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Severe chronic metabolic acidosis (CMA) in rats is associated with poor food intake and downregulation of growth hormone (GH), insulin-like growth factors (IGFs), and liver receptors; the administration of recombinant GH (rGH) fails to improve the growth failure. In mice with carbonic anhydrase II deficiency (CAD), a model of moderate CMA with food intake close to normal, we studied serum levels of GH, IGFs, and IGF-binding proteins, and the growth response to rGH. CAD was associated with low serum levels of GH in males. Randomized administration of rGH from similar to 5 to similar to 12 wk to CAD mice improved food efficiency and increased serum IGF-I levels, final length, and weight compared with placebo without affecting blood pH. Although administration of rGH also increased linear growth in healthy animals, the effect was less than that in CAD mice and was only observed when started before 6 wk of life. Thus growth failure in CAD mice is associated with a decrease in GH secretion in males but not in females. Long-term administration of rGH increases linear growth in CAD mice despite persistent CMA.
Peripheral insulin sensitivity decreases after puberty in both humans and rodents and can be explained mostly by a reduction in insulin-mediated glycogen synthesis. We tested the hypothesis that the increase in postpubertal fat mass (FM), reflecting an alternative energy store, regulates a decrease in the capacity to store muscle glycogen. We studied Sprague-Dawley rats (n = 21) before puberty (Pre) or after puberty (at 4 mo of age) in groups that were either ad libitum fed (Post) or moderately caloric restricted (CR). FM (by (H2O)-H-3 isotope dilution technique) was decreased by >40% in CR compared with Post. Glucose uptake (R-d, by 18 mU.kg(-1).min(-1) hyperinsulinemic clamp) was 63 +/- 8 mg.kg(-1).min(-1) in Pre and decreased to 39 +/- 2 mg.kg(-1).min(-1) in Post (P < 0.001). However, it increased in CR to 53 +/- 2 mg.kg(-1).min(-1) (P < 0.001 vs. Post). This increase in R-d was mainly accounted for by an increase in glycogen synthesis (R-d glycolysis determined by the rate of conversion of H-3-labeled glucose to (H2O)-H-3) from 23 +/- 2 in Post to 33 +/- 2 mg.kg(-1).min(-1) in CR (P < 0.001; 38 +/- 7 mg.kg(-1).min(-1) in Pre). Correction of glycogen synthesis in CR to near-prepubertal levels was further supported by directly assayed muscle glycogen content after insulin stimulation that was 45% higher and by a 35% enhanced accumulation of [H-3]glucose into glycogen. No changes in the enzyme kinetics of glycogen synthase or phosphorylase were observed. An additional group of 2-mo-old postpubertal ad libitum-fed rats was matched with CR for lean body mass but had more FM. This group demonstrated 25% lower rates of insulin-mediated glycogen synthesis compared with CR, further supporting the notion that a moderate reduction of FM prevents the decline in insulin responsiveness and glycogen synthesis occurring after puberty. These data suggest a cause-effect relationship between the increased deposition of fat and the reduced ability to store glucose in skeletal muscle after puberty.
Mutations in the GHR locus may play a role in the cause of idiopathic short stature (ISS) by impairing growth-hormone (GH) receptor (GHR) function. At one extreme, mutations that nullify the function of the GH receptor are linked to complete GH insensitivity syndrome, or Laron syndrome, and we hypothesized that less-disruptive mutations could contribute to partial GH insensitivity syndrome. Low levels of GH binding protein may indicate mutations in the extracellular domain of the receptor, and by focusing on 14 children with ISS who had low GH binding protein and insulin-like growth factor I levels, we found three heterozygotes and one compound heterozygote for mutations in the extracellular domain of the receptor. We have since extended our study to a broader spectrum of patients, adding 76 patients with ISS who were treated with GH in a phase II study of the safety and efficacy of recombinant human GH in ISS and also adding 10 patients who were ascertained as having ISS by pediatric endocrinologists in private practice. The GHR gene has thus been analyzed in 100 patients with ISS, eight of whom were found to carry mutations: four in our original study and four with normal or elevated levels of GH binding protein. The latter group consists of three carriers of heterozygous extracellular domain mutations and one carrier of a heterozygous intracellular domain mutation. Family data suggest that the carriers of these mutations have a range of phenotypes, supporting our hypothesis that the expression of these heterozygous mutations as partial GH insensitivity syndrome depends on the genetic makeup of the person.
