RESUMO
PURPOSE: Prior research has focused on glucose/insulin responses to meal challenges to create personalized diets to improve health, though it is unclear if these responses predict chronic diseases. We aimed to identify glucose and insulin responses to a mixed meal tolerance test (MMTT) that predict the development of diabetic retinopathy (DR) and compare the predictive abilities with the oral glucose tolerance test (OGTT). METHODS: Indigenous American adults without diabetes (n = 168) underwent a 4-h MMTT, body composition assessment, and a 3-h OGTT at baseline. During follow-up (median 13.4 years), DR was diagnosed by direct ophthalmoscopy (n = 28) after onset of type 2 diabetes. Total and incremental area under the curve (AUC and iAUC) were calculated from glucose/insulin responses after the MMTT and OGTT. RESULTS: In separate Cox proportional hazards models adjusted for age, sex, and body fat (%), MMTT glucose AUCs (180-min and 240-min) and iAUC (180-min) predicted DR (HR 1.50, 95% CI 1.06, 2.12; HR 1.50, 95% CI 1.05, 2.14; HR 1.58, 95% CI 1.01, 2.46). The predictive abilities were better than the fasting OGTT glucose (p < 0.01) but similar to the 120-min OGTT glucose (p = 0.53). MMTT insulin AUCs (180-min and 240-min) and iAUC (180-min) also predicted DR (HR 1.65, 95% CI 1.09, 2.51; HR 1.58, 95% CI 1.00, 2.35; HR 1.53 95% CI 1.06, 2.22) while insulin AUC and iAUC from the OGTT did not (p > 0.05). CONCLUSIONS: Higher MMTT glucose and insulin responses predicted DR and were comparable to the OGTT, supporting the use of a meal challenge for precision nutrition. TRIAL REGISTRATIONS: Clinical Trial Registry: ClinicalTrials.gov identifier: NCT00340132, NCT00339482.
Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Adulto , Humanos , Tecido Adiposo , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/etiologia , Glucose/metabolismo , Insulina/metabolismoRESUMO
PURPOSE: To examine the association of epicardial and pericardial fat volume (EFV, PFV) with cardiovascular risk factors and kidney function in Native Americans of southwestern heritage with youth and early adult onset type 2 diabetes mellitus (T2DM) versus healthy controls. METHODS: Using computed tomography, we quantified EFV and PFV in 149 Native Americans (92 women, 57 men), 95 of which had T2DM (38 diagnosed prior to age 20 years). Duration of T2DM, mean carotid arterial mass (AM), coronary artery calcification (CAC), IL-6, and estimated glomerular filtration rate eGFRcr(CKD-EPI) were measured. RESULTS: EFV and PFV were associated with BMI (r = 0.37, p < 0.0001; r = 0.26, p = 0.001) and did not differ between onset age-groups and controls (p > 0.05). EFV was associated with AM only in controls (r = 0.51, p < 0.0001). After adjustment for BMI, T2DM duration, HbA1C, age, and sex, EFV was a predictor of CAC and IL-6 concentrations in early adult onset T2DM (ß = 0.05 ± 0.02 cm3, p = 0.03; ß = 0.05 ± 0.01 pg/ml/cm3, p = 0.002). EFV and PFV were independent predictors of reduced eGFRcr(CKD-EPI) in the youth onset T2DM group (ß = -0.3 ± 0.08 ml/min/cm3, p = 0.001; ß = -0.25 ± 0.05 ml/min/cm3, p < 0.0001). CONCLUSIONS: Epicardial fat volume may be a risk factor for heart disease in individuals with early adult onset T2DM and a predictor of decreased kidney function in individuals with youth onset T2DM.
Assuntos
Tecido Adiposo/patologia , Biomarcadores/análise , Doença da Artéria Coronariana/diagnóstico , Diabetes Mellitus Tipo 2/complicações , Pericárdio/patologia , Insuficiência Renal/diagnóstico , Adolescente , Adulto , Idade de Início , Estudos de Casos e Controles , Criança , Doença da Artéria Coronariana/etiologia , Mapeamento Epicárdico , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Prognóstico , Insuficiência Renal/etiologia , Fatores de Risco , Adulto JovemRESUMO
PURPOSE: Glucagon-like peptide 1 (GLP-1) is an incretin hormone that appears to play a major role in the control of food intake. The aim of this investigation was to evaluate and quantify the association of circulating GLP-1 concentration with ad libitum total calorie and macronutrient intake. METHODS: One-hundred and fifteen individuals (72 men) aged 35 ± 10 years were admitted for an inpatient study investigating the determinants of energy intake. Ad libitum food intake was assessed during 3 days using a reproducible vending machine paradigm. Fasting plasma GLP-1 concentrations were measured on the morning of the first day and on the morning of the fourth day after ad libitum feeding. RESULTS: Plasma GLP-1 concentrations increased by 14% after 3 days of ad libitum food intake. Individuals overate on average 139 ± 45% of weight-maintaining energy needs. Fasting plasma GLP-1 on day 1 was negatively associated with carbohydrate intake (r = - 0.2, p = 0.03) and with daily energy intake from low fat-high simple sugar (r = - 0.22, p = 0.016). CONCLUSION: Higher plasma GLP-1 concentrations prior to ad libitum food intake were associated with lower carbohydrate intake and lower simple sugar ingestion, indicating a possible role of the GLP-1 in the reward pathway regulating simple sugar intake. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00342732.
