RESUMO
The treatment of severe forms of 21-hydroxylase deficiency (21OHD) remains unsatisfactory in many respects. As a monogenic disease caused by loss-of-function mutations, 21OHD is a potential candidate for a gene therapy (GT) approach. The first step of GT is to demonstrate positive effects of the therapeutic vector in the Cyp21-/- mouse model. Thus, we tested the adrenal tropism of an AAVrh10-CAG-GFP vector ('GFP vector') then attempted to correct the phenotypic and biochemical alterations in Cyp21-/- mice using an AAVrh10-CAG-humanCYP21A2-HA vector ('CYP21 vector'). Cyp21-/- mice had decreased body mass, high progesterone (4 ×), impaired stress response, increased adrenal expression of genes involved in steroidogenesis or ACTH signaling. Following injection of the GFP vector, Cyp21-/- mice showed abundant GFP expression in the adrenal cortex. Intravenous injection of the therapeutic CYP21 vector allowed 21OH expression in adrenal tissue, resulting in increased body weight and near normalization of urinary progesterone for more than 15 weeks, improved response to stress and restoration of near-normal expression of (several important genes) in the adrenal cortex. The adrenal tropism of AAVrh10 and the persistent correction of phenotypic and biochemical traits in Cyp21-/- mice pave a first step on the way to GT of 21OHD in humans.
Assuntos
Hiperplasia Suprarrenal Congênita/terapia , Terapia Genética/métodos , Esteroide 21-Hidroxilase/genética , Córtex Suprarrenal/metabolismo , Hiperplasia Suprarrenal Congênita/genética , Hormônio Adrenocorticotrópico/metabolismo , Animais , Peso Corporal , Linhagem Celular Tumoral , Dependovirus/genética , Vetores Genéticos/genética , Humanos , Camundongos , Progesterona/sangue , Esteroide 21-Hidroxilase/metabolismoRESUMO
Short children using growth hormone (GH) to accelerate their growth respond to this treatment with a variable efficacy. The causes of this individual variability are multifactorial and could involve epigenetics. Quantifying the impact of epigenetic variation on response to treatments is an emerging challenge. Here we show that methylation of a cluster of CGs located within the P2 promoter of the insulin-like growth factor 1 (IGF1) gene, notably CG-137, is inversely closely correlated with the response of growth and circulating IGF1 to GH administration. For example, variability in CG-137 methylation contributes 25% to variance of growth response to GH. Methylation of CGs in the P2 promoter is negatively associated with the increased transcriptional activity of P2 promoter in patients' mononuclear blood cells following GH administration. Our observation indicates that epigenetics is a major determinant of GH signaling (physiology) and of individual responsiveness to GH treatment (pharmacoepigenetics).
Assuntos
Nanismo/tratamento farmacológico , Epigênese Genética , Hormônio do Crescimento Humano/uso terapêutico , Fator de Crescimento Insulin-Like I/genética , Regiões Promotoras Genéticas , Células Sanguíneas/metabolismo , Criança , Ilhas de CpG , Metilação de DNA , Nanismo/genética , Nanismo/fisiopatologia , Feminino , Loci Gênicos , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Proteínas Recombinantes/uso terapêutico , Transcrição GênicaRESUMO
BACKGROUND: The incidence of childhood type 1 diabetes (T1D) incidence is rising in many countries, supposedly because of changing environmental factors, which are yet largely unknown. The purpose of the study was to unravel environmental markers associated with T1D. METHODS: Cases were children with T1D from the French Isis-Diab cohort. Controls were schoolmates or friends of the patients. Parents were asked to fill a 845-item questionnaire investigating the child's environment before diagnosis. The analysis took into account the matching between cases and controls. A second analysis used propensity score methods. RESULTS: We found a negative association of several lifestyle variables, gastroenteritis episodes, dental hygiene, hazelnut cocoa spread consumption, wasp and bee stings with T1D, consumption of vegetables from a farm and death of a pet by old age. CONCLUSIONS: The found statistical association of new environmental markers with T1D calls for replication in other cohorts and investigation of new environmental areas. TRIAL REGISTRATION: Clinical-Trial.gov NCT02212522 . Registered August 6, 2014.
