Human insulin induces a higher glucagon response to induced hypoglycemia in short normal children, compared to porcine insulin.

After transfer of diabetic patients from porcine to human insulin, many reports emerged supporting an increased hypoglycemia unawareness. Several studies were then undertaken in both diabetic and healthy adults to investigate counterregulatory hormone responses to both porcine and human insulin-induced hypoglycemia as a possible underlying cause for this different hypoglycemia awareness. Most studies demonstrated similar neuroendocrine responses to both insulin species in adults. However, no such studies have ever been performed in healthy children. We undertook a double-blinded study of counterregulatory hormone responses to both porcine and human insulin-induced hypoglycemia in 17 short normal children randomly assigned to two groups, one receiving human and the other porcine insulin. We found similar responses of growth hormone, cortisol, epinephrine, norepinephrine and dopamine to both porcine insulin- and human insulin- induced hypoglycemia. Interestingly, we observed a significantly higher glucagon secretion when hypoglycemia was induced by human insulin. In conclusion, human insulin induces a higher glucagon secretion in healthy children than porcine insulin. Evidently, this observation cannot be extrapolated to diabetic patients. This study, however, further underlines the importance of performing investigations in children, since results found in adults differ from those observed in children.

Plasma 3 alpha-androstanediol glucuronide in normal children and in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Monitoring therapy for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase is difficult, although plasma determinations of 17 alpha-hydroxyprogesterone (17OHP), delta 4-androstenedione (delta 4A) and testosterone are helpful. We have studied the usefulness of monitoring plasma 3 alpha-androstanediol glucuronide (3 alpha-AG) in group of 24 CAH patients aged from birth to 18 years. For comparison, normal values for age and pubertal stage were determined in a control group of 115 girls and 118 boys. Mean plasma levels were higher during the first year of life, decreased to a nadir between 1 and 4 years, and increased steadily thereafter, there was also a significant increase with pubertal stage. In 24 pairs of blood samples obtained at the time of venopuncture and 2 h after, 3 alpha-AG levels did not change (p > 0.05) demonstrating that 3 alpha-AG levels were not affected by stress. In the patients with CAH, positive correlations between plasma 3 alpha-AG and delta 4A (females, r = 0.73; males, r = 0.98), 17OHP (females, r = 0.58; males, r = 0.84) and testosterone (females, r = 0.83; males, r = 0.97) were observed. Concordance between 3 alpha-AG and delta 4A was observed in 90% of all samples, and in 91% between 3 alpha-AG and testosterone. Our study demonstrates that 3 alpha-AG is a valid marker of control and its determination appears to be a reliable tool to monitor CAH.

Chronic administration of neuropeptide Y into the lateral ventricle inhibits both the pituitary-testicular axis and growth hormone and insulin-like growth factor I secretion in intact adult male rats.

Neuropeptide Y (NPY) is known to be involved in the central regulation of appetite, sexual behavior, and reproductive function. Whereas central administration of NPY strongly stimulates feeding in satiated animals, diet restriction or other unfavorable metabolic situations, such as diabetes, produce enhanced NPY gene expression and NPY release in the hypothalamus. Numerous studies have indicated that acute central administration of NPY results in various actions on LH secretion in the rat, either stimulatory or inhibitory. We recently demonstrated that chronic infusion of NPY into the lateral ventricle of adult intact female rats profoundly inhibited both the gonadotropic and somatotropic axes, with disruption of estrous cyclicity. Furthermore, we showed that central chronic infusion of NPY delayed sexual maturation in female rats. To analyze the effects of the same type of chronic NPY treatment on the pituitary-testicular axis, 45-day-old Sprague-Dawley male rats were implanted with stainless steel cannulas in the right lateral ventricle. Ten days later, Alzet osmotic minipumps were filled with different NPY solutions, adjusted to deliver 6, 18, or 36 micrograms/day, connected to the intracerebroventricular (icv) cannula, and sc implanted dorsally. The effects of these treatments were evaluated over 7 days. In one case, rats were castrated 5 days after initiation of NPY treatment, and the effect of castration was evaluated 2 days later. Chronic icv infusion of NPY produced the expected dose-related increases in food intake from 33.0 +/- 0.9 (basal) to 53.4 +/- 3.3 g/day (18 micrograms NPY/day) and body weight gain (5.7 +/- 0.7 to 10.5 +/- 1.2 d/day). As in female rats, this orexigenic action of NPY resulted in a significant dose-related decrease in pituitary weight, from 12.4 +/- 0.7 to 9.9 +/- 0.4 mg. The 7-day NPY infusion produced highly significant decreases in seminal vesicle weight (853 +/- 77 to 230 +/- 31 mg) and testis weight (3.82 +/- 0.09 to 3.18 +/- 0.15 g; P = 0.003). Plasma levels of testosterone (231 +/- 71 to 48 +/- 13 ng/dl), LH (20.7 +/- 3.7 to 9.1 +/- 1.2 ng/ml), and FSH (282 +/- 17 to 190 +/- 18 ng/ml) were markedly decreased at the 18 micrograms/day dosage, as also demonstrated for the 36 micrograms/day dosage. None of these effects was observed if vehicle was infused into the lateral ventricle instead of the NPY solution. When bilateral orchidectomy was performed 5 days after initiation of the NPY infusion (18 micrograms/day), the immediate LH and FSH rises usually seen after castration were seriously blunted.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuropeptide Y administered chronically into the lateral ventricle profoundly inhibits both the gonadotropic and the somatotropic axis in intact adult female rats.