Assuntos
Carboidratos/administração & dosagem , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Energia/efeitos dos fármacos , Jejum/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Hiperfagia/sangue , Adulto , Feminino , Seguimentos , Humanos , MasculinoRESUMO
The pathogenesis of human obesity is the result of dysregulation of the reciprocal relationship between food intake and energy expenditure (EE), which influences daily energy balance and ultimately leads to weight gain. According to principles of energy homeostasis, a relatively lower EE in a setting of energy balance may lead to weight gain; however, results from different study groups are contradictory and indicate a complex interaction between EE and food intake which may differentially influence weight change in humans. Recently, studies evaluating the adaptive response of one component to perturbations of the other component of energy balance have revealed both the existence of differing metabolic phenotypes ("spendthrift" and "thrifty") resulting from overeating or underfeeding, as well as energy-sensing mechanisms linking EE to food intake, which might explain the propensity of an individual to weight gain. The purpose of this review is to debate the role that human EE plays on body weight regulation and to discuss the physiologic mechanisms linking EE and food intake. An increased understanding of the complex interplay between human metabolism and food consumption may provide insight into pathophysiologic mechanisms underlying weight gain, which may eventually lead to prevention and better treatment of human obesity.
Assuntos
Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Ingestão de Energia/fisiologia , Metabolismo Energético/fisiologia , Obesidade/metabolismo , Composição Corporal/fisiologia , Humanos , Obesidade/etiologia , Fenótipo , Aumento de Peso/fisiologiaRESUMO
BACKGROUND: Body weight and adiposity are heritable traits. To date, it remains unknown whether obesity-associated brain structural alterations are under a similar level of genetic control. METHODS: For this study, we utilized magnetic resonance imaging data from the Human Connectome Project. Voxel-based morphometry was used to investigate associations between body mass index (BMI) and regional gray matter volume (GMV) in a sample of 875 young adults with a wide BMI range (386 males/489 females; age 28.8±3.7 years; BMI 26.6±5.3 kg m-2) that included 86 pairs of monozygotic twins and 82 pairs of dizygotic twins. Twin data were analyzed by applying the additive genetic, common environmental and residual effects model to determine heritability of brain regions that were associated with BMI. RESULTS: We observed positive associations between BMI and GMV in the ventromedial prefrontal cortex and the right cerebellum and widespread negative associations within the prefrontal cortex, cerebellum, temporal lobes and distinct subcortical structures. Varying degrees of heritability were found for BMI-associated brain regions, with the highest heritability estimates for cerebellar GMV and subcortical structures. CONCLUSIONS: These data indicate that brain regions associated with obesity are subject to differing levels of genetic control and environmental influences. Specific brain regions with high heritability might represent an inherent vulnerability factor for obesity.
Assuntos
Encéfalo/patologia , Imageamento por Ressonância Magnética , Obesidade/genética , Obesidade/patologia , Adiposidade , Adulto , Feminino , Substância Cinzenta/anatomia & histologia , Substância Cinzenta/patologia , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Neuroimagem , Obesidade/fisiopatologia , Fenótipo , Característica Quantitativa Herdável , Gêmeos Dizigóticos , Gêmeos MonozigóticosRESUMO
BACKGROUND/OBJECTIVES: In animal models, a role in the regulation of energy expenditure (EE) has been ascribed to sphingolipids, active components of cell membranes participating in cellular signaling. In humans, it is unknown whether sphingolipids have a role in the modulation of EE and, consequently, influence weight gain. The present study investigated the putative association of EE and weight gain with sphingolipid levels in the human skeletal muscle, a component of fat-free mass (the strongest determinant of EE), in adipose tissue and plasma. SUBJECTS/METHODS: Twenty-four-hour EE, sleeping metabolic rate (SMR) and resting metabolic rate (RMR) were assessed in 35 healthy Native Americans of Southwestern heritage (24 male; 30.2±7.73 years). Sphingolipid (ceramide, C; sphingomyelin, SM) concentrations were measured in skeletal muscle tissue, subcutaneous adipose tissue and plasma samples. After 6.68 years (0.26-12.4 years), follow-up weights were determined in 16 participants (4 females). RESULTS: Concentrations of C24:0, SM18:1/26:1 and SM18:0/24:1 in muscle were associated with 24-h EE (r=-0.47, P=0.01), SMR (r=-0.59, P=0.0008) and RMR (r=-0.44, P=0.01), respectively. Certain muscle sphingomyelins also predicted weight gain (for example, SM18:1/23:1, r=0.74, P=0.004). For specific muscle sphingomyelins that correlated with weight gain and EE (SM18:1/23:0, SM18:1/23:1 and SMR, r=-0.51, r=-0.41, respectively, all P<0.03; SM18:1/24:2 and RMR, r=-0.36, P=0.03), associations could be reproduced with SMR in adipose tissue (all r<-0.46, all P<0.04), though not in plasma. CONCLUSIONS: This study provides preliminary, novel evidence, that specific muscle and adipose tissue sphingolipid compounds are associated with EE and weight gain in Native Americans of Southwestern heritage. Further studies are warranted to investigate whether sphingolipids of different body compartments act in concert to modulate energy balance in humans.