RESUMO
OBJECTIVE: To compare the effectiveness of a free-mix of aspart (A) and detemir (D) insulins (ADIM) with a commonly used premixed fixed-ratio aspart and neutral protamine Hagedorn (NPH) insulin mixture (ANIM) in young children with type 1 diabetes (T1D) treated with twice-daily injections. The trial thus compares not only D vs. NPH, but also flexible, personalized insulin preparations vs. a fixed premixed preparation. RESEARCH DESIGN AND METHODS: This single-center, open-label, randomized trial included 82 children with T1D. Patients stayed on ANIM for 1 yr of optimization of disease management, then were randomized to either ANIM (N = 41) or ADIM (N = 41) for another year. OUTCOMES: Frequency of severe or symptomatic episodes, glycated hemoglobin A1c (HbA1c), and blood glucose (BG) values. RESULTS: Compared with ANIM, ADIM decreases symptomatic hypoglycemia by approximately 2 fold (p < 0.001) and severe hypoglycemia by 7-10 fold (p = 0.04). ADIM somewhat reduced BG variation. Mean HbA1c was comparable on ADIM (7.9 ± 0.8 %; 63 ± 9 mmol/mol) and ANIM (8.2 ± 0.7 %; 66 ± 8 mmol/mol). CONCLUSIONS: Using a free-mixing preparation of aspart and detemir insulin decreases hypoglycemia in young children with type 1 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Hipoglicemia/epidemiologia , Hipoglicemiantes/administração & dosagem , Insulina Aspart/administração & dosagem , Insulina Detemir/administração & dosagem , Adolescente , Glicemia/metabolismo , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Combinação de Medicamentos , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Insulina/administração & dosagem , Insulina/efeitos adversos , Insulina Aspart/efeitos adversos , Insulina Detemir/efeitos adversos , Insulina Isófana/administração & dosagem , Insulina Isófana/efeitos adversos , MasculinoRESUMO
To identify some of the genetic factors that contribute to obesity in children of Central European and North African descent, we studied the parental transmission of alleles at the insulin locus to offspring with early-onset obesity. A variable nucleotide tandem repeat (VNTR) polymorphism upstream of the insulin gene (INS) is associated with variations in the expression of INS and the nearby gene encoding insulin-like growth factor 2 (IGF2). We found an excess of paternal transmission of class I VNTR alleles to obese children: children who inherited a class I allele from their father (but not those inheriting it from their mother) had a relative risk of early-onset obesity of 1.8. Due to the frequency of class I alleles in this population, this risk concerns 65-70% of all infants. These results suggest that increased in utero expression of paternal INS or IGF2 due to the class I INS VNTR allele may predispose offspring to postnatal fat deposition.
Assuntos
Alelos , Predisposição Genética para Doença , Impressão Genômica , Insulina/genética , Repetições Minissatélites , Obesidade/genética , Adolescente , Criança , Estudos de Coortes , Feminino , Humanos , MasculinoRESUMO
In millions of people, obesity leads to type 2 diabetes (T2D; also known as non-insulin-dependent diabetes mellitus). During the early stages of juvenile obesity, the increase of insulin secretion in proportion to accumulated fat balances insulin resistance and protects patients from hyperglycaemia. After several decades, however,beta-cell function deteriorates and T2D develops in approximately 20% of obese patients. In modern societies, obesity has thus become the leading risk factor for T2D (ref. 5). The factors that predispose obese patients to alteration of insulin secretion upon gaining weight remain unknown. To determine which genetic factors predispose obese patients to beta-cell dysfunction, and possibly T2D, we studied single-nucleotide polymorphisms (SNPs) in the region of the insulin gene (INS) among 615 obese children. We found that, in the early phase of obesity, alleles of the INS variable number of tandem repeat (VNTR) locus are associated with different effects of body fatness on insulin secretion. Young obese patients homozygous for class I VNTR alleles secrete more insulin than those with other genotypes.
