RESUMO
OBJECTIVE: African-Americans are at increased risk for type 2 diabetes. We have previously demonstrated that African-American children are hyperinsulinemic and insulin resistant compared with their white American peers. The aim of the present investigation was to assess the impact of family history of type 2 diabetes on insulin sensitivity in African-American children. RESEARCH DESIGN AND METHODS: A total of 13 prepubertal healthy children with negative family history (FH-) and 9 with positive family history (FH+) of type 2 diabetes underwent a 3-h hyperinsulinemic (40 mU x m(-2) x min(-1))-euglycemic clamp study to assess insulin sensitivity. The groups were comparable for age, pubertal status, total body adiposity determined by dual-energy X-ray absorptiometry, abdominal adiposity assessed by computed tomography scan at the level of L4-5 lumbar vertebra, and physical fitness measured by maximal oxygen consumption (VO2max). RESULTS: The FH+, compared with the FH-, group had lower insulin-stimulated glucose disposal (10.9+/-1.2 vs. 14.2+/-0.9 mg x kg(-1) x min(-1), P = 0.035) and lower nonoxidative glucose disposal (5.7+/-0.8 vs. 8.3+/-0.6 mg x kg(-1) x min(-1), P = 0.015), with no differences in rates of glucose oxidation, fat oxidation, or insulin-mediated free fatty acid suppression. Fasting hepatic glucose production assessed with [6,6-2H2]glucose and basal rates of glucose and fat oxidation were not different between the two groups. CONCLUSIONS: These data suggest that in African-American children, family history of type 2 diabetes is a risk factor for insulin resistance. These children manifest important metabolic alterations, including impaired insulin-stimulated total and nonoxidative glucose disposal early in the first decade of life. We propose that this familial tendency, combined with environmental influences, could lead to type 2 diabetes decades later.
Assuntos
População Negra/genética , Diabetes Mellitus Tipo 2/genética , Saúde da Família , Resistência à Insulina , Metabolismo Basal , Criança , Feminino , Técnica Clamp de Glucose , Humanos , Hiperinsulinismo/genética , Masculino , AnamneseRESUMO
The roles of insulin resistance and insulin secretion in the pathogenesis of glucose intolerance in polycystic ovary syndrome (PCOS) were evaluated in 11 adolescents with impaired glucose tolerance (IGT) and 10 with normal glucose tolerance (NGT). Hepatic glucose production and insulin-stimulated glucose disposal were measured using [6,6-(2)H(2)]glucose and a 3-h hyperinsulinemic (80 mu/m(2).min)-euglycemic clamp. First and second phase insulin secretions were evaluated during a hyperglycemic clamp. Automated blood pressure measurements were made to assess the nocturnal change in blood pressure. Hepatic glucose production was significantly higher in IGT vs. NGT. Insulin-stimulated glucose disposal was not different between the two groups. The first phase insulin level was lower in IGT (207.9 +/- 21.0 vs. 357.0 +/- 62.9 muu/mL; P = 0.025; 1247 +/- 126 vs. 2142 +/- 377 pmol/L) without a difference in second phase insulin. The glucose disposition index (product of insulin sensitivity x first phase insulin) was lower in IGT vs. NGT (278 +/- 40 vs. 567 +/- 119 mg/kg.min; P = 0.023; 1546 +/- 223 vs. 3249 +/- 663 micromol/kg.min). The glucose disposition index correlated inversely with OGTT glucose concentrations at 30, 60, and 120 min. Adolescents with PCOS-IGT lacked the normal nocturnal decline in blood pressure. We conclude that in obese adolescents with PCOS, glucose intolerance is associated with 1) decreased first phase insulin secretion, 2) decreased glucose disposition index, and 3) increased hepatic glucose production. These metabolic abnormalities are precursors of type 2 diabetes and are present early in the course of PCOS. Furthermore, the absence of nocturnal dipping in blood pressure may herald the early expression of cardiovascular disease risk in these adolescents.
