ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents.

Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (TIDM). Mortality is predominantly related to the occurrence of cerebral oedema; only a minority of deaths in DKA are attributed to other causes. Cerebral oedema occurs in about 0.3-1% of all episodes of DKA, and its aetiology, pathophysiology, and ideal method of treatment are poorly understood. There is debate as to whether physicians treating DKA can prevent or predict the occurrence of cerebral oedema, and the appropriate site(s) for children with DKA to be managed. There is agreement that prevention of DKA and reduction of its incidence should be a goal in managing children with diabetes.

Diurnal rhythmicity in intestinal SGLT-1 function, V(max), and mRNA expression topography.

Mechanisms underlying the circadian rhythmicity in intestinal sugar absorption remain unclear. To test whether this rhythmicity is caused by changes in Na(+)-glucose cotransporter 1 (SGLT-1) function, we measured phloridzin-inhibitable sugar fluxes as an index of SGLT-1 activity. Jejunum obtained from rats killed at 6-h intervals during a 12-h light-dark cycle (CT0 is circadian time 0 h, time of light onset) were mounted in Ussing chambers, and 3-O-methylglucose (3-OMG) fluxes were calculated before and after addition of phloridzin. 3-OMG-induced change in short-circuit current and absorptive flux were significantly greater at CT9 than at CT3. This increase was phloridzin inhibitable. Kinetic studies indicated a significant increase in SGLT-1 maximal velocity (V(max)) at CT9. Food intake between CT3 and CT9 was <10% of the daily total, indicating that the increased SGLT-1 activity was anticipatory. Diurnicity of SGLT-1 mRNA was confirmed by Northern blotting. Expression topography analyzed by in situ hybridization revealed more intense labeling along the entire villus axis at CT9 and CT15 compared with CT3 and CT21. We conclude that diurnicity in intestinal sugar absorption is caused by periodicity in SGLT-1 V(max).

The effects of anorexia nervosa on bone metabolism in female adolescents.

Osteopenia is a frequent, often persistent, complication of anorexia nervosa (AN) in adolescent girls and occurs during a critical time in bone development. Little is known about bone metabolism in this patient population. Therefore, we measured bone density (BMD) and body composition by dual energy x-ray absorptiometry, nutritional status, bone turnover, calcium, and hormonal status in 19 adolescent girls with AN (mean +/- SEM, 16.0+/-0.4 yr) and 19 bone age-matched controls. The mean duration of AN was 19+/-5 months. Spinal (L1-L4) osteopenia was common in AN. Lumbar anterioposterior BMD was more than 1 SD below the mean in 42% of patients, and lateral spine BMD was more than 1 SD below in 63% of patients compared with controls. Lean body mass significantly predicted lumbar bone mineral content (r = 0.75; P < 0.0001) in controls only. In AN, duration of illness was the most significant predictor of spinal BMD (lumbar: r = -0.44; P = 0.06; lateral: r = -0.59; P = 0.008). AN adolescents with mature BA (15 yr and greater) were hypogonadal [estradiol, 16.2+/-1.9 vs. 23.3+/-1.6 pg/mL (P = 0.01); free testosterone, 0.70+/-0.17 vs. 1.36+/-0.14 pg/mL (P = 0.01)] although dehydroepiandrosterone sulfate and urinary free cortisol levels did not differ. Leptin levels were reduced in AN (2.9+/-2.1 vs. 16.5+/-1.8 ng/mL; P < 0.0001). Insulin-like growth factor I (IGF-I) was reduced in AN to 50% of control levels (219+/-41 vs. 511+/-35 ng/mL; P < 0.0001) and correlated with all measures of nutritional status, particularly leptin (r = 0.80; P < 0.0001). Surrogate markers of bone formation, serum osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP), were significantly (P = 0.02) reduced in AN vs. controls (OC, 39.1+/-6.4 vs. 59.2+/-5.2 ng/mL; BSAP, 27.9+/-4.0 vs. 40.6+/-3.4 U/L). The majority of the variation in bone formation in AN was due to IGF-I levels (OC: r2 = 0.72; P = 0.002; BSAP: r2 = 0.53; P = 0.01) in stepwise regression analyses. Bone resorption was comparable in patients and controls. These data demonstrate that bone formation is reduced and uncoupled to bone resorption in mature adolescents with AN in association with low bone density. Lean body mass was a significant predictor of BMD in controls, but not AN patients. The major correlate of bone formation in AN was the nutritionally dependent bone trophic factor, IGF-I. Reduced IGF-I during the critical period of bone mineral accumulation may be an important factor in the development of osteopenia in adolescents with AN.