Assuntos
Insulina/sangue , Insulina/genética , Repetições Minissatélites , Obesidade/genética , Adolescente , Alelos , Índice de Massa Corporal , Criança , Estudos de Coortes , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Jejum/sangue , Genótipo , Humanos , Insulina/metabolismo , Secreção de Insulina , Modelos Lineares , Obesidade/complicações , Obesidade Mórbida/complicações , Obesidade Mórbida/genética , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
BACKGROUND: The neonatal-midinfancy surge in pulsatile gonadotropin secretion is attributable to an increase in GnRH pulse amplitude and is associated with a rapid expansion of Leydig and Sertoli cell populations with concomitant surges in testosterone, inhibin, and anti-Mullerian hormone production as well as an increase in testicular volume. Boys with congenital hypogonadotropic hypogonadism (HH) do not activate these processes. A potential cause for azoospermia and infertility in adult life is deficient proliferation of immature Sertoli cells before and during puberty due to the absence of FSH. OBJECTIVE: The objective of the study was to investigate whether early postnatal continuous sc infusion of gonadotropins could mimic the physiological growth of testes and to evaluate responses of the Leydig and Sertoli cells to early gonadotropin replacement. DESIGN AND METHODS: Two neonates (P1 with hypotuitarism and P2 with HH) with micropenis and microorchidism were treated for 6 months with high doses of recombinant LH and FSH (a gift of Luveris and Gonal-F from Serono, Lyon, France) delivered sc with an insulin pump. RESULTS: Gonadotropin continuous sc infusion increased mean serum LH and FSH to normal or supranormal levels. Mean testosterone increased from undetectable levels to 7.6 and 5.2 nmol/liter, respectively, in P1 and P2. Inhibin B and anti-Müllerian hormone increased to normal levels. Mean testicular volume increased from 0.45 to 0.57 ml at birth to 2.10 ml at 7 months. Stretched penile length increased from 8 to 30 mm (P1) and 12 to 48 mm (P2). CONCLUSIONS: The present regimen induced physiological postnatal testes growth and high-normal activation of Leydig and Sertoli cells.
Assuntos
Hormônio Foliculoestimulante/administração & dosagem , Hipogonadismo/tratamento farmacológico , Hormônio Luteinizante/administração & dosagem , Hormônio Antimülleriano/sangue , Gonadotropinas/sangue , Terapia de Reposição Hormonal , Humanos , Hipogonadismo/patologia , Lactente , Recém-Nascido , Bombas de Infusão , Inibinas/sangue , Injeções Subcutâneas , Masculino , Tamanho do Órgão/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Testículo/efeitos dos fármacos , Testículo/patologia , Testosterona/sangue , Fatores de TempoRESUMO
Our objective was to test the ventricular repolarization response to a controlled hypoglycaemia test in Type 1 diabetic adolescents, an age group at risk for 'dead in bed syndrome'. We measured QTc, blood glucose level, potassium, heart rate, blood pressure and urinary metanephrine levels in 16 Type 1 diabetic adolescents during an insulin clamp mimicking the transition from mild hyperglycaemia to hypoglycaemia. QTc increased in all patients by 146 +/- 44 ms (mean +/-sd) ranging from 70 to 230 ms. The longest QTc (630 ms) was recorded in the sibling of a diabetic patient found 'dead in bed'. Heart rate and urinary metanephrine levels correlated with QTc (r = 0.60 and 0.79, respectively; P = 0.02 and 0.003). QTc in euglycaemia showed no correlation with hypoglycaemia associated QTc prolongation. The prognostic value of the hypoglycaemia test for the risk of recurrent episodes of QTc prolongation should be evaluated in real-life conditions in large-scale studies of diabetic adolescents.