Assuntos
Metabolismo Basal/fisiologia , Metabolismo Energético/fisiologia , Indígenas Norte-Americanos , Músculo Esquelético/metabolismo , Esfingolipídeos/metabolismo , Aumento de Peso/fisiologia , Adulto , Composição Corporal , Calorimetria Indireta , Feminino , Seguimentos , Voluntários Saudáveis , Humanos , Masculino , Sono , Sudoeste dos Estados UnidosRESUMO
OBJECTIVE: To evaluate early changes in glycemia, insulin physiology and gut hormone responses to an easily tolerated and slowly ingested solid, low-carbohydrate mixed meal test (MMT) following laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB) surgery. SUBJECTS/METHODS: This was a prospective non-randomized study. Plasma glucose, insulin and c-peptide (to estimate hepatic insulin extraction; %HIE), incretins (GIP, aGLP-1) and pancreatic polypeptide (PP) responses to the MMT were measured at 4-8 weeks before and after surgery in obese, metabolically healthy patients (RYGB=10F or LAGB =7F/1M). Supplementary clamp data on basal endogenous glucose production (EGP) and peripheral insulin action (Rd=rate of glucose disposal) and metabolic clearance rates of insulin (MCR-INS) were available in five of the RYGB patients. Repeated measures were appropriately accounted for in the analyses. RESULTS: Following LAGB surgery, C-peptide and insulin MMT profiles (P=0.004 and P=0.0005, respectively) were lower with no change in %HIE (P=0.98). In contrast, in RYGB subjects, both fasting glucose and insulin (Δ=-0.66 mmol l-1, P⩽0.05 and Δ=-44.4 pmol l-1, P⩽0.05, respectively) decreased, and MMT glucose (P<0.0001) and insulin (P=0.001) but not c-peptide (P= 0.69) decreased. Estimated %HIE increased at fasting (Δ=8.4%, P⩽0.05) and during MMT (P=0.0005). Early (0-20 min) prandial glucose (0.27±0.26 versus 0.006±0.21 mmol l-1, P⩽0.05) and insulin (63(48, 66) versus 18(12, 24) pmol l-1, P⩽0.05) responses increased after RYGB. RYGB altered the trajectory of prandial aGLP-1 responses (treatment × trajectory P=0.02), and PP was lower (P<0.0001). Clamp data in a subset of RYGB patients showed early improvement in basal EGP (P=0.001), and MCR-INS (P=0.015). CONCLUSION: RYGB results in distinctly different changes in plasma glucose, insulin and gut hormone response patterns to a solid, slowly ingested low-carbohydrate MMT versus LAGB. Altered nutrient delivery, along with indirect evidence for changes in hepatic and peripheral insulin physiology, are consistent with the greater early improvement in glycemia observed after RYGB versus LAGB surgery.
Assuntos
Glicemia/metabolismo , Dieta com Restrição de Carboidratos , Derivação Gástrica , Insulina/metabolismo , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Período Pós-Prandial/fisiologia , Redução de Peso/fisiologia , Adulto , Peptídeo C/metabolismo , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Técnica Clamp de Glucose , Humanos , Incretinas/metabolismo , Masculino , Refeições , Obesidade Mórbida/dietoterapia , Cuidados Pós-Operatórios , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND/OBJECTIVES: In small studies, a thrifty human phenotype, defined by a greater 24-hour energy expenditure (EE) decrease with fasting, is associated with less weight loss during caloric restriction. In rodents, models of diet-induced obesity often have a phenotype including a reduced EE and decreased core body temperature. We assessed whether a thrifty human phenotype associates with differences in core body temperature or body composition. SUBJECTS/METHODS: Data for this cross-sectional analysis were obtained from 77 individuals participating in one of two normal physiology studies while housed on our clinical research unit. Twenty-four-hour EE using a whole-room indirect calorimeter and 24-h core body temperature were measured during 24 h each of fasting and 200% overfeeding with a diet consisting of 50% carbohydrates, 20% protein and 30% fat. Body composition was measured by dual X-ray absorptiometry. To account for the effects of body size on EE, changes in EE were expressed as a percentage change from 24-hour EE (%EE) during energy balance. RESULTS: A greater %EE decrease with fasting correlated with a smaller %EE increase with overfeeding (r=0.27, P=0.02). The %EE decrease with fasting was associated with both fat mass and abdominal fat mass, even after accounting for covariates (ß=-0.16 (95% CI: -0.26, -0.06) %EE per kg fat mass, P=0.003; ß=-0.0004 (-0.0007, -0.00004) %EE kg(-1) abdominal fat mass, P=0.03). In men, a greater %EE decrease in response to fasting was associated with a lower 24- h core body temperature, even after adjusting for covariates (ß=1.43 (0.72, 2.15) %EE per 0.1 °C, P=0.0003). CONCLUSIONS: Thrifty individuals, as defined by a larger EE decrease with fasting, were more likely to have greater overall and abdominal adiposity as well as lower core body temperature consistent with a more efficient metabolism.
