Long-term prospective evaluation of offspring of diabetic mothers.

We have suggested that altered maternal metabolism may affect the subsequent anthropometric and neuropsychological development of children who were in utero during disturbances in maternal fuel economy. This study reports the physical growth through 8 yr of age and the neuropsychological development through 4 yr of age in offspring of diabetic mothers (ODM). At birth, 50% of infants had weights greater than 90th percentile for gestational age. By 12 mo, length and weight were similar to the general population. Height remained normal until 7 yr of age, when it became slightly greater than average. After 5 yr of age, relative weight increased dramatically, and by 8 yr of age, half of the ODM had weights greater than 90th percentile. This childhood obesity in ODM is correlated with maternal prepregnant weight and independently with amniotic fluid insulin at 32-38 wk gestation. The Brazelton Neonatal Behavioral Assessment Scale (BNBAS) was administered to 185 newborn ODM. Significant correlations were found between poorer second- and third-trimester glycemic regulation and lower scores in three of four newborn BNBAS dimensions. The Stanford-Binet Intelligence Scale was measured in 102 ODM at 4 yr of age. We found an inverse correlation between childhood IQ and second- and third-trimester maternal lipid metabolism (serum free fatty acids and beta-hydroxybutyrate). This correlation is not explained by adverse perinatal events, socioeconomic status, maternal IQ, ethnicity, or diabetes type. These long-range associations between altered maternal metabolism and childhood growth and development continue to support Freinkel's hypothesis of fuel-mediated teratogenesis.

Amniotic fluid insulin concentration as a predictor of obesity.

Longitudinal correlations were obtained between amniotic fluid insulin concentration at 32 to 38 weeks' gestation and anthropometric characteristics at the age of 6 years in 56 children of diabetic mothers. The prospective studies indicated that at the age of 6 years, as at birth, the greatest increase in weight in relation to height (relative obesity) was seen in children who experienced the greatest exposures to insulin in the uterus (as judged by amniotic fluid insulin concentration). Significant correlations between amniotic fluid insulin and relative obesity at the age of 6 years were found after adjustment for maternal obesity and macrosomia at birth. The highest amniotic fluid insulin values are clustered in the subgroup of 14 children who were obviously obese by the age of 6 years. These findings are consistent with the hypothesis that there is an association between anthropometric development and intrauterine metabolism, and suggest that premature and excessive exposure to insulin during gestation may predispose to obesity in childhood. The amniotic fluid insulin concentration may predict this eventuality.

Insulin resistance and abnormal ovarian responses to human chorionic gonadotropin in chronically anovulatory women.

We studied the interrelationships between insulin resistance, obesity, and abnormal ovarian androgen secretion in chronically anovulatory women with clinical or biochemical evidence of hyperandrogenism. Four groups of six subjects each were studied: (1) normal weight (within 10% ideal body weight) anovulatory, (2) obese (greater than 120% ideal body weight) anovulatory, (3) normal weight eumenorrheic, and (4) obese eumenorrheic. After dexamethasone suppression, human chorionic gonadotropin (2000 IU/1.5m2 body surface area intramuscularly) was administered to each subject. Serum testosterone levels were subsequently determined hourly for 17 hours. On a separate occasion, an oral glucose tolerance test was administered to five subjects from each group. Serum glucose and immunoreactive insulin levels were determined before and after the ingestion of a standard 100 gm glucose load. As a group, the anovulatory women had higher (p less than 0.05) basal testosterone levels (1005 +/- 97 pg/ml) than did the ovulatory women (241 +/- 21 pg/ml) (values +/- SE). Obesity per se was not associated with increased basal testosterone levels. Testosterone levels rose in response to human chorionic gonadotropin (p less than 0.005) only in obese anovulatory women, reached maximal levels after 3 hours, and subsequently remained stable. Basal immunoreactive insulin levels were elevated (p less than 0.05) only in obese anovulatory women (52.4 +/- 20 microU/ml) compared with obese eumenorrheic (8.7 +/- 1.0 microU/ml), normal weight anovulatory (5.8 +/- 2.4 microU/ml), and normal weight eumenorrheic (4.6 +/- 0.4 microU/ml) women. Similarly, maximal increases in immunoreactive insulin levels after glucose ingestion were significantly greater (p less than 0.01) in obese anovulatory women compared with other groups. Of note is the observation that maximal changes in testosterone observed within the first 3 hours after human chorionic gonadotropin and maximal changes in insulin were correlated (r = 0.91, p less than 0.01). These data suggest that (1) both insulin resistance and an abnormal acute response to human chorionic gonadotropin are seen only in obese anovulatory women and (2) the degree to which these two abnormalities are manifested is clearly correlated. The mechanism(s) responsible for this interrelationship, as well as the underlying cause(s) of these biochemical defects, remain to be elucidated.