Circadian periodicity of intestinal Na+/glucose cotransporter 1 mRNA levels is transcriptionally regulated.

Intestinal expression of the high affinity Na+/glucose cotransporter 1 (SGLT1), which absorbs dietary glucose and galactose, exhibits both circadian periodicity in its activity and induction by dietary carbohydrate. Because the daily variation in SGLT1 activity is established by the feeding schedule (whether ad libitum or imposed) and persists in the absence of food, this variation has been described as anticipatory. To delineate the mechanisms regulating SGLT1, its expression was examined in rats maintained in a 12-h photoperiod with free access to chow. SGLT1 mRNA levels varied significantly, with the maximum abundance occurring near the onset of dark and the minimum near the onset of light. The SGLT1 transcription rate was 7-fold higher in the morning (1000-1100 h) than in the afternoon (1600-1700 h). An element for hepatocyte nuclear factor 1 (HNF-1) was identified in the SGLT1 promoter that formed different complexes with small intestinal nuclear extracts, depending on the time when the source animal was killed. Serological tests indicated that HNF-1alpha was present in complexes throughout the day, while HNF-1beta binding exhibited circadian periodicity. We propose that exchange of HNF-1 dimerization partners contributes to circadian changes in SGLT1 transcription. Because SGLT1 mRNA levels also varied in rhesus monkeys (offset by approximately one-half day from rats), a similar mechanism appears to be present in primates.

Glucose regulation of glucose transporters in cultured adult and fetal hepatocytes.

GLUT2 is the major glucose transporter of adult hepatocytes. In vivo, membrane GLUT1 is localized to a ring of perivenous cells and increases slightly after fasting or insulin deprivation. GLUT1 also increases in vitro after prolonged culture of isolated adult hepatocytes. We have previously shown that GLUT1 mRNA, protein, and activity are present in the rat fetal hepatocyte, and that both GLUT1 and GLUT2 are important for the pattern of glucose transport in the fetal hepatocyte. We tested the hypothesis that the hypothesis that the postnatal increase in circulating glucose is one of the regulators of the changed pattern of GLUT1 and GLUT2 in the hepatocyte after the fetal to neonatal transition. Fetal and adult rat hepatocytes were cultured for 45 hours in supplemented Dulbecco's modified Eagle's medium at glucose concentrations of 1, 8.3, or 30 mmol/L. Culture at 8.3 and 30 mmol/L glucose diminished GLUT1 mRNA levels were lower in adult versus fetal hepatocyte cultures at 8.3 and 30 mmol/L (P < .05). Similarly, GLUT1 protein levels were significantly diminished in hepatocytes cultured at higher medium glucose (P < .05 for fetal cells at 30 v 1 mmol/L; P < .05 for adult cells at 8.3 and 30 v 1 mmol/L). GLUT2 mRNA abundance was enhanced by medium glucose in adult hepatocytes (P < .05 at 8.3 and 30 v 1 mmol/L) and was unchanged by medium glucose in fetal hepatocytes. In contrast, GLUT2 protein level was unchanged by medium glucose in adult hepatocytes, and was diminished at 30 mmol/L as compared with mmol/L glucose in fetal hepatocytes (P < .05). In confirmation of these findings, uptake of 2-deoxyglucose (2-DOG) by fetal hepatocytes was significantly diminished after culture in 8.3 or 30 mmol/L glucose versus 1 mmol/L glucose (P < .05 and < .01, respectively). These studies confirm that the fetal hepatocyte glucose transporter pattern could be maintained in part by low fetal portal glucose levels. However, the resistance of the fetal hepatocyte glucose transporter pattern as compared with that of the adult hepatocyte to the effects of hyperglycemia suggests additional undefined control mechanisms.

Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women.

Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency often have a polycystic ovary-like syndrome, consisting of hyperandrogynism, infertility, menstrual irregularities, and elevated LH levels. This is generally considered secondary to poor control of the congenital adrenal hyperplasia. However, our experience led us to suspect that ovarian hyperandrogenism occurs even when congenital adrenal hyperplasia is well controlled on glucocorticoid therapy. Therefore, we tested the hypothesis that congenital adrenal virilizing disorders result in ovarian hyperandrogenism. We studied eight women with congenital adrenal virilizing disorders, seven with well controlled classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma removed at 1.7 yr of age. We also studied six women with late-onset 21-hydroxylase deficiency, without signs of congenital virilization. An ovarian source of androgens was assessed after suppressing adrenal function with dexamethasone and then testing pituitary-ovarian function by a GnRH agonist (nafarelin) test. Five women with congenital adrenal virilizing disorders (four with classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma) and one women with late-onset 21-hydroxylase deficiency had ovarian hyperandrogenism as determined by subnormal suppression of free testosterone after dexamethasone and/or by increased 17-hydroxyprogesterone response to nafarelin while on dexamethasone. All women with congenital adrenal virilization and ovarian hyperandrogenism had elevated LH levels after dexamethasone or elevated early LH response to nafarelin, which suggests that LH excess is the cause of their ovarian hyperandrogenism. This was not the case for the late-onset 21-hydroxylase-deficient woman. Our data are compatible with the hypothesis that congenital adrenal virilization programs the hypothalamic-pituitary axis for hypersecretion of LH at puberty. This is postulated to frequently cause ovarian hyperandrogenism even when adrenal androgen excess is subsequently controlled by glucocorticoid therapy.

GLUT-1 and GLUT-2 mRNA, protein, and glucose transporter activity in cultured fetal and adult hepatocytes.

To understand glycogenesis in the fetal hepatocyte, we examined glucose transport in cultured fetal and adult male rat hepatocytes. GLUT-1 mRNA was detected in fetal hepatocytes at isolation but in adult hepatocytes only after culture. GLUT-1 mRNA was more abundant in fetal than in adult hepatocytes (P < 0.005). GLUT-1 protein paralleled its message. GLUT-2 mRNA was more abundant in adult than in fetal hepatocytes (P < 0.05), and abundance did not change during culture, but GLUT-2 protein was discordantly regulated. There was more GLUT-2 protein in fetal hepatocytes at 45 h (P < 0.025). An Eadie-Hofstee plot of 3-O-methylglucose transport appeared to have two linear components. One component was presumed to be GLUT-1 [variable Michaelis constant (Km) approximating 6-8 mM, maximal uptake rate (Vmax) for fetal vs. adult hepatocytes 106 vs. 35 nmol.min-1.mg protein-1], and a second was presumed to be GLUT-2 (Km of 23 mM, Vmax for fetal vs. adult hepatocytes 198 vs. 92 nmol.min-1.mg protein-1). Early phosphorylation of 2-deoxyglucose was greater in fetal than in adult hepatocytes, but transport was always greater than phosphorylation. Increased expression of both GLUT-1 and GLUT-2 by fetal hepatocytes permits greater glucose uptake and positions the fetal rat hepatocyte for efficient glycogenesis at low plasma glucose concentration.

Glutamine carbon disposal and net glutamine uptake in fetuses of fed and fasted ewes.