Assuntos
Adiposidade/fisiologia , Composição Corporal/fisiologia , Temperatura Corporal/fisiologia , Metabolismo Energético/fisiologia , Fenótipo , Absorciometria de Fóton , Tecido Adiposo , Adulto , Arizona , Restrição Calórica , Estudos Transversais , Jejum/fisiologia , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , TermogêneseRESUMO
BACKGROUND: Genetic variants that predispose individuals to obesity may have differing influences during childhood versus adulthood, and additive effects of such variants are likely to occur. Our ongoing studies to identify genetic determinants of obesity in American Indians have identified 67 single-nucleotide polymorphisms (SNPs) that reproducibly associate with maximum lifetime non-diabetic body mass index (BMI). This study aimed to identify when, during the lifetime, these variants have their greatest impact on BMI increase. SUBJECTS/METHODS: A total of 5906 Native Americans of predominantly Pima Indian heritage with repeated measures of BMI between the ages of 5 and 45 years were included in this study. The association between each SNP with the rates of BMI increase during childhood (5-19 years) and adulthood (20-45 years) were assessed separately. The significant SNPs were used to calculate a cumulative allelic risk score (ARS) for childhood and adulthood, respectively, to assess the additive effect of these variants within each period of life. RESULTS: The majority of these SNPs (36 of 67) were associated with rate of BMI increase during childhood (P-value range: 0.00004-0.05), whereas only nine SNPs were associated with rate of BMI change during adulthood (P-value range: 0.002-0.02). These 36 SNPs associated with childhood BMI gain likely had a cumulative effect as a higher childhood-ARS associated with rate of BMI change (ß=0.032 kg m(-2) per year per risk allele, 95% confidence interval: 0.027-0.036, P<0.0001), such that at age 19 years, individuals with the highest number of risk alleles had a BMI of 10.2 kg m(-2) greater than subjects with the lowest number of risk alleles. CONCLUSIONS: Overall, our data indicates that genetic polymorphisms associated with lifetime BMI may influence the rate of BMI increase during different periods in the life course. The majority of these polymorphisms have a larger impact on BMI during childhood, providing further evidence that prevention of obesity will need to begin early in life.
Assuntos
Índice de Massa Corporal , Variação Genética , Indígenas Norte-Americanos/genética , Obesidade/genética , Adolescente , Adulto , Alelos , Arizona/epidemiologia , Composição Corporal/genética , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença/epidemiologia , Genótipo , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/prevenção & controle , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND/OBJECTIVES: Prader-Willi syndrome (PWS) is a type of human genetic obesity that may give us information regarding the physiology of non-syndromic obesity. The objective of this study was to investigate the functional correlates of hunger and satiety in individuals with PWS in comparison with healthy controls with obesity, hypothesizing that we would see significant differences in activation in the left dorsolateral prefrontal cortex (DLPFC) based on prior findings. SUBJECTS/METHODS: This study compared the central effects of food consumption in nine individuals with PWS (7 men, 2 women; body fat 35.3±10.0%) and seven controls (7 men; body fat 28.8±7.6%), matched for percentage body fat. H2(15)O-PET (positron emission tomography) scans were performed before and after consumption of a standardized liquid meal to obtain quantitative measures of regional cerebral blood flow (rCBF), a marker of neuronal activity. RESULTS: Compared with obese controls, PWS showed altered (P<0.05 family-wise error cluster-level corrected; voxelwise P<0.001) rCBF before and after meal consumption in multiple brain regions. There was a significant differential rCBF response within the left DLPFC after meal ingestion with decreases in DLPFC rCBF in PWS; in controls, DLPFC rCBF tended to remain unchanged. In more liberal analyses (P<0.05 family-wise error cluster-level corrected; voxelwise P<0.005), rCBF of the right orbitofrontal cortex (OFC) increased in PWS and decreased in controls. In PWS, ΔrCBF of the right OFC was associated with changes in appetite ratings. CONCLUSIONS: The pathophysiology of eating behavior in PWS is characterized by a paradoxical meal-induced deactivation of the left DLPFC and activation in the right OFC, brain regions implicated in the central regulation of eating behavior.
