Dihydrotestosterone treatment in adolescents with delayed puberty: does it explain insulin resistance of puberty?

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.

Lipolysis in African-American children: is it a metabolic risk factor predisposing to obesity?

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.

Glucose intolerance in obese adolescents with polycystic ovary syndrome: roles of insulin resistance and beta-cell dysfunction and risk of cardiovascular disease.

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.

Early metabolic abnormalities in adolescent girls with polycystic ovarian syndrome.

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.

Insulin sensitivity in African-American children with and without family history of type 2 diabetes.

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.

Determination of body composition in African-American children: validation of bioelectrical impedence with dual energy X-ray absorptiometry.

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.

Leptin in African-American children.

Leptin, the protein product of the obesity gene, produced by adipose tissue, regulates body weight and energy expenditure through CNS feedback mechanisms. In obesity, leptin levels are elevated suggestive of leptin resistance. Because of increased prevalence of obesity in African-Americans, the aim of this study was to assess leptin and its relationship to adiposity in African-American children. We measured plasma leptin levels in 42 African-American children (23 M, 19 F), age 11.8 +/- 0.3 yr, and compared them with 30 American-White children matched for age, body composition and puberty. Body composition was assessed by bioelectrical impedance and plasma leptin by RIA. Data are presented as means +/- SEM and statistical significance is implied by p < 0.05. There was no racial difference in plasma leptin levels (Blacks: 9.8 +/- 1.6, Whites 9.8 +/- 1.9 ng/ml). Leptin correlated with %BF in Black (r = 0.75, p = 0.005) and White (r = 0.79, p = 0.005) children. There were no gender or puberty related differences in leptin levels in African-American children. We concluded that leptin levels are comparable between African-American and American White children of similar body composition. The major determinant of serum leptin levels in these children is degree of adiposity with no gender or puberty related differences. Longitudinal studies are needed to assess leptin's role during puberty in both genders.

Insulin secretion, insulin sensitivity and diabetes in black children.

Historically, type 2 diabetes has been considered rare in the pediatric population. However, over the last decade, there has been a disturbing upswing in the rate of non-type 1 diabetes in the pediatric age group, particularly adolescents, with a greater proportion of Black children being affected. In this review, the following questions will be addressed: (1) what are the clinical characteristics of youth-onset atypical diabetes, (2) how common is it, (3) what are the risk factors, and (4) how should it be treated?

Outcome and cost of child abuse.

OBJECTIVE: To compare the cases of child abuse (CA) with other admissions in a pediatric intensive care unit (PICU) for differences in patient-specific health care costs, severity of illness (SI) and mortality, and describe their outcome. METHOD: A retrospective cohort study of all patients admitted to the PICU between January 1991 and August 1994. Discharge diagnosis, age, SI, mortality rate, length of stay, hospitalization charges ($Hosp), and mortality were retrieved. RESULTS: There were 937 admissions; 13 were secondary to CA. Cases of CA represented 1.4% of admissions and 17% of deaths. CA patients had the highest SI (61%), $Hosp ($30,684), daily charges ($5,294) and mortality rates (53%) than any other group. In our patients, SI is a factor that affects charges. Even when compared to a cohort group with SI, child abuse patients had higher daily hospitalization charges (p < .05). The medical bills for the acute care of a CA patient averaged $35,641 per case. Even with these expenditures, 70% died and 60% of the survivors had severe residual morbidity. CONCLUSION: These results confirm that interventional medical care in response to severe CA is very costly and the ultimate outcome is significantly worse than other diseases. Therefore, we believe it is imperative to allocate resources to prevention.