Neuropeptide Y (NPY) is known to be involved in the central regulation of appetite, sexual behavior, and reproductive functions. Whereas central administration of NPY strongly stimulates feeding in satiated animals, diet restriction produces overexpression of NPY in the arcuate and paraventricular nuclei that might reflect behavioral adaptations to shortage of food. Previous studies indicated that central administration of NPY resulted in controversial actions on LH secretion, either stimulatory or inhibitory. In order to analyze the chronic effect on pituitary function of centrally administered NPY, stainless steel cannulae were implanted in the right lateral ventricles of intact 45-day-old Sprague-Dawley female rats. Ten days later, Alzet osmotic minipumps filled with saline or different concentrations of NPY adjusted to deliver 3, 6, 12, or 18 micrograms/day were connected to the intracerebroventricular (icv) cannulae, implanted sc dorsally, and the effects of these treatments evaluated after 7 days. Chronic icv infusion of NPY produced the expected dose-related increase in food intake [25.3 +/- 0.8 g/day (basal) to 47.9 +/- 4.3 g/day (highest NPY dose)] and body wt gain (3.7 +/- 0.4-11.5 +/- 1.4 g/day). Basal insulinemia was highly correlated to the increase in food intake. This orexigenic action of NPY was accompanied by a drastic dose-related decrease in pituitary wt (14.0 +/- 0.5-8.3 +/- 0.3 mg), pituitary concentration of GnRH receptors, a known marker of the activity of the hypothalamo-pituitary gonadal axis (15.2 +/- 1.7-5.2 +/- 0.5 fmol/mg), and ovarian wt (84.0 +/- 4.2-49 +/- 6.7 mg). Ovulation was impaired in NPY-treated animals as seen by daily inspection of vaginal smears. A sharp dose-dependent decrease in plasma levels of insulin-like growth factor I was also observed [934 +/- 64 ng/ml (basal) to 385 +/- 26 ng/ml (highest NPY dose)], probably secondary to a decrease in GH secretion. Whereas these data confirm the central action of NPY to stimulate appetite in satiated animals, they provide the first demonstration that chronic icv administration of NPY unequivocally inhibits gonadotropin secretion and sexual function in intact female rats. These data also confirm that NPY can suppress GH secretion and other anabolic hormones. In conclusion, these results may indicate a physiological role of NPY as an integrator of different adaptive behaviors in periods of unfavorable metabolic conditions such as diet restriction, extending its action to inhibition of sexual functions and anabolic processes.

Early diagnosis and treatment of neonatal medium-chain acyl-CoA dehydrogenase deficiency: report of two siblings.

Two siblings are reported who were symptomatic in the neonatal period. The first died suddenly at 4 days of age after regurgitating a meal. The postmortem examination showed steatosis of the liver, kidney and muscle. In the second, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency was diagnosed at 3 days of age with muscular hypotonia, vomiting, hyperammonaemia and mild acidosis. Thus disorders of fatty acid oxidation should also be considered in newborns. The biochemical work up indicates that in neonates, analysis of serum medium-chain fatty acids and of acyl and free carnitine are more likely to lead to a diagnosis than determining dicarboxylic acids alone in urine. Long-term treatment was effective and monitored by the acyl/free carnitine ratio.

Skinfold thickness and adiposity index in premature infants.