Assuntos
Período Pós-Prandial , Síndrome de Prader-Willi/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Adulto , Mapeamento Encefálico , Circulação Cerebrovascular , Comportamento Alimentar , Feminino , Neuroimagem Funcional , Humanos , Imageamento por Ressonância Magnética , Masculino , Refeições , Síndrome de Prader-Willi/epidemiologia , Recompensa , Saciação , Resposta de SaciedadeRESUMO
AIMS: To investigate the effects of metformin on appetite and energy intake in obese children with hyperinsulinaemia. METHODS: We conducted a 6-month randomized, double-blind, placebo-controlled trial to evaluate the effects of metformin 1000 mg twice daily on body weight and energy balance in 100 obese children with hyperinsulinaemia aged 6-12 years. The children ate ad libitum from standardized food arrays on two separate occasions before and after 6 months of study medication. The first test meal was consumed after an overnight fast. The second was preceded by a pre-meal load. For each test meal, energy intake was recorded, and the children completed scales of hunger, fullness and desire to eat. RESULTS: Data from the meal studies at baseline and after treatment with study medication were available for 84 children (metformin-treated, n = 45; placebo-treated, n = 39). Compared with placebo, metformin treatment elicited significant reductions from baseline in adjusted mean ± standard error of the mean energy intake after the pre-meal load (metformin: -104.7 ± 83.8 kcal vs. placebo: +144.2 ± 96.9 kcal; p = 0.034) independently of changes in body composition. Metformin also significantly decreased ratings of hunger (-1.5 ± 5.6 vs. +18.6 ± 6.3; p = 0.013) and increased ratings of fullness (+10.1 ± 6.2 vs. -12.8 ± 7.0; p = 0.01) after the pre-meal load. CONCLUSIONS: These data suggest that decreased perceived hunger resulting in diminished food intake are among the mechanisms by which metformin treatment reduces body weight in overweight children with hyperinsulinaemia.
Assuntos
Depressores do Apetite/uso terapêutico , Fenômenos Fisiológicos da Nutrição Infantil/efeitos dos fármacos , Ingestão de Energia/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Obesidade Infantil/tratamento farmacológico , Resposta de Saciedade/efeitos dos fármacos , Depressores do Apetite/efeitos adversos , Índice de Massa Corporal , Criança , Comportamento Infantil/efeitos dos fármacos , Terapia Combinada/efeitos adversos , Dieta Redutora , Método Duplo-Cego , Feminino , Humanos , Hiperinsulinismo/etiologia , Hiperinsulinismo/prevenção & controle , Hipoglicemiantes/efeitos adversos , Estilo de Vida , Masculino , Metformina/efeitos adversos , Atividade Motora , National Institutes of Health (U.S.) , Uso Off-Label , Pais/educação , Educação de Pacientes como Assunto , Obesidade Infantil/sangue , Obesidade Infantil/fisiopatologia , Obesidade Infantil/terapia , Estados Unidos , Redução de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Obesity is the result of chronic positive energy balance. The mechanisms underlying the regulation of energy homeostasis and food intake are not understood. Despite large increases in fat mass (FM), recent evidence indicates that fat-free mass (FFM) rather than FM is positively associated with intake in humans. METHODS: In 184 humans (73 females/111 males; age 34.5±8.8 years; percentage body fat: 31.6±8.1%), we investigated the relationship of FFM index (FFMI, kg m(-2)), FM index (FMI, kg m(-2)); and 24-h energy expenditure (EE, n=127) with ad-libitum food intake using a 3-day vending machine paradigm. Mean daily calories (CAL) and macronutrient intake (PRO, CHO, FAT) were determined and used to calculate the relative caloric contribution of each (%PRO, %CHO, %FAT) and percent of caloric intake over weight maintaining energy needs (%WMENs). RESULTS: FFMI was positively associated with CAL (P<0.0001), PRO (P=0.0001), CHO (P=0.0075) and FAT (P<0.0001). This remained significant after adjusting for FMI. Total EE predicted CAL and macronutrient intake (all P<0.0001). FMI was positively associated with CAL (P=0.019), PRO (P=0.025) and FAT (P=0.0008). In models with both FFMI and FMI, FMI was negatively associated with CAL (P=0.019) and PRO (P=0.033). Both FFMI and FMI were negatively associated with %CHO and positively associated with %FAT (all P<0.001). EE and FFMI (adjusted for FMI) were positively (EE P=0.0085; FFMI P=0.0018) and FMI negatively (P=0.0018; adjusted for FFMI) associated with %WMEN. CONCLUSION: Food and macronutrient intake are predicted by FFMI and to a lesser degree by FMI. FFM and FM may have opposing effects on energy homeostasis.