Assuntos
Arritmias Cardíacas/fisiopatologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Hipoglicemia/diagnóstico , Adolescente , Eletrocardiografia , Teste de Tolerância a Glucose/métodos , Humanos , Hipoglicemia/fisiopatologiaRESUMO
OBJECTIVES: The objectives of the study were 2-fold: 1) a detailed description of sexual and reproductive outcomes in adult women with congenital adrenal hyperplasia (CAH) of different phenotypic severity at birth; and 2) comparisons of these outcomes among CAH subtypes and between CAH women and non-CAH control women. DESIGN: This was a cross-sectional study using a face-to-face interview, a written questionnaire, the Female Sexual Function Index, and a gynecological examination. PATIENTS: Patients included 35 women with CAH, representing Prader stages I-V at birth, aged 18-43 yr, who had been treated from birth to adolescence in the same pediatric endocrine clinics. Sixty-nine non-CAH healthy control women were selected from hospital-staff families. RESULTS: None of the CAH women expressed doubts about their gender assignment. Twenty percent (seven of 35) had homosexual inclinations; 23% (eight of 35) were married; three reported a complete lack of sexual activity; and 37% (13 of 35) said they never had heterosexual intercourse with vaginal penetration. Sexual functioning as assessed by the Female Sexual Function Index was much lower in CAH women than controls and lowest in CAH women with high Prader stages. Eighty-one percent (18 of 22) experienced pain during vaginal penetration. Only eight women became pregnant, and 17% (six of 35) had children. CONCLUSIONS: Despite expert medical and surgical care by physicians dedicated to this rare disease, women with CAH still suffer major limitations in their sexual function and reproductive life.
Assuntos
Hiperplasia Suprarrenal Congênita/fisiopatologia , Sexualidade , Adolescente , Adulto , Nível de Alerta , Clitóris/cirurgia , Feminino , Humanos , Menstruação , Orgasmo , Síndrome de Prader-Willi/fisiopatologia , Valores de Referência , Inquéritos e Questionários , Vagina/cirurgiaRESUMO
Measurement of beta-cell function is an important marker of progression to diabetes in individuals at risk for the disease. Although the peak incidence for the disease occurs before 17 years of age, normal values for insulin secretion were not available in this age group. We performed a simplified intravenous glucose tolerance test in 167 normal children, and in 98 islet cell antibody (ICA)-negative and 12 ICA-positive siblings of diabetic patients. Their age range was 1-16 yr. The first phase of insulin secretion, evaluated as the sum of plasma insulin concentrations at 1 and 3 min, increased with age and was significantly lower in ICA-negative siblings (86 +/- 6 microU/ml, P < 0.002) than in normal controls (115 +/- 6 microU/ml). This difference was not apparent before 8 yr of age. None of the ICA-negative siblings developed diabetes after an average of 4.5 yr. ICA-positive siblings at first study had a first phase insulin response similar to that of ICA negative siblings, but significantly lower than that of the normal controls (74 +/- 13 microU/ml, P < 0.02). The reason for the decreased insulin secretion in ICA-negative siblings is unknown, but could involve a defect in the growth of beta-cell mass or insulin secretion that could be part of the multifactorial pathogenesis of type 1 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/genética , Glucose/fisiologia , Insulina/metabolismo , Ilhotas Pancreáticas/imunologia , Adolescente , Autoanticorpos/imunologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Humanos , Lactente , Secreção de Insulina , LinhagemRESUMO
Using a continuous intravenous infusion of D-(-)-3-hydroxy[4,4,4-2H3]butyrate tracer, we measured total ketone body transport in 12 infants: six newborns, four 1-6-mo-olds, one diabetic, and one hyperinsulinemic infant. Ketone body inflow-outflow transport (flux) averaged 17.3 +/- 1.4 mumol kg-1 min-1 in the neonates, a value not different from that of 20.6 +/- 0.9 mumol kg-1 min-1 measured in the older infants. This rate was accelerated to 32.2 mumol kg-1 min-1 in the diabetic and slowed to 5.0 mumol kg-1 min-1 in the hyperinsulinemic child. As in the adult, ketone turnover was directly proportional to free fatty acid and ketone body concentrations, while ketone clearance declined as the circulatory content of ketone bodies increased. Compared with the adult, however, ketone body turnover rates of 12.8-21.9 mumol kg-1 min-1 in newborns fasted for less than 8 h, and rates of 17.9-26.0 mumol kg-1 min-1 in older infants fasted for less than 10 h, were in a range found in adults only after several days of total fasting. If the bulk of transported ketone body fuels are oxidized in the infant as they are in the adult, ketone bodies could account for as much as 25% of the neonate's basal energy requirements in the first several days of life. These studies demonstrate active ketogenesis and quantitatively important ketone body fuel transport in the human infant. Furthermore, the qualitatively similar relationships between the newborn and the adult relative to free fatty acid concentration and ketone inflow, and with regard to ketone concentration and clearance rate, suggest that intrahepatic and extrahepatic regulatory systems controlling ketone body metabolism are well established by early postnatal life in humans.