In order to assess the validity of the weight per square of length ratio as an index of adiposity during the neonatal period, 37 premature infants (gestational age, mean +/- SD, = 31.5 +/- 1.1 weeks, birthweight, mean +/- SD, = 1.448 +/- 147 g) were studied for weight, length and skinfold thickness at 5 sites (biceps, triceps, subscapular, suprailiac and quadriceps) during their stay in the Neonatal Unit of the University Hospital in Lausanne. The results show a significant correlation between the adiposity index and the sum of 5 skinfold thickness sites in premature infants. The adiposity index gives a fair estimate of the body fat mass during the postnatal growth in premature infants.

Composition of weight gain during the neonatal period and longitudinal growth follow-up in premature babies.

Changes in the rate of growth and adiposity index (Quetelet index), calculated as weight/(length)2, kg/m2, were monitored from birth to 3 years in 19 premature babies (post-conceptional age 31.2 +/- 2 weeks) who were subjected during rapid growth (16 +/- 4 g/kg.day) to initial metabolic balance studies in the first weeks of life. These studies showed that the rate of fat accretion in these infants (3.3 +/- 0.9 g/kg.day) was substantially greater than that observed in fetuses of the same gestational age (2 g/kg.day) but the adiposity index was lower (9.6 +/- 1 kg/m2) than intrauterine values (11 kg/m2). Since at 6 months of age (corrected for gestational age at birth) the adiposity index was close to normality (103% of standard), the greater rate of fat accretion in early life contributed to progressively restore total body fat in premature babies. It is concluded that despite substantial fat deposition during the first weeks of life, the future evolution of these premature babies is favourable as judged from the normalization of adiposity index within the first 2 years of life.

Whole body protein synthesis and energy expenditure in very low birth weight infants.

The aim of the present work was to study whole body protein synthesis and breakdown, as well as energy metabolism, in very low birth weight premature infants (less than 1500 g) during their rapid growth phase. Ten very low birth weight infants were studied during their first and second months of life. They received a mean energy intake of 114 kcal/kg X day and 3 g protein/kg X day as breast milk or milk formula. The average weight gain was 15 g/kg X day. The apparent energy digestibility was 88%, i.e. 99 kcal/kg X day. Their resting postprandial energy expenditure was 58 kcal/kg X day, indicating that 41 kcal/kg X day was retained. The apparent protein digestibility was 89%, i.e. 2.65 g/kg X day. Their rate of protein oxidation was 0.88 g/kg X day so that protein retention was 1.76 g/kg X day. There was a linear relationship between N retention and N intake (r = 0.78, p less than 0.001). The slope of the regression line indicates a net efficiency of N utilization of 67%. Estimates of body composition from the energy balance, coupled with N balance method, showed that 25% of the gain was fat and 75% was lean tissue. Whole body protein synthesis and breakdown were determined using repeated oral administration of 15N glycine for 60-72 h, and 15N enrichment in urinary urea was measured. Protein synthesis averaged 11.2 g/kg X day and protein breakdown 9.4 g/kg X day. Muscular protein breakdown, as estimated by 3-methylhistidine excretion, contributed to 12% of the total protein breakdown.(ABSTRACT TRUNCATED AT 250 WORDS)

Energy expenditure and whole body protein synthesis in very low birth weight (VLBW) infants.

To examine the rates of whole body protein synthesis and energy expenditure during the rapid growing period, premature infants of very low birth weight (VLBW) (less than 1500 g), appropriate for gestational age were kept under standard thermoneutrality conditions and received a formula diet providing 110 kcal/kg.d metabolisable energy (ME) and 3.3 g protein/kg.d. Their energy expenditure was measured by open circuit indirect calorimetry. Nitrogen turnover and whole body protein synthesis and catabolism were determined using repeated oral administration of 15N-glycine for 60-72 h followed by the analysis of 15N-enrichment in urinary urea. These VLBW infants grew at an average rate of 15 g/kg.d. About half of the ME intake (i.e. 50 kcal/kg.d) was invested in weight gain while the remainder (i.e. 60 kcal/kg.d) was oxidised. The energy equivalent of the weight gain (i.e. the amount of energy stored per g weight gain) and the N balance indicated that lean tissue made up approximately 2/3 of the weight gained and fat tissue the remaining 1/3. The plateau value for 15N enrichment reached on the third day of administration allowed us to calculate a rate of protein synthesis of 14 g/kg.d and protein breakdown of 12 g/kg.d in five VLBW fed a formula diet. The elevated energy expenditure of the very low birth weight infant seems to be related to its rapid rate of weight gain which is accompanied by a high rate of body protein synthesis. More than 20% of the total energy expenditure of the VLBW infants was accounted for by whole body protein synthesis.