Pancreatic endocrine insufficiency in posttransplant cystinosis.

Nephropathic cystinosis causes renal death by approximately age 10 years. With increased life span due to kidney transplantation, ten to 25 years of cystine accumulation has resulted in pancreatic complications in individuals with cystinosis. We noted severe hyperglycemia in five posttransplant patients, three of whom remained insulin-dependent diabetics several years after transplant. The clinical findings were not consistent with steroid-dependent or insulin-resistant diabetes. Pancreatic cystine deposition was detected histologically and biochemically on post-mortem examination of two other patients. We conclude that hyperglycemia may be anticipated in the immediate posttransplant period in cystinotic patients and that some patients will require insulin therapy years later. The use of cystine-depleting agents should be considered in posttransplant cystinosis as an attempt to prevent potential damage to the pancreas and other organs from cystine deposition.

Cyclosporine A inhibits calcemic hormone-induced bone resorption in vitro.

We have investigated the in vitro effects of cyclosporine (CsA), a potent immunosuppressive agent, on bone resorption induced by calcemic hormones. CsA inhibited parathyroid hormone (PTH), prostaglandin E2, 1,25-dihydroxy vitamin D3 (1,25(OH)2D3), and osteoclast-activating factor induced resorption of fetal rat limb bones in a dose-dependent manner. Established ongoing resorptive activity in bone was also inhibited by CsA. The CsA inhibition of bone resorption could be partially surmounted by higher concentrations of PTH and 1,25(OH)2D3. The inhibitory effects of CsA on limb bone resorption were reversible. Neither protein nor DNA synthesis were inhibited by treatment of limb bones with CsA. Thus, the inhibitory effect of this agent on bone resorption is not a cytotoxic one. These data could suggest that the induction of bone resorption by the calcemic hormones involves an immune cell derived mediator such as a lymphokine.

Virilizing adrenocortical tumors in childhood: eight cases and a review of the literature.

Eight cases of adrenocortical tumor are presented with a review of the literature. Although such tumors are rare, they are important causes of inappropriate virilization and Cushing's syndrome in childhood. Clinical virilization with or without hypercortisolism was found in all eight children, who were 5 years old or younger. Excessive linear growth was noted, despite evidence of hypercortisolism. Serum levels of dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone, and cortisol were elevated in all cases tested and appear to be useful diagnostic alternatives to the more traditional determinations of urine 17-ketosteroids and 17-hydroxycorticosteroids. Abdominal sonography and computed tomography have proven to be reliable tools for tumor localization. Surgical resection was the definitive therapy in all patients, and perioperative steroid replacement was essential. Histologic diagnosis appeared to have little bearing on prognosis, and the majority of pediatric patients have had clinically benign disease. At a mean follow-up of 3 years, seven of the eight children were alive and had no evidence of tumor recurrence.

Plasma progesterone concentrations and infant temperament.

Progesterone and its metabolites are potent depressors of the central nervous system. Plasma progesterone concentrations significantly correlated with temperament ratings for approach/withdrawal (r = -0.35, p = 0.01) and intensity (r = -0.28, p = 0.04) among 42 normal infants. The median age at the time of the progesterone sample was 36 days. Easier infants tended to have higher plasma progesterone concentrations compared with more difficult infants (mean +/- SEM: 25 +/- 4 ng/dl versus 17 +/- 3 ng/dl, p = 0.15). Results are consistent with the hypothesis that progesterone or its metabolites may exert a behavioral depressor effect in infancy.

Effect of thyroxine and growth hormone on the hypercholesterolemia of growth hormone deficiency.

