Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome.

Women with PCO have a unique but poorly characterized disorder of insulin action. Obese (n = 16) and nonobese (n = 14) PCO women and age- and weight-matched normal, nondiabetic ovulatory women (obese, n = 15; nonobese, n = 17) had insulin action determined in vivo with sequential multiple insulin dose euglycemic clamps and in isolated abdominal adipocytes to clarify the mechanisms of insulin resistance. PCO resulted in significant increases in the ED50 insulin for glucose utilization in vivo (P less than 0.001) and in adipocytes (P less than 0.01), without significant changes in adipocyte insulin-binding sites. PCO also resulted in significant decreases in maximal insulin-stimulated rates of glucose utilization in vivo (P less than 0.01) and in adipocytes (P less than 0.01). Obesity resulted in smaller decreases in insulin sensitivity than PCO (ED50 insulin, P less than 0.001 in vivo and P less than 0.05 in adipocytes), but greater decreases in insulin responsiveness (Vmax, P less than 0.001 in vivo and in adipocytes). The ED50 insulin for suppression of HGP was increased only in obese PCO women (P less than 0.001), and the interactions between PCO and obesity on this parameter were statistically significant. No significant correlations between androgen or estrogen levels and adipocyte insulin binding or action were found. Because insulin binding was not changed, we conclude that the major lesion causing insulin resistance in PCO is a striking decrease in insulin sensitivity secondary to a defect in the insulin receptor and/or postreceptor signal transduction. PCO also is associated with modest but significant decreases in glucose transport. These defects in insulin action appear to represent intrinsic abnormalities that are independent of obesity, metabolic derangements, body fat topography, and sex hormone levels. Conversely, changes in hepatic insulin sensitivity appear to be acquired with obesity.

Energy balance, viral burden, insulin-like growth factor-1, interleukin-6 and growth impairment in children infected with human immunodeficiency virus.

OBJECTIVE: To determine the relationship between energy metabolism and growth abnormalities in HIV-infected children and to assess clinical or laboratory characteristics which may be contributing factors to their growth impairment. DESIGN: A comparative study. METHODS: We measured energy intake by inpatient calorie count/outpatient 24 h food recalls, resting energy expenditure by indirect calorimetry, total energy expenditure by the doubly-labeled water technique, iron metabolism, protein metabolism, and lipid metabolism markers as well as CD4 count, viral load, insulin-like growth factor-1 (IGF-1), serum interleukin-6 (IL-6), and whole blood stimulated IL-6 levels in prepubertal congenitally HIV-infected children with normal and impaired growth patterns. RESULTS AND CONCLUSIONS: Differences in energy expenditures were not found between normal and growth-impaired HIV-infected children. Energy intake but not energy expenditure was significantly reduced when HIV-infected children were compared to expected normal values for age and gender. Advanced HIV clinical disease, severe immune suppression, increased viral burden, increased IL-6 activity, decreased total serum protein, and decreased IGF-1 levels were more likely to be found in HIV-infected children with growth impairment in comparison with HIV-infected children with normal growth.

Normocortisolemic Cushing's syndrome initially presenting with increased glucocorticoid receptor numbers.

A girl who developed Cushingoid features in peripuberty, but was eucortisolemic, was previously reported to have markedly elevated lymphocyte glucocorticoid receptor sites per cell with normal binding affinity as a potential cause of her phenotype. Her circadian rhythm of cortisol and pituitary-adrenal axis were initially intact, but later proved to be dysregulated. The patient presented at age 10.8 yr with centripetal obesity, moon facies, buffalo hump, and purple striae, but no statural stunting, which is a cardinal sign of Cushing's syndrome. At 11.5 yr she suffered a compression fracture of the L1 vertebra. That prompted treatment with the antiprogestin drug mifepristone (RU486), which was administered at high dose to achieve an antiglucocorticoid effect. From ages 13.75 yr through 15.5 yr, RU486 was administered in various intervals to suppress her Cushingoid features. Once RU486 was introduced, however, a consistent correlation over time between the Cushingoid features and glucocorticoid receptor sites per cell was no longer observed. However, the number of glucocorticoid receptor sites per cell tended to decrease in response to administering RU486. Ultimately, her Cushingoid phenotype proved to be transient.

Differential effects of oral glucose-mediated versus intravenous hyperinsulinemia on circulating androgen levels in women.

OBJECTIVE: To determine whether transient endogenous or continuous exogenous hyperinsulinemia produced different changes in circulating gonadal steroid levels because insulin is a putative regulator of gonadal steroid secretion in polycystic ovarian syndrome (PCOS). DESIGN: An oral glucose tolerance test (OGTT) and a 2-hour euglycemic clamp (+100 microU/mL [718 pmol/L] steady-state insulin levels) were performed in obese patients with PCOS (n = 7) in nonobese patients with PCOS (n = 5), and in age- and weight-matched ovulating normal women (obese normal n = 7, nonobese normal n = 6). RESULTS: Despite increased insulin levels, the levels of T and androstenedione (A) decreased in three of the four groups during the OGTT (nonobese normal women showed a slight increase in T during the OGTT). In contrast, the continuous 2-hour insulin infusion resulted in increased androgen levels. When all four groups were pooled, the difference in the changes in A levels between the two tests was significant, and the difference in T levels between the two tests approached significance. CONCLUSIONS: Transient physiological hyperinsulinemia produced by an oral glucose load was associated with a decrease rather than an increase in circulating androgen levels. The effects on circulating androgen levels of oral glucose-mediated increases in insulin levels were significantly different from those of a continuous intravenous insulin infusion. Sustained hyperinsulinemia produced by exogenous insulin infusion appeared to be required to increase androgen levels in women; transient physiological increases in insulin levels after an oral glucose load were insufficient to produce hyperandrogenism. Postmeal hyperinsulinemia does not contribute to hyperandrogenism in women.