Assuntos
Recém-Nascido , Corpos Cetônicos/sangue , Ácido 3-Hidroxibutírico , Acetoacetatos/sangue , Transporte Biológico Ativo , Glicemia/metabolismo , Jejum , Ácidos Graxos não Esterificados/sangue , Feminino , Humanos , Hidroxibutiratos/sangue , Lactente , MasculinoRESUMO
A decreased mobilization of triglycerides may contribute to fat accumulation in adipocytes, leading to obesity. However, this hypothesis remains to be proven. In this study, epinephrine-induced lipid mobilization was investigated in vivo in nine markedly obese children (160+/-5% ideal body weight) aged 12.1+/-0.1 yr during the dynamic phase of fat deposition, compared with six age-matched nonobese children. As an in vivo index of lipolysis, we measured glycerol flux using a nonradioactive tracer dilution approach, and plasma free fatty acid concentrations. In the basal state, the obese children had a 30% lower rate of glycerol release per unit fat mass than the lean children. To study the regulation of lipolysis, epinephrine was infused stepwise at fixed doses of 0.75 and then 1. 50 microg/min in both groups. In lean children, glycerol flux and plasma free fatty acid increased to an average of 249-246% of basal values, respectively, in response to a mean plasma epinephrine of 396+/-41 pg/ml. The corresponding increase was only 55-72% in the obese children, although their mean plasma epinephrine reached 606+/-68 pg/ml. All obese and nonobese children, except an Arg64Trp heterozygote, were homozygotes for Trp at position 64 of their beta3-adrenoreceptor. The resistance of lipolysis to epinephrine showed no relationship with the Arg64 polymorphism of the beta3-adrenoreceptor gene. In summary, in vivo lipolysis, which mostly reflects the mobilization of lipid stores from subcutaneous adipose tissue, shows a decreased sensitivity to epinephrine in childhood onset obesity. Since our study was carried out in obese children during the dynamic phase of fat accumulation, the observed resistance to catecholamines might possibly be causative rather than the result of obesity.
Assuntos
Agonistas Adrenérgicos/administração & dosagem , Epinefrina/administração & dosagem , Lipólise/efeitos dos fármacos , Obesidade/metabolismo , Adolescente , Criança , Feminino , Humanos , Infusões Intravenosas , MasculinoRESUMO
Free fatty acid (FFA) transport was measured in 11 and glycerol turnover in 5 newborns with continuous tracer infusion of [1-(13)C]palmitate or [2-(13)C]glycerol, respectively. In addition, simultaneous determination of glucose production in the latter group with [6,6-(2)H(2)]glucose tracer and measurement of the appearance rate of [(13)C]glucose derived from [(13)C]glycerol allowed calculation of gluconeogenesis from glycerol.The average FFA inflow rate was 11.5+/-1.7 mumol kg(-1)min(-1), 2.5-4.5 h after the last feeding, and 16.7+/-2.8 mumol kg(-1)min(-1), 5-12 h after the last meal. These rates are comparable to those found in adults only after 8-16 h and approximately 72 h of fasting, respectively. FFA inflow in the newborn was directly correlated with time of fasting, plasma FFA level, and plasma glycerol level. Palmitate clearance and fractional removal were inversely related to palmitate level. Glycerol flux averaged 4.4+/-0.5 mumol kg(-1)min(-1), a value three- to fourfold that of the postabsorptive adult. Approximately 75% of transported glycerol was converted to glucose and represented 5.0+/-0.6% of hepatic glucose production. Furthermore, there was a direct relationship between glycerol turnover and the fraction of glucose coming from glycerol. Despite the absolutely elevated neonatal FFA and glycerol transport rates, these were quantitatively similar to values found in adults with comparable elevated substrate levels. Furthermore, other similarities with the adult in the relationships between inflow transport and substrate values, and between transport and fractional removal suggest that the regulatory aspects of lipid transport in man are already well developed by the first day of life.