Assuntos
Tecido Adiposo/metabolismo , Composição Corporal , Ingestão de Energia , Metabolismo Energético , Adulto , Composição Corporal/fisiologia , Índice de Massa Corporal , Peso Corporal , Gorduras na Dieta/administração & dosagem , Fibras na Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Metabolismo Energético/fisiologia , Feminino , Teste de Tolerância a Glucose , Homeostase/fisiologia , Humanos , Masculino , Valor Preditivo dos TestesRESUMO
BACKGROUND: In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. OBJECTIVE: The objective of this study is to compare BDNF concentrations of subjects with loss-of-function (LOF) and gain-of-function (GOF) MC4R variants with those of controls with common sequence MC4R. METHODS: Circulating BDNF was measured in two cohorts with known MC4R sequence: 148 subjects of Pima Indian heritage ((mean±s.d.): age, 15.7±6.5 years; body mass index z-scores (BMI-Z), 1.63±1.03) and 69 subjects of Hispanic heritage (10.8±3.6 years; BMI-Z, 1.57±1.07). MC4R variants were characterized in vitro by cell surface expression, receptor binding and cyclic AMP response after agonist administration. BDNF single-nucleotide polymorphisms (SNPs) rs12291186, rs6265 and rs7124442 were also genotyped. RESULTS: In the Pima cohort, no significant differences in serum BDNF was observed for 43 LOF subjects versus 65 LOF-matched controls (age, sex and BMI matched; P=0.29) or 20 GOF subjects versus 20 GOF-matched controls (P=0.40). Serum BDNF was significantly associated with genotype for BDNF rs12291186 (P=0.006) and rs6265 (P=0.009), but not rs7124442 (P=0.99); BDNF SNPs did not interact with MC4R status to predict serum BDNF. In the Hispanic cohort, plasma BDNF was not significantly different among 21 LOF subjects, 20 GOF subjects and 28 controls (P=0.79); plasma BDNF was not predicted by BDNF genotype or BDNF-x-MC4R genotype interaction. CONCLUSIONS: Circulating BDNF concentrations were not significantly associated with MC4R functional status, suggesting that peripheral BDNF does not directly reflect hypothalamic BDNF secretion and/or that MC4R signaling is not a significant regulator of the bulk of BDNF expression in humans.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hispânico ou Latino , Hipotálamo/metabolismo , Indígenas Norte-Americanos , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único , Receptor Tipo 4 de Melanocortina/metabolismo , Adolescente , Adulto , Arizona , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genótipo , Hispânico ou Latino/genética , Hispânico ou Latino/estatística & dados numéricos , Humanos , Indígenas Norte-Americanos/genética , Indígenas Norte-Americanos/estatística & dados numéricos , Estudos Longitudinais , Masculino , Mutação , Obesidade/etnologia , Obesidade/genética , Regiões Promotoras Genéticas , Receptor Tipo 4 de Melanocortina/sangue , Receptor Tipo 4 de Melanocortina/genéticaRESUMO
OBJECTIVE: To investigate the correlation of peripheral insulin concentrations with food intake and body weight. DESIGN: Cross sectional and longitudinal clinical study: we investigated the association of peripheral insulin concentrations in response to an oral glucose tolerance test (OGTT) with subsequent measures of ad libitum food intake and body weight change. SUBJECTS: Food intake analysis: Pima Indians (n=67, 63% male; body mass index (mean ± s.d.) 34.2 ± 9.4 kg m(-2)) with normal glucose regulation (NGR; fasting glucose <5.6 mmol l(-1) and 2-h glucose <7.8 mmol l(-1)) participated in a study of ad libitum food intake measured over 3 days by an automated vending machine system. Weight change analysis: Pima Indians with NGR (n=339) who also participated in a longitudinal study of risks for type 2 diabetes and had follow-up weights. RESULTS: Food intake analysis: incremental area under the curve (iAUC) for insulin during the OGTT was negatively associated with mean daily ad libitum energy intake (DEI) (r=-0.26, P=0.04), calories consumed as percent weight-maintenance energy needs (%WMEN) (r=-0.38, P=0.002) and carbohydrate intake (gram per day) (r=-0.35, P=0.005). Adjustment for age and sex attenuated the association of iAUC with DEI (P=0.06) not with %WMEN and carbohydrate intake (P=0.005, P=0.008). Weight change analysis: after adjustment for age, sex, follow-up time and initial body weight, higher insulin iAUC predicted less absolute and percent weight change (ß=-6.9, P=0.02; ß=-0.08, P=0.008, respectively). CONCLUSIONS: In healthy Pima Indians with NGR, higher plasma iAUC during an OGTT predicted lower food intake and carbohydrate consumption and less weight gain. These data indicated a role for peripheral insulin as a negative feedback signal in the regulation of energy intake and body weight.