Studies in humans and animals indicate that peripheral insulin sensitivity is decreased after puberty, Although glucose, after its uptake and phosphorylation, will be diverted to either the glycolytic or glycogen synthesis pathway, these pathways have not been characterized after the transition to puberty, Thus, we examined the changes in the pathways of glucose utilization in conscious (n = 22) prepuberty (81 +/- 3 g), and postpuberty (258 +/- 9 g) Sprague-Dawley rats. Insulin stimulated (by insulin clamp 18 mU/kg/min) glucose uptake [rate of glucose disappearance (R(d))] was decreased by similar to 30% postpuberty (from 339 +/- 22 to 239 +/- 28 mu mol/kg/min; p < 0.001). Although glycolysis (estimated by the rate of conversion of [H-3]glucose to (H2O)-H-3) decreased by similar to 15% (p < 0.05), glycogen synthesis decreased by similar to 40% (from 200 +/- 17 prepuberty to 122 +/- 22 mu mol/kg/min postpuberty; p < 0.001), and accounted for similar to 80% of the decrease in R(d) postpuberty, Decrease in the capacity to store glycogen in response to insulin was also confirmed by similar to 40% decrease in both glycogen levels, and in H-3 accumulation into glycogen (from H-3-glucose) at the end of the clamp study. This occurred in the absence of any changes in either the K-m or the V-max of glycogen synthase nor in the activity of glycogen phosphorylase, We conclude that the postpubertal decrease in insulin responsiveness is characterized by decreased ability to store muscle glycogen. We propose that high capacity for muscle glycogen synthesis may be required to sustain the increased metabolic requirements during peripubertal growth.
Pseudotumor cerebri is generally a benign disorder. It has been reported to occur in hypothyroidism, particularly after the initiation of L-thyroxine replacement therapy. Previous case reports have involved children primarily in the peripubertal age range (similar to 8 to 13 years). We report here the development of pseudotumor cerebri in an infant who required treatment with L-thyroxine for transient neonatal hypothyroidism as a result of maternal thyroid-stimulating hormone receptor-blocking antibodies.
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Total Results:
116
American journal of physiology. Regulatory, integrative, & comparative physiology. 1998:275:R120-R128.DOI:
Disturbances of growth hormone insulin-like growth factor axis and response to growth hormone in acidosis [Meeting Abstract]
ISI:000074512100017
ISSN: 0363-6119
CID: 3491992
Growth hormone and idiopathic short stature - it is too soon to call it a mis-trial [Editorial]
ISI:000073019700006
ISSN: 0804-4643
CID: 3491982
Growth hormone therapy of Turner's syndrome: beneficial effect on adult height
OBJECTIVE:To carry out a multicenter, prospective, randomized trial of human growth hormone (GH), alone or in combination with oxandrolone (OX), in patients with Turner's syndrome (TS). METHODS:In an initial phase lasting 12 to 24 months, 70 girls with TS, verified by karyotype, were randomly assigned to one of four groups: (1) observation, (2) OX, (3) GH, or (4) GH plus OX. After completion of the first phase, group 3 subjects continued to receive GH only. All other subjects were treated with GH plus OX. Subjects were followed up until attainment of adult height and/or cessation of treatment. Data from this trial were compared with growth characteristics of 25 American historical subjects with TS (matched for age, height, parental target height, and karyotype) who never received either GH or androgens. RESULTS:Of the 70 subjects enrolled, 60 completed the clinical trial. The 17 subjects receiving GH alone all completed the trial and reached a height of 150.4+/-5.5 cm (mean +/- SD), 8.4+/-4.5 cm taller than their mean projected adult height at enrollment (95% confidence interval [CI]: 6.3 to 10.6 cm). The 43 subjects receiving GH plus OX attained a mean height of 152.1+/-5.9 cm, 10.3+/-4.7 cm taller than their mean projected adult height (95% CI: 8.9 to 11.7 cm). The historical control subjects had a mean adult height of 144.2+/-6.0 cm, precisely matching their original projected adult height of 144.2+/-6.1 cm. CONCLUSIONS:GH, either alone or in combination with OX, is capable of stimulating short-term growth and augmenting adult height in girls with TS. With early diagnosis and initiation of treatment, an adult height of more than 150 cm is a reasonable goal for most girls with TS.