To study the selective effect of thyroid hormone and growth hormone, alone and in combination on plasma cholesterol, 12 children were monitored monthly during three 4-month treatment periods. Plasma cholesterol was unaltered by growth hormone therapy alone (mean +/- SD, basal cholesterol level: 202 +/- 26 mg/dL; cholesterol level after growth hormone 200 +/- 24 mg/dL). With thyroxine (T4) replacement alone, or combined with growth hormone, a significant (P less than 0.01) decrement in plasma cholesterol occurred. (Thyroxine alone: 172 +/- 11 mg/dL; thyroxine and growth hormone: 172 +/- 10 mg/dL). Basal thyroid function tests, including TRH stimulation, were normal. Serum thyroxine levels decreased and serum triiodothyronine (T3) levels increased in response to growth hormone therapy. Linear growth increased significantly in response to growth hormone alone and both therapies combined. Serum values of T4 and T3 were significantly (P less than 0.001) correlated with basal cholesterol, r = 0.84 and r = 0.83, respectively. Our experience with euthyroid growth hormone deficiency confirms that modest hypercholesterolemia is characteristic of that disorder, and that growth hormone therapy has no statistically significant effect on plasma cholesterol. The modest hypercholesterolemia that does respond to thyroid replacement is further evidence of a subtle abnormality of thyroid function in such individuals. The mechanism whereby thyroid hormone has its cholesterol lowering effect in these apparently euthyroid subjects is unclear.

Serum cholesterol and triglycerides in children with growth hormone deficiency.

To test the hypothesis that hyperlipidemia is characteristic of growth hormone deficiency in childhood, we have measured serum cholesterol and triglyceride concentrations in 24 euthyroid children with growth hormone deficiency. Although modest elevations of cholesterol and/or triglyceride above the 95th percentile for age, race, and sex were present in 46% of the children studied, the mean (+/- 1 SD) cholesterol of 173 +/- 36 mg/dl and the mean triglyceride of 80 +/- 42 mg/dl were not significantly different from published normal mean values. Administration of human growth hormone for 4 mo to 15 of these subjects did not alter these mean cholesterol and triglyceride values, but did result in a marked improvement in the growth rate. Some individuals (n = 6) with a subnormal growth response to therapy and/or a low serum thyroxine and high serum cholesterol were treated for an additional 4 mo with growth hormone and thyroid hormone together. There was a statistically significant decrement in serum cholesterol in this group. We conclude that modest hyperlipidemia does exist in some children with growth hormone deficiency. Subclinical hypothyroidism may play a role in the hypercholesterolemia of some children, as may growth hormone deficiency itself. Any association of growth hormone and lipid metabolism remains to be clarified.

Somatomedin activity and diabetic control in children with insulin-dependent diabetes.

To test the hypothesis that somatomedin activity is influenced by diabetes and its metabolic regulation, the relationship between somatomedin activity and diabetic control as assessed by hemoglobin A1C was investigated in 40 children with insulin-dependent diabetes. An inverse correlation between hemoglobin A1C and serum somatomedin activity was statistically significant. The data suggest that abnormalities of linear growth, which can occur in children with poorly controlled diabetes, may involve abnormalities in net somatomedin activity.

A clinical scoring system for chronic inflammatory bowel disease in children.

A clinical scoring system for the assessment of children with chronic inflammatory bowel disease has been devised. A close correlation is demonstrated between severity of disease and the level of serum albumin. The clinical score is simple to perform, sensitive to changes in clinical status, reproducible by different observers, and specifically designed to evaluate inflammatory bowel disease in children and adolescents. The clinical score is a useful adjunct in the management of children with chronic inflammatory bowel disease and can be used in prospective studies of various therapeutic modalities.

Standard parameters of diabetic control: are they reliable?

To evaluate the reliability of the tradional methods to assess short-term control of diabetes, 25 children with insulin-dependent diabetes were studied with a 24-h glucose profile in addition to the traditional assessment techniques. Patient compliance was elminated as much as possible from the experimental design. The correlation of the routine methods with the 24-h glucose profile was excellent, and a scoring system for control was empirically derived. The single method of assessment that correlated best with the overall control score was the traditional daily urine test. In 6 of the 25 subjects studied, relative hypoglycemia was observed, occurring asymptomatically at night, and was followed by a hyperglycemic rebound. Traditional assessment techniques did not detect this event. Five additional patients had symptomatic daytime hypoglycemia. We conclude that the traditional daily urine tests are adquate indicators of day-to-day control in most diabetic patients, given adquate compliance. Our data also suggest that asymptomatic nocturnal hypoglycemia occurs frequently in children with diabetes, although clinical proof is difficult in the absence of a 24-h glucose profile.