Assuntos
Peso Corporal , Ingestão de Alimentos , Ingestão de Energia , Indígenas Norte-Americanos , Resistência à Insulina , Insulina/sangue , Obesidade/sangue , Aumento de Peso , Adulto , Área Sob a Curva , Glicemia/metabolismo , Índice de Massa Corporal , Estudos Transversais , Feminino , Teste de Tolerância a Glucose , Humanos , Estudos Longitudinais , Masculino , Obesidade/dietoterapia , Valor Preditivo dos Testes , Reprodutibilidade dos TestesRESUMO
AIM/HYPOTHESIS: Low-grade inflammation may contribute to obesity-related insulin resistance and has been associated with increased risk of type 2 diabetes mellitus. The present study evaluated whether treatment with salsalate, a traditional anti-inflammatory medication, would improve insulin action in obese non-diabetic individuals. METHODS: The study was a randomised, double-blind, placebo-controlled, parallel trial conducted at the inpatient clinical research unit of the NIDKK (Phoenix, AZ, USA). Participants were 54 adults (18 to 45 years of age) with BMI >or= 30 kg/m(2). The intervention was salsalate (3 g/day, n = 28) or identical placebo (n = 26) for 7 days. The allocation was kept concealed by giving the investigator only a number corresponding to a vial of placebo or salsalate sequentially randomised in blocks by sex. Main outcomes were changes in insulin action assessed as rate of glucose disposal (R (d)) by euglycaemic-hyperinsulinaemic clamp (insulin infusion rate 40 mU m(-2) min(-1)) and glucose tolerance by 75 g OGTT. RESULTS: The study was completed by 47 participants, of which 40 were analysed (salsalate n = 22, placebo n = 18). Salsalate treatment resulted in decreased fasting plasma glucose concentration (mean [SD]; 4.83 [0.28] vs 5.11 [0.33] mmol/l, p = 0.001) and glucose AUC during the OGTT (p = 0.01), and in increased R (d) (20 [8] vs 18 [6] micromol [kg estimated metabolic body size](-1) min(-1), p = 0.002), while there was no significant change in these variables with placebo (p > 0.3 for all). The effect of salsalate on R (d) disappeared (p = 0.9) after normalising to increased insulin concentrations (701 [285] vs 535 [201] pmol/l, p < 0.0001) measured during the clamp. No side effects of salsalate were observed during the study. CONCLUSIONS/INTERPRETATION: The glucose-lowering potential of salicylates appears to be due to effects on insulin concentration rather than improved insulin action. Salicylate-based compounds may be useful for the treatment and prevention of type 2 diabetes.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Glicemia/metabolismo , Insulina/fisiologia , Obesidade/tratamento farmacológico , Salicilatos/uso terapêutico , Adiponectina/sangue , Adolescente , Adulto , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Método Duplo-Cego , Ácidos Graxos não Esterificados/sangue , Feminino , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo , Insulina/sangue , Insulina/farmacologia , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Placebos , Tamanho da Amostra , Adulto JovemRESUMO
BACKGROUND: The diabetic intrauterine environment is a known risk factor for the development of diabetes in the offspring. OBJECTIVE: We compared anthropometric and metabolic characteristics of 41 nondiabetic children whose mothers developed diabetes either before (ODM, n = 19, 9.3 +/- 1.1 yr) or after (OPDM, n = 22, 9.5 +/- 1.3 yr) the pregnancy of interest. Maternal diabetes status was established from OGTT results before, during, and after the pregnancy of interest. DESIGN: After consuming a standardized diet for 2 d, a mixed-meal breakfast was given after an overnight fast. Fasting concentrations and responses of plasma glucose and insulin were evaluated using linear regression analyses to assess potential independent determinants of plasma insulin concentration at each time point. RESULTS: After adjustment for age and sex, there were no differences between ODM and OPDM children for maternal age at diagnosis, height, weight, body mass index, BMI z score, or percent body fat (dual energy x-ray absorptiometry). After adjusting for age, sex, percent body fat, and the corresponding glucose level at each time point, ODM had a lower plasma insulin level at the 15-min time point during the meal test than OPDM (P = 0.01). CONCLUSION: A lower initial insulin response to a standard mixed-meal challenge can be detected in nondiabetic ODM compared with OPDM children as early as 9 yr of age. This response may be another indicator for an attenuated early insulin response and explain the increased risk for diabetes in these children.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Ingestão de Alimentos/fisiologia , Insulina/sangue , Gravidez em Diabéticas/epidemiologia , Efeitos Tardios da Exposição Pré-Natal , Adulto , Glicemia/metabolismo , Criança , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Indígenas Norte-Americanos/estatística & dados numéricos , Resistência à Insulina , Modelos Lineares , Masculino , Gravidez , Gravidez em Diabéticas/fisiopatologia , Fatores de RiscoRESUMO
It has been proposed that inflammation or infection may contribute to the development of type 2 diabetes. We examined whether serum gamma globulin, a nonspecific measure of the humoral immune system, predicted changes in glucose tolerance in 2,530 members of the Pima Indian population, a group with a marked predisposition to type 2 diabetes. Cross-sectionally, gamma globulin was positively related to age (r = 0.08, P < 0.0005), BMI (r = 0.09; P < 0.0001), and female sex (P < 0.0001). Gamma globulin concentrations were familial, being positively correlated among siblings (r = 0.23; P < 0.0001) and between parents and their children (mother/child: r = 0.17, P < 0.0001; father/child: r = 0.25, P < 0.0001). Gamma globulin concentrations were higher with greater degrees of American Indian heritage (P < 0.004, with adjustment for age, sex, and BMI) and in the presence of a family history of type 2 diabetes (P < 0.04). Higher gamma globulin levels predicted risk of diabetes. In univariate analysis, a 1 SD difference in gamma globulin was associated with a 20% higher incidence of diabetes in those who were normal glucose tolerant at baseline (hazard rate ratio 1.20 [CI 