-weighted images. Blinded analysis of morphologic measurements (luminal area and vessel wall area), SNR for vessel wall (SNRVW), and the CNR between the lumen and the vessel wall were compared between 7 and 3 T. RESULTS: Morphologic carotid vessel wall measurements were comparable between 7 and 3 T for both T1-weighted images (luminal area: intraclass correlation [ICC], 0.81 and vessel wall area: ICC, 0.84) and T2-weighted images (luminal area: ICC, 0.97 and vessel wall area: ICC, 0.92). At 7 T, SNRVW and CNR were significantly higher compared with 3-T MRI for both T1- (P < 0.001) and T2-weighted images (P < 0.05), with gain factors ranging from 1.3 to 3.6. CONCLUSIONS: Ultrahigh-field 7-T MR carotid vessel wall imaging is feasible. 7-T MRI of the common carotid artery has comparable accuracy for determining luminal area and vessel wall area and has improved SNRVW and CNR compared with 3-T MRI. Therefore, ultrahigh-field 7-T vessel wall MRI may enable a more detailed assessment of plaque morphology.