Assuntos
Ácidos Graxos não Esterificados/sangue , Gluconeogênese , Glicerol/metabolismo , Recém-Nascido , Fígado/metabolismo , Ácidos Palmíticos/sangue , Glicemia/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Cinética , Masculino , Taxa de Depuração Metabólica , Ácido PalmíticoRESUMO
The association of insulin-dependent diabetes mellitus (IDDM) with certain HLA alleles is well documented in pediatric patients. Whether a similar association is found in adult-on-set IDDM is not clear, although the disease occurs after the age of 20 in 50% of cases. HLA class II DRB1, DQA1, and DQB1 alleles were studied in 402 type I diabetics and 405 healthy controls (all Caucasian) using oligonucleotide typing after gene amplification. Alleles DRB1*03, DRB1*04, DQB1*0201, DQB1*0302, DQA1*0301, and DQA1*0501 were indeed enriched in diabetics and the highest relative risk was observed in patients carrying both the DRB1*03-DQB1*0201 and the DRB1*0402 or DRB1*0405-DQB1*0302 haplotypes. However none of these alleles, or specific residues, could alone account for the susceptibility to IDDM. Furthermore, there were major differences in HLA class II gene profiles according to the age of onset. Patients with onset after 15 yr (n = 290) showed a significantly higher percentage of non-DR3/non-DR4 genotypes than those with childhood onset (n = 112) and a lower percentage of DR3/4 genotypes. These non-DR3/non-DR4 patients, although presenting clinically as IDDM type 1 patients, showed a lower frequency of islet cell antibodies at diagnosis and a significantly milder initial insulin deficiency. These subjects probably represent a particular subset of IDDM patients in whom frequency increases with age. The data confirm the genetic heterogeneity of IDDM and call for caution in extrapolating to adult patients the genetic concepts derived from childhood IDDM.
Assuntos
Diabetes Mellitus Tipo 1/genética , Genes MHC da Classe II , Antígenos HLA-DR/genética , Adolescente , Adulto , Fatores Etários , Alelos , Antígenos HLA-DQ/genética , Haplótipos , Humanos , Fatores de RiscoRESUMO
To study the initial period of fat deposition in human obesity, we measured glycerol turnover in 12 children of 135-253% ideal body weight, who had continuously gained weight since the onset of obesity 2-9 yr previously. Hyperinsulinemia developed in these children depending on obesity duration (r = 0.74, P less than 0.01). Whole-body glycerol production was twofold greater in the obese children (311 vs. 156 mumol.min-1, P less than 0.01) and correlated with body fat (r = 0.67, P less than 0.005). Normalization of glycerol flux to fat mass revealed that the rate of triglyceride hydrolysis was in fact lower in the adipose tissue of obese children (9.4 vs. 17.7 mumol.min-1/kg body fat) and correlated with plasma insulin (r = 0.64, P less than 0.005). Euglycemic insulin clamps showed that the response of glycerol production to a unit increment in plasma insulin concentration was increased in obese children, suggesting increased insulin sensitivity of adipose tissue. As a direct consequence (r = 0.67, P less than 0.025) of their elevated plasma glycerol concentration (65 +/- 4 vs. 37 +/- 2 microM, P less than 0.05) obese children had an increased glycerol utilization by the whole body, as well as per unit of lean body mass (9.1 +/- 1 vs. 6.5 +/- 0.9 mumoles.min-1.kg lean body mass-1, P less than 0.025).