We have traced ovine fetal glutamine carbon uptake and disposal in 7 chronically catheterized fetuses of fed ewes and 10 fetuses of 48-h fasted ewes. Net fetal glutamine uptake (Fick principle, antipyrine blood flow) was 10.0 +/- 2.0 mumol.kg-1 x min-1 in fed fetuses and 6.4 +/- 1.4 mumol.kg-1 x min-1 in fasted fetuses [not significant (NS)]. However, net fetal glutamine uptake was linearly related to the umbilical vein glutamine level (P < 0.05) in fed and fasted fetuses. In contrast, fetal glutamate transfer to the placenta was 4.0 +/- 0.8 mumol.kg-1.min-1 in the fed state and 2.7 +/- 0.1 mumol.kg-1 x min-1 in the fasted state. Net fetal glutamine uptake and fetal glutamate transfer to the placenta were directly correlated (P < 0.05). Fetal glutamine carbon disposal was measured using a primed continuous infusion of [U-14C]-glutamine over a 3-h period and blood sampling during the last hour of infusion (steady state). Disposal was 20.9 +/- 2.6 mumol.kg-1 x min-1 in the fed state and 18.6 +/- 2.3 mumol.kg-1 x min-1 in the maternal fasted state (NS). Glutamine carbon disposal did not correlate with fetal arterial glutamine levels and was not influenced by maternal nutritional state.

Diabetes mellitus during adolescence.

Poorly controlled diabetes may affect the tempo and course of pubertal growth and development. Pubertal changes induce glucose metabolism or specific insulin resistance. Because puberty greatly increases the risk of diabetes complications, the management offered at this transitional age is critically important. An understanding of the environmental and developmental influences on diabetes control and the effect of the physiologic changes of puberty improves the approach to diabetes management in the adolescent with diabetes.

Maturation of gonadotropin and sex steroid responses to gonadotropin-releasing hormone agonist in males.

We have previously demonstrated that a single dose of the GnRH agonist nafarelin stimulates both gonadotropin and sex steroid secretion in adult men and women. In order to define the maturational steps involved in this response, we tested the effect of nafarelin on LH, FSH, testosterone (T), and estradiol (E2) secretion over 24 h in four groups of males: prepubertal (P1; n = 4), early pubertal (P2; n = 8), and midpubertal boys (P3; n = 4) with variations in the timing of puberty, and normal young adult males (P4; n = 10). Nafarelin stimulated rapid gonadotropin release in all groups, but the pattern of LH response varied. In prepubertal and pubertal boys, LH levels peaked 3-4 h after nafarelin and declined by 50% or more at 24 h post nafarelin. By contrast, adults reached an initial LH peak at 1 h, and LH secretion was sustained with levels 24 h post nafarelin equivalent to those during the early response phase. Nafarelin stimulated T secretion in all groups, but the response was greatest in groups P3 and P4; the maximal incremental rise (delta) in T was 1.2 +/- 0.5, 4.4 +/- 1.0, 18.8 +/- 5.4, and 15.3 +/- 1.4 nmol/L in P1, P2, P3, and P4 males, respectively (analysis of variance: F = 14.4, P < 0.001). E2 concentrations increased much more in adults than in the other groups post nafarelin: delta E2 was 5.5 +/- 1.1, 22.1 +/- 14.7, 83.9 +/- 47.5, and 323.8 +/- 14.7 pmol/L in the P1, P2, P3, and P4 groups, respectively (F = 71.1, P < 0.001). Similarly, the delta E2/delta T ratio was significantly greater in adult males than in less mature males. This developmental pattern of response to nafarelin suggests that male pubertal maturation involves increase of the gonadotrope LH readily releasable and reserve pools. The dissociation of E2 from T responses to nafarelin during puberty suggests that aromatase activity does not fully mature in males until puberty is complete. These findings indicate that a single dose of the GnRH agonist nafarelin is a promising means of assessing the maturation of the pituitary-gonadal axis in males.

Glycogenesis in the cultured fetal and adult rat hepatocyte is differently regulated by medium glucose.