1.11-1.30]; P < 0.0001) and remained as a significant predictor of diabetes, even when controlled for effects of sex, BMI, and 2-h glucose as additional predictors (hazard rate ratio for 1 SD difference in gamma globulin, 1.14 [1.05-1.24]; P = 0.002). Gamma globulin was also associated in univariate analysis with later development of impaired glucose tolerance (IGT) (hazard rate ratio 1.15 [1.07-1.23]; P < 0.0001), but not with the transition from IGT to diabetes (hazard rate ratio 1.04 [0.90-1.20]; P = 0.6). Thus, gamma globulin levels predict increased risk of diabetes in the Pima population. We suggest that immune function or activation may play a role in the development of type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Indígenas Norte-Americanos , gama-Globulinas/análise , Adulto , Arizona , Biomarcadores/análise , Índice de Massa Corporal , Estudos Transversais , Diabetes Mellitus Tipo 2/genética , Família , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Valor Preditivo dos Testes , Fator Reumatoide/análise , Aumento de PesoRESUMO
BACKGROUND: Although more classically associated with insulin-dependent diabetes mellitus, diabetic ketoacidosis (DKA) can occur in some patients with non-insulin-dependent diabetes mellitus (NIDDM). To better define the clinical features that may be associated with ketoacidosis in patients with NIDDM, we reviewed the medical histories of Apache Indians with NIDDM who had been treated for an episode of DKA. METHODS: Cases of ketoacidosis among patients with NIDDM were identified at 2 separate Apache Indian reservations. Chart data were used to confirm and characterize the diagnosis of NIDDM, the metabolic disturbances associated with DKA, and the historical features of the patients. RESULTS: Among 724 patients with NIDDM, 17 patients experiencing at least 1 episode of DKA were identified. The mean (+/-SD) age at the time of the episode was 40.8 +/- 13.9 years. The patients were predominantly male (15[88%]), with a mean (+/-SD) body mass index (calculated as the weight in kilograms divided by the square of the height in meters) of 24.9 +/- 4.4 kg/m2. Causes of DKA included infections (8[47%]) and omission of treatment (3/15[20%]). Concurrent abuse of alcohol was noted in 4 (27%) of the patients. In addition, a lifetime history of alcohol abuse was noted in 15 (94%) of 16 patients. CONCLUSIONS: This report confirms the growing recognition that DKA occurs in some patients with NIDDM. The present study also adds male sex, alcohol abuse, and relatively low body mass index as clinical factors that may play a role in the development of DKA in this setting.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Cetoacidose Diabética/etiologia , Indígenas Norte-Americanos/estatística & dados numéricos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Distribuição por SexoRESUMO
OBJECTIVE: To examine whether the current adult guidelines for diagnosis of diabetes are applicable to youth (age <20 years). RESEARCH DESIGN AND METHODS: We analyzed fasting plasma glucose (FPG) and 2-h plasma glucose (PG) in two groups of Pima Indians, youths aged 5-19 years and adults aged 20-34 years, in relation to the incidence of microvascular disease when subjects were reexamined at ages 25-39 (youths) and 40-54 (adults). Microvascular disease was defined as retinopathy or a urine protein-to-creatinine ratio > or =0.5 g. RESULTS: An increase in the incidence of microvascular disease occurred at nearly the same level of glycemia in both groups. For youths, this increase occurred at FPG approximately 7.3 mmol/l and 2-h PG approximately 10.0 mmol/l; for adults, this increase occurred at FPG approximately 7.5 mmol/l and 2-h PG approximately 10.3 mmol/l. Sensitivity of the adult diagnostic guidelines of FPG > or =7.0 mmol/l and 2-h PG > or =11.1 mmol/l for the detection of microvascular disease was much lower (with higher specificity) in youths than in adults. Receiver operating characteristics (ROC) curve areas were lower for FPG and 2-h PG for youths, suggesting that microvascular disease was less strongly predicted by baseline glucose. CONCLUSION: The current adult guidelines for diagnosis of diabetes are applicable to youth, as they identify a population at high risk of microvascular complications.
Assuntos
Glicemia/análise , Diabetes Mellitus/fisiopatologia , Angiopatias Diabéticas/epidemiologia , Hiperglicemia/fisiopatologia , Adolescente , Adulto , Fatores Etários , Idade de Início , Arizona/epidemiologia , Biomarcadores/sangue , Criança , Pré-Escolar , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Angiopatias Diabéticas/fisiopatologia , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/fisiopatologia , Feminino , Humanos , Hiperglicemia/sangue , Incidência , Indígenas Norte-Americanos , Estudos Longitudinais , Masculino , Microcirculação , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Prevalência , Prognóstico , Sensibilidade e Especificidade , Fatores de TempoRESUMO
Chronic severe hypercortisolism is associated with life-threatening infections, diabetes and a high surgical mortality rate. Oral medical therapy can inhibit steroidogenesis and reduce the risk of these complications. However, apart from a few reports using an ethyl alcohol formulation of the iv anesthetic etomidate, there is no well-tested parenteral steroidogenesis inhibitor. We used the propylene glycol preparation of etomidate available in the United States to control hypercortisolism in a 39-yr-old man with ectopic ACTH secretion who was unable to take oral medications. Etomidate was administered over a period of 5.5 months. We titrated the dose of etomidate daily using serum cortisol levels, to avoid steroid over replacement and allow for a response to ongoing stress. A reduced dose during a period of acute renal failure achieved adequate control of hypercortisolemia. Suppression of steroidogenesis persisted for at least 14 d and perhaps as long as 6 wk after cessation of the medication. Except for transient myoclonus, the patient tolerated this preparation well. Parenteral propylene glycol containing etomidate can be used safely for a prolonged period to reduce hypercortisolemia in patients unable to take oral medications.