Assuntos
Intolerância à Glucose , Obesidade/complicações , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/fisiopatologia , Adolescente , Glicemia/análise , Pressão Sanguínea , Doenças Cardiovasculares/etiologia , Jejum/sangue , Feminino , Técnica Clamp de Glucose , Humanos , Insulina/sangue , Resistência à Insulina , Ilhotas Pancreáticas/fisiopatologia , Fatores de RiscoRESUMO
Rates of obesity and type 2 diabetes are higher in African-American (AA), compared with American white (AW), adults and children. It is not known whether biologic and/or environmental differences are responsible for this racial disparity. We and others have demonstrated that AA children are hyperinsulinemic, compared with their AW peers. This investigation tested the hypothesis that hyperinsulinemia in AA children is associated with lower rates of lipolysis, which could be a risk factor for future obesity. Forty prepubertal children (20 AA and 20 AW) with comparable body composition (assessed by dual-energy x-ray absorptiometry) and visceral adiposity (evaluated with computed tomography scan) were studied. Total body lipolysis was measured with [(2)H(5)]glycerol after overnight fasting. Basal lipolysis was approximately 40% lower in AA vs. AW children, whether the data were expressed for total body (85.7 +/- 8.9 vs. 130.3 +/- 14.1 micromol/min, P = 0.011) or per-kilogram BW (2.4 +/- 0.2 vs. 3.8 +/- 0.4 micromol/min.kg, P = 0.002) or per kilogram fat free mass (FFM) (3.3 +/- 0.3 vs. 5.2 +/- 0.5 micromol/min.kg FFM, P = 0.004), or per kg fat mass (FM) (13.7 +/- 1.6 vs. 21.3 +/- 3.3 micromol/min.kg FM, P = 0.046). Fasting insulin levels were higher in AA children (99.6 +/- 7.8 vs. 77.4 +/- 5.9 pmol/L, P = 0.032). Lipolysis correlated positively with fat mass, percent body fat, and abdominal fat mass. However, in multiple-regression analysis models after controlling for insulin and body composition, race remained a significant contributor to the variance in lipolysis. In summary, the present study demonstrates that rates of lipolysis are significantly lower in AA children, compared with their white peers. This may constitute an early metabolic phenotype that may mediate fat trapping and susceptibility to obesity in a specific environmental context of energy excess conducive to fat accretion.
Assuntos
População Negra , Hiperinsulinismo/epidemiologia , Lipólise , Obesidade/etiologia , Absorciometria de Fóton , Tecido Adiposo , Glicemia/análise , Composição Corporal , Criança , Deutério , Jejum , Feminino , Glicerol/sangue , Glicerol/metabolismo , Humanos , Hiperinsulinismo/metabolismo , Insulina/sangue , Masculino , Obesidade/epidemiologia , Análise de Regressão , Fatores de Risco , Tomografia Computadorizada por Raios XRESUMO
Puberty is characterized by temporary insulin resistance, which subsides with the completion of pubertal development. This insulin resistance is manifested by lower rates of insulin-stimulated glucose metabolism and compensatory hyperinsulinemia in pubertal compared with prepubertal children. Whether or not pubertal insulin resistance is the result of sex steroids or GH or a combination of both has been investigated in our laboratory. Previously, we demonstrated that T treatment in adolescents with delayed puberty was not associated with the deterioration of insulin action. The present investigation evaluated the effects of 4 months of dihydrotestosterone administration (50 mg im every 2 wk) on body composition, glucose, fat, and protein metabolism, and insulin sensitivity. Ten adolescents with delayed puberty were evaluated before and after 4 months of DHT administration. Body composition was assessed by dual energy x-ray absorptiometry. Insulin-stimulated glucose metabolism was measured during a 3-h hyperinsulinemic (40 mU/m(2).min)-euglycemic clamp procedure. Lipolysis and proteolysis were evaluated by stable isotopes of [(2)H(5)]glycerol and [1-(13)C]leucine. After 4 months of dihydrotestosterone treatment, height, weight, and fat free mass increased and percentage of body fat decreased. IGF-I and nocturnal GH levels did not change. There was no significant change in insulin-stimulated glucose metabolism (57.2 +/- 3.9 vs. 58.3 +/- 3.9 micromol/kg.min). Total body proteolysis and lipolysis did not change. In summary, based on the present and past studies, we conclude that during puberty insulin resistance/hyperinsulinemia is not attributable to gonadal sex steroids in boys.
Assuntos
Di-Hidrotestosterona/uso terapêutico , Puberdade Tardia/tratamento farmacológico , Adolescente , Composição Corporal/efeitos dos fármacos , Estradiol/fisiologia , Gorduras/metabolismo , Glucose/metabolismo , Hormônio do Crescimento Humano/fisiologia , Humanos , Resistência à Insulina , Lipídeos/sangue , Masculino , Proteínas/metabolismo , Puberdade Tardia/metabolismoRESUMO
OBJECTIVE: To determine if the Trp(64)Arg (W64R) variant of the beta(3)-adrenergic receptor (ADRB3) could be used as a genetic marker to define risk for polycystic ovary syndrom (PCOS) and/or obesity in children and adolescents. DESIGN: Association study. SETTING: Academic research environment. PATIENT(S): Children referred for evaluation of premature pubic hair (n = 63), adolescent girls referred for evaluation of hirsutism and/or oligomenorrhea (n = 33), and healthy adult controls (n = 67). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Relationship of body mass index (BMI) to presence or absence of W64R variant and frequency of W64R variant in our patient population. RESULT(S): Body mass index (kg/m(2)) was determined for 63 children (55 girls and 8 boys) and 33 adolescent girls. Presence or absence of the W64R variant was assayed by polymerase chain reaction (PCR) amplification followed by allele-specific restriction fragment digest. Twelve subjects and 11 healthy controls were found to be heterozygous for the W64R variant. One subject was found to be homozygous for the W64R variant. Allele frequency for the W64R variant was comparable between patients and controls. Among the patients, mean BMI values were not different between carriers and noncarriers. CONCLUSION(S): Although other studies suggest that the W64R variant is associated with the development of obesity and insulin resistance, we cannot demonstrate that it has a major effect on BMI in children with premature pubarche or in adolescent girls with hyperandrogenism. Serial observations are necessary to determine if this variant predicts the development of obesity and/or PCOS in adulthood.