We examined the glycogenic response to glucose in cultured fetal and adult rat hepatocytes. After a 48-h culture in Dulbecco's modified Eagle's medium, 1 mM glucose, insulin, and cortisol, cells were cultured for 4 h in serum-free medium containing glucose (1-30 mM) and U-14C-glucose. Incorporation of 14C-glucose into glycogen was greater in fetal hepatocytes compared with adult hepatocytes at all glucose concentrations (p < 0.001). Net glycogenic rate in fetal cells was greatest between 1 and 8.3 mM (7.7- +/- 1.1-fold increase) compared with a 3.8- +/- 0.6-fold increase in adult cells. In contrast, there was a 19.4- +/- 2.7-fold increase in glycogen accumulated between 8.3 and 30 mM glucose in the adult and a 1.6 +/- 0.1-fold increase in the fetus. Total glycogen synthetase activity was higher in fetal than adult hepatocytes (p < 0.001), but the active a form was similar in fetal and adult hepatocytes. Glycogen synthase a/+b was stimulated at 8.3 mM or greater glucose in fetal hepatocytes, and 5.7 mM or greater in adult hepatocytes (p < 0.05). Total phosphorylase did not change with medium glucose, but glycogen phosphorylase a/a4+b decreased in adult hepatocytes incubated in 5.7 mM glucose or greater (p < 0.05). Fetal phosphorylase a/a+b was increased at 8.3 mM or greater glucose (p < 0.05). In contrast, both adult and fetal phosphorylase were activated by glycogen. A glucose-induced increase in active phosphorylase may induce the decrease in net glycogenic rate at high glucose in fetal hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoprotein(a) levels in black and white children and adolescents with IDDM.

OBJECTIVE: To examine the relationship between levels of lipoprotein(a) [Lp(a)], diabetes, and glycemic control in white and black nondiabetic control and insulin-dependent diabetic (IDDM) children and adolescents, fasting blood analyses were conducted on a subject sample drawn from referral-based diabetes and endocrine clinics and a primary-care general pediatric clinic. RESEARCH DESIGN AND METHODS: Thirty-six white and 16 black children with IDDM who volunteered to participate in this study were compared with 30 white and 42 black nondiabetic control children. RESULTS: Lp(a) protein levels were significantly higher (P less than 0.05) in both groups of black children compared with whites (black vs. white nondiabetic children 6.8 +/- 0.95 vs. 3.1 +/- 0.68 mg/dl and black vs. white diabetic children 7.5 +/- 1.52 vs. 3.0 +/- 0.64 mg/dl). Lp(a) protein levels directly correlated with the level of glycosylated hemoglobin (r = 0.46, P less than 0.01) in white diabetic children but not in black diabetic children. Well-controlled white diabetic children (n = 12, glycosylated hemoglobin less than 10%) had a mean Lp(a) protein level of 1.4 +/- 0.3 mg/dl compared with poorly controlled white diabetic children (n = 10, glycosylated hemoglobin greater than 13%) whose mean Lp(a) protein level was 5.7 +/- 1.7 mg/dl (P less than 0.01). CONCLUSIONS: We conclude that circulating levels of Lp(a) protein are increased in hyperglycemia. A genetically determined elevated level of Lp(a) is a risk factor for atherosclerotic disease in white and Asian adults. Elevated Lp(a) should be investigated as an independent risk factor for atherosclerotic disease in IDDM. It could prove to be an additional mechanism for the development of diabetic complications in selected populations.

Preserving adult height potential in girls with idiopathic true precocious puberty.

We designed a prospective study of height potential in girls with idiopathic precocious puberty, comparing the presenting features of girls with and without evidence of reduced adult height potential. The 14 girls with impaired adult height prognoses (group 1) were reexamined after treatment with a gonadotropin releasing hormone agonist, nafarelin. The seven girls with the prognosis of unimpaired height (group 2) were followed without therapy. We found that the group could be distinguished at initial examination by the greater bone age/height age ratio of group 1 (mean +/- SEM: 1.4 +/- 0.06 vs 1.0 +/- 0.05; p less than 0.005) and by the greater difference between predicted height and target height in group 1. The mean predicted height in group 1 was significantly less than the mean target height (150.7 +/- 2.1 vs 165.4 +/- 3.0 cm; p less than 0.005), whereas the mean predicted and target heights in group 2 were similar (165.4 +/- 3.0 vs 164.3 +/- 2.1 cm). Initial estradiol levels were also greater in group 1 than in group 2 (21.6 vs 10.6 pg/ml; p less than 0.05), although this difference was not sustained during follow-up. In group 1, nafarelin therapy suppressed the pituitary-gonadal axis, and although there was a transient reduction in height potential in girls with the youngest bone ages during the first 6 months of therapy, 2 years of treatment slightly improved predicted heights from 150.7 +/- 2.1 to 152.7 +/- 2.0 cm (p less than 0.05). Height predictions also increased without therapy during the 2-year observation period in group 2, from 165.4 +/- 3.0 to 168.7 +/- 4.1 cm (p less than 0.05). Our data indicate that gonadotropin releasing hormone agonist therapy preserves height potential in girls with an initially impaired height prognosis, and that height potential is preserved without therapy in those with a good initial height prognosis.