Assuntos
Glicerol/metabolismo , Obesidade/metabolismo , Glicemia/análise , Peso Corporal/fisiologia , Criança , Feminino , Glicerol/sangue , Humanos , Hiperinsulinismo/etiologia , Hiperinsulinismo/fisiopatologia , Insulina/sangue , Masculino , Obesidade/complicações , Obesidade/fisiopatologia , Triglicerídeos/metabolismoRESUMO
The development of hyperinsulinemia and insulin resistance, both common in adults with established obesity, was studied in 16 children, weighing 169 +/- 8% ideal body weight who were 12.7 +/- 0.4 years of age with obesity duration of 0.5-8.5 years and continuous weight gain in excess of normal, and compared with 11 age-matched normal children. Early in the evolution of obesity, insulin and C-peptide responses to a normal meal were increased by 76 and 80%. The first insulin peak was higher (613 +/- 53 pmol/ml) than normal (413 +/- 59 pmol/ml, P < 0.02) and occurred only 50 +/- 7 min after onset of lunch versus 33 +/- 11 min in normal children (P < 0.0005). Obese patients had a total of 3.0 +/- 0.2 large insulin peaks within the 6-h period after the lunch versus only 1.5 +/- 0.2 peaks in normal children (P < 0.0005). In contrast, fasting plasma insulin and C-peptide levels remained normal during the initial years of obesity, then increased progressively with duration (r = 0.73, P < 0.001) and degree (r = 0.59, P < 0.02) of obesity. Insulin sensitivity evaluated as the rate of glucose uptake during a three-step hyperinsulinemic euglycemic clamp was comparable in the obese (20 +/- 1.5 mmol.m-2.min-1) and the normal (21.7 +/- 1.5 mmol.m-2.min-1) children. Initially higher than normal in obese children, the maximal rate of glucose uptake decreased with both obesity duration (r = -0.67, P < 0.005) and children's age (r = -0.66, P < 0.005), indicating the progressive development of insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Glicemia/metabolismo , Peptídeo C/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Ingestão de Alimentos , Insulina/metabolismo , Obesidade/fisiopatologia , Estado Pré-Diabético/fisiopatologia , Adolescente , Análise de Variância , Peso Corporal , Peptídeo C/sangue , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Feminino , Técnica Clamp de Glucose , Humanos , Insulina/sangue , Secreção de Insulina , Masculino , Obesidade/sangue , Estado Pré-Diabético/sangue , Valores de Referência , Fatores de TempoRESUMO
To determine the time course of metabolic dysfunctions in recent active obesity, we studied basal energy expenditure and lipid and glucose oxidation in 31 obese children (duration of obesity 1-11.5 yr), compared with 14 lean age-matched control subjects. Using indirect calorimetry in basal overnight fasting conditions, we found that obese children produced 15% more energy than control subjects. Obese children oxidized twice as much lipid (56 +/- 4 mg/min) as normal children (25 +/- 5 mg/min, P < 0.0005), so that lipid oxidation provided 61 +/- 6% of overall energy production (vs. 33 +/- 3% in control subjects, P < 0.0005). This increase of lipid oxidation was already present in the earlier stages of obesity. Glucose oxidation was diminished in the obese (93 +/- 6 mg/min) compared with the control children (136 +/- 6 mg/min, P < 0.0005) and accounted for only 39 +/- 3% of energy production (67 +/- 6% in control subjects, P < 0.0005). This decrease was not present initially and appeared after approximately 4 yr and worsened with obesity duration (r = 0.72, P < 0.0005). The results were similar when lipid and glucose oxidation were normalized to body surface area or lean body mass. We hypothesize that increased lipid oxidation is one of the earlier dysfunctions observed in recent-onset obesity and that lipid oxidation may induce a progressive decrease of glucose oxidation, insulin resistance, and increased fasting insulin secretion.