Assuntos
Peso Corporal/genética , Variação Genética , Hiperandrogenismo/genética , Puberdade Precoce/genética , Receptores Adrenérgicos beta/genética , Adolescente , Criança , Pré-Escolar , Feminino , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Fenótipo , Síndrome do Ovário Policístico/genética , Grupos Raciais/genética , Receptores Adrenérgicos beta 3RESUMO
Body compositional differences between Black and White adults are well-known. It has become increasingly apparent that these racial variations may begin in childhood. Previously, our group validated tetrapolar bioelectrical impedance (BIA) measurements against H2(18O) dilution method to develop prediction formulas of fat free mass (FFM) in healthy White-American children: FFM = 0.524 Ht2/R + 0.415 Wt 0.32. In the present study we used BIA to establish a FFM prediction equation for forty African-American children (19 males and 21 females). Of the females, six were diagnosed with polycystic ovary syndrome (PCOS) and were obese. FFM was determined by dual energy X-ray absorptiometry (DEXA). Impedence measurements by BIA showed a strong correlation with FFM determined by DEXA. In healthy Black children, FFM = 0.84 Ht2/R + 1.10 with a standard error of estimate (SEE) of 1.47 kg (R2 = 0.97). In Black females with PCOS, FFM = 0.62 Ht2/R + 0.21 Wt - 1.94 with a SEE of 1.43 kg (R2 = 0.99). The observed differences in the prediction equations of FFM between White-American and African-American children underline the importance of using race-specific formulas in evaluating body composition. With the overall increase in rates of childhood obesity and more so in the Black race, BIA is an easy and useful tool for the assessment and follow up of body compositional changes with lifestyle interventions.
Assuntos
População Negra , Composição Corporal/fisiologia , Absorciometria de Fóton , Adolescente , Criança , Impedância Elétrica , Feminino , Humanos , Masculino , Síndrome do Ovário Policístico/fisiopatologia , Valores de ReferênciaRESUMO
OBJECTIVE: To investigate insulin sensitivity and secretion in young adolescent girls with childhood onset polycystic ovarian syndrome (PCOS) and to identify the early metabolic derangement(s). STUDY DESIGN: Twelve obese girls with PCOS (age 12.0+/-0.7 years) were compared with 10 obese nonhyperandrogenic girls (control group). The groups were matched for age, percent body fat, and abdominal fat. All subjects underwent a 3-hour hyperinsulinemic (80 mu/m(2)/min)-euglycemic clamp to determine in vivo insulin sensitivity and a 2-hour hyperglycemic clamp (225 mg/dL) to determine insulin secretion. Fasting hepatic glucose production was determined with the use of [6,6-(2)H(2)]glucose. RESULTS: Fasting glucose and hepatic glucose production were comparable between the 2 groups, but fasting insulin was 2-fold higher in the PCOS group. The fasting glucose to insulin ratio was lower in the PCOS group versus the control group (1.9+/- 0.3 vs 3.1+/-0.3, P =.02). During the hyperinsulinemic-euglycemic clamp, insulin sensitivity was lower in the PCOS group (1.4+/-0.2 vs 2.7+/-0.3 mg/kg/min per microu/mL, P =.002). During the hyperglycemic clamp, insulin secretion was significantly higher in the PCOS group. Insulin sensitivity correlated negatively with fasting insulin (r = -0.71, P =.0002) and positively with the fasting glucose to insulin ratio (r = 0.79, P<.0001). CONCLUSION: Adolescent girls with PCOS have profound metabolic derangements detected early in the course of the syndrome, including (1) approximately 50% reduction in peripheral tissue insulin sensitivity, (2) evidence of hepatic insulin resistance, and (3) compensatory hyperinsulinemia. These observations may predict an increased risk of type 2 diabetes mellitus in adolescents with PCOS.