Use of nafarelin for testing pituitary-ovarian function.

A single dose of nafarelin can test pituitary-ovarian function from infancy through maturity.

A new test of combined pituitary-testicular function using the gonadotropin-releasing hormone agonist nafarelin in the differentiation of gonadotropin deficiency from delayed puberty: pilot studies.

There is evidence that the capacity to synthesize gonadotropins is less in teenage boys with gonadotropin deficiency (GD) than in those with constitutional delay of puberty (DP). We hypothesized that this might predispose the latter group to have a greater pituitary-testicular response to the potent long-acting GnRH agonist nafarelin. We evaluated GD patients 14.3-24.0 yr of age (n = 8) and prepubertal DP boys 14.8-17.6 yr of age (n = 3). In most subjects the response to nafarelin was compared to that of frequent nocturnal blood sampling for LH and testosterone levels. All subjects received a single dose of nafarelin (1.0 micrograms/kg, sc), and blood was then sampled at 0.5- to 4.0-h intervals for 24 h. Patients with GD could not be distinguished from those with DP by pubertal staging criteria or by baseline values of LH, FSH, or testosterone. Patients with GD exhibited no rise in plasma LH levels during sleep, in contrast to those with DP. All GD patients had LH and FSH responses distinctly less than those of the DP group between 3-24 h postnafarelin. The peak incremental responses of GD and DP to nafarelin were, respectively: LH, 5.5 +/- 2 3 (+/- SEM and 77.2 +/- 8.6 IU/L (P less than 0.02); FSH, 2.7 +/- 1.2 and 9.4 +/- 0.8 IU/L (P less than 0.005). Testosterone peak responses were lower as well (0.26 +/- 0.2 vs 1.6 +/- 0.5 nmol/L, P = 0.05). This pilot study suggests that the response to a single test dose of nafarelin distinguishes GD from DP in the teenage years as well as does measurement of nocturnal LH levels. The testosterone response to the GnRH agonist adds a new dimension to GnRH testing. Nafarelin also allows assessment of the bioactivity of endogenous gonadotropin, is a more potent stimulus of pituitary-testicular function than endogenous GnRH secretion, and is more cost-effective than nocturnal sampling.

Hypersecretion of growth hormone and prolactin in McCune-Albright syndrome.

Acromegaly and hyperprolactinemia have been reported in association with the McCune-Albright syndrome, but the pathophysiology of the GH and PRL hypersecretion that occurs in patients with this disorder has not been defined. We studied GH and PRL secretory dynamics in three patients with McCune-Albright syndrome and hypersecretion of these hormones. Each patient had excessive linear growth, glucose-non-suppressible plasma GH concentration, and GH responsiveness to TRH and GHRH. In response to exogenous GHRH, plasma GH concentrations rose approximately 2-fold in all three patients. Plasma GHRH levels were 20-40 ng/L (normal, less than 30). Study of the spontaneous GH secretory pattern in two patients indicated nocturnal augmentation of GH release. Bromocriptine therapy failed to reduce plasma GH in all patients; in one patient treatment with octreotide, a long-acting somatostatin analog, partially suppressed plasma GH and insulin-like growth factor I levels. These results suggest that hypersecretion of GH in the McCune-Albright syndrome is not due to ectopic GHRH production or autonomous somatotroph function. The results are similar to those described in classic acromegaly due to GH-secreting pituitary tumors. However, the lack of radiographic pituitary enlargement, the variable pituitary pathology reported in similar patients, and frequent concordance of GH and PRL excess suggest that the pathogenesis of this disorder may differ fundamentally from other forms of acromegaly or gigantism. The pathophysiology may reflect abnormal hypothalamic regulation and/or an embryological defect in pituitary cellular differentiation and function.