Assuntos
Metabolismo Energético , Glucose/metabolismo , Metabolismo dos Lipídeos , Obesidade/metabolismo , Adolescente , Glicemia/metabolismo , Constituição Corporal , Criança , Ácidos Graxos não Esterificados/sangue , Feminino , Humanos , Insulina/sangue , Masculino , Oxirredução , Puberdade/metabolismo , Valores de Referência , Aumento de PesoRESUMO
We report that cyclosporin A (CsA) suppresses the insulin autoantibodies that are present before insulin therapy in the sera of one-third of studied type I (insulin-dependent) diabetic children. CsA also reversibly blocks the production of antibodies after exogenous insulin injection, whereas high titers of heterologous insulin antibody are observed in all type I patients not receiving CsA.
Assuntos
Autoanticorpos/biossíntese , Ciclosporinas/farmacologia , Diabetes Mellitus Tipo 1/imunologia , Anticorpos Anti-Insulina/biossíntese , Insulina/uso terapêutico , Criança , Diabetes Mellitus Tipo 1/sangue , Humanos , Insulina/sangueRESUMO
Mutations in the leptin gene lead to rare obese syndromes of Mendelian inheritance in humans and rodents. However, no relevant mutations are found in the coding region of leptin gene DNA in patients with common multifactorial obesity. These obese patients tend to have an elevation of serum leptin proportional to their adiposity but with a rather wide dispersion of leptin levels for a given body fat content, which in part is attributable to sexual dimorphism. The current study, performed in two independent Caucasian cohorts of obese girls, shows that a frequent promoter variant of the leptin gene is associated with changes in the relationship between serum leptin and body fatness. Girls of comparable adiposity have different circulating leptin levels, depending on their genotype at this locus. Girls with the -/- Lep -2,549 genotype have 25% lower mean leptin levels than the girls with other genotypes, as reflected by differences in the regression slopes of leptin-to-fat mass. Therefore, genetic factors related to the leptin gene may be important in defining the set point of obese individuals (i.e., the circulating leptin level for a given degree of body fatness). This definition may be of both physiological and therapeutic relevance, although a phenotypic association with an individual single-nucleotide polymorphism is not sufficient to assign function to this particular nucleotide site.
Assuntos
Tecido Adiposo/patologia , Variação Genética , Leptina/sangue , Leptina/genética , Obesidade/sangue , Obesidade/genética , Regiões Promotoras Genéticas , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genótipo , Humanos , Obesidade/patologia , Tamanho do ÓrgãoRESUMO
To characterize the abnormalities of glucose homeostasis and insulin action early in the course of human obesity, we studied in vivo glucose kinetics in seven children who were recently massively overweight. At time of study they were gaining weight at a rate of 13.5 +/- 1.4 kg/yr. They were compared with six age-matched control subjects. Six adults with long-term obesity and five normal adults were studied in parallel. The obese children and adults were normoglycemic and hyperinsulinemic. We found that glucose production and utilization were remarkably higher in obese children (295 +/- 18 mg/min; 7.6 mg.kg-1 lean body mass.min-1) than in control children (129 +/- 13 mg/min; 4.4 mg.kg-1 lean body mass.min-1, P less than .01) and obese adults (151 +/- 8 mg/min; 3.1 +/- 0.3 mg.kg-1 lean body mass.min-1, P less than .01). Obese adults had normal rates of glucose production and utilization. Insulin- and non-insulin-mediated glucose uptake, estimated with somatostatin-induced suppression of endogenous insulin secretion, contributed almost equally to the excess glucose utilization observed in the obese children. When studied with the euglycemic-hyperinsulinemic clamp, obese children could not increase glucose disposal to the same extent as normal children and were not able to adequately suppress their endogenous glucose production. Recently obese children are therefore characterized by an increased basal glucose turnover rate and an already established insulin resistance of the liver and probably the skeletal muscles.