Placental transfer and fetal effects of maternal sodium beta-hydroxybutyrate infusion in the baboon.

We examined the effects of maternal sodium beta-hydroxybutyrate (NaBOHB) on the primate fetus to investigate the impact of ketosis not associated with acidosis on fetal metabolism. After a loading dose (600 mg/kg), NaBOHB was infused for 70 min (300 mg/kg.hr) into the maternal femoral vein of eight pregnant baboons, and placental transfer and fetal and maternal metabolic changes were observed during an acute experimental protocol. Maternal arterial levels rose from 0.70 +/- 0.21 to 5.42 +/- 0.93 mM (p less than 0.001), and fetal arterial levels from 0.34 +/- 0.09 to 2.76 +/- 0.64 mM (p less than 0.01). A maternal-fetal gradient of approximately 2:1 was observed in both baseline and steady-state infusion conditions and is similar to the human maternal-fetal ketone gradient. This is in contrast to the sheep where significantly higher gradients have been described. The elevated lactate, from 1.90 +/- 0.34 to 2.88 +/- 0.54 mM (p less than 0.05) and somewhat decreased pO2 values in the fetus from 54.8 +/- 8.9 to 45.0 +/- 3.8 mm Hg (p greater than 0.05 less than 0.1), without change in oxygen consumption (2.00 +/- 0.28 versus 1.73 +/- 0.15 mM/min) are features common to conditions of increased levels of fetal energy substrate. NaBOHB does not appear to contribute to oxidative energy metabolism of the whole fetus but may contribute to lipid stores. The significance of higher levels of BOHB in the primate fetus compared to the sheep fetus remains to be elucidated.

Effect of growth hormone therapy in growth hormone-deficient children on cytochrome P-450-dependent 3-N-demethylation of caffeine as measured by the caffeine 13CO2 breath test.

In 6 growth hormone-deficient children, we have demonstrated that 3-N-demethylation of caffeine as measured by the 13CO2 caffeine breath test is decreased following 1 month of growth hormone therapy (8.4 +/- 1.0 vs. 6.8 +/- 1.2% 13C/2 h after treatment). These findings could be of clinical importance. The initiation of growth hormone therapy in growth hormone-deficient children could alter the clearance of drugs metabolized through the mixed-function oxidase pathway given for concurrent conditions, and necessitate adjustment of the therapeutic regimen.

Precursors to glycogen in ovine fetuses.

Postprandial hepatic glycogenesis in the adult animal is now felt to proceed largely through gluconeogenic pathways rather than directly from glucose. The ovine fetus, like the mature sheep, lacks specific hepatic glucokinase. Therefore, we examined the role of lactate as a fetal glycogenic precursor in seven chronically catheterized 125-day sheep fetuses. Fetuses were infused with L-[U-14C]lactate and D-[3-3H]glucose (50 microCi load, 50 microCi/h for 5 h), while maternal glucose was maintained at 50 mg/dl. Mean fetal hepatic glycogen specific activity (microCi/mg x 10(3] was 0.82 +/- 0.08 for 14C and 2.6 +/- 0.4 for 3H, whereas fetal renal glycogen specific activity was 0.46 +/- 0.22 for 14C and 0.78 +/- 0.16 for 3H. In contrast, [14C]glucose specific activity was undetectable in blood (limit of detectability 1 microCi/mg x 10(3] and mean [3H]glucose specific activity was 8.9 +/- 1.3 microCi/mg x 10(3]. The least detectable specific activity of [14C]glucose did not differ significantly from the [14C]glycogen enrichment in liver, whereas [3H]glucose specific activity was significantly (P less than 0.02) greater than [3H]glycogen enrichment. We conclude that glycogenesis from glucose is partly through the indirect gluconeogenic route and that lactate may be a glycogenic precursor in the ovine fetus.