PMID: 9506648
ISSN: 0022-3476
CID: 3894792
American journal of physiology. Regulatory, integrative, & comparative physiology. 1997:273:R1534-R1539.DOI:
Fat accretion and the regulation of insulin-mediated glycogen synthesis after puberty in rats [Meeting Abstract]
ISI:A1997YA44700041
ISSN: 0363-6119
CID: 3492572
Partial growth-hormone insensitivity: The role of growth-hormone receptor mutations in idiopathic short stature [Meeting Abstract]
ISI:A1997XP74100013
ISSN: 0022-3476
CID: 3492562
Hyperinsulinemia and decreased insulin-like growth factor-binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche
The fasting insulin resistance index, mean blood glucose, mean serum insulin (MSI), early insulin response to glucose, glucose uptake rate in peripheral tissues, and insulin sensitivity indexes in response to a standard oral glucose tolerance test; serum insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), IGFBP-3, and sex hormone binding-globulin (SHBG) levels; and the free androgen indexes were evaluated in 98 girls with premature pubarche [PP; prepubertal (B1; n = 32), early pubertal (B2; n = 27), midpubertal (B3; n = 23), and postmenarcheal (B5; n = 16)] and in 86 Tanner stage- and bone age-matched controls. We ascertained whether hyperinsulinemia is already present in PP girls before or during pubertal development and whether these patients show a similar pattern of growth factor secretion as normal girls. Body mass indexes did not differ significantly between patients and controls within the same pubertal stage. MSI levels showed a significant increase with pubertal onset in all subjects, as expected. Patients showed significantly higher MSI values than controls at all Tanner stages (P < 0.03, P = 0.03, P = 0.03, and P < 0.05 for B1, B2, B3, and B5, respectively); higher insulin response to glucose at B1, B2, and B3 (P < 0.03, P = 0.03, and P < 0.05, respectively); higher glucose uptake rate in peripheral tissues at B1 and B2 (P < 0.04 and P = 0.02, respectively); and a later rise in insulin sensitivity compared to controls. PP girls also showed lower IGFBP-1 levels at B1 and B5 (P < 0.01 and P = 0.02, respectively), lower SHBG concentrations at B5 (P < 0.0005), and higher free androgen indexes at B1, B3, and B5 (P < 0.01, P < 0.05, and P < 0.001, respectively) compared to controls. Among others, significant correlations between SHBG and MSI levels (r = -0.49; P < 0.0001) and between SHBG and IGFBP-1 levels (r = 0.41; P < 0.0001) were found in all subjects. Hyperinsulinemia, increased early insulin responses to glucose, increased glucose uptake rate in peripheral tissues, elevated free androgen indexes, and decreased SHBG and IGFBP-1 levels are present in most girls with PP from childhood. These findings lend strong support to the concept that PP is not a benign condition, and long term follow-up of these patients into adulthood is recommended. The possible causal role of hyperinsulinemia in adrenal and/or ovarian androgen hypersecretion remains to be established.
PMID: 9215308
ISSN: 0021-972x
CID: 3894462
New developments in congenital lipoid adrenal hyperplasia and steroidogenic acute regulatory protein [Case Report]
To date, studies of patients with lipoid CAH have shown the indispensable role of StAR in the production of steroids by adrenal gland and gonads. Lipoid CAH is the first and so far only inborn disorder of steroid hormone synthesis and metabolism that is not caused by a defective steroidogenic enzyme but rather by a defect in cholesterol transport.
PMID: 9130927
ISSN: 0031-3955
CID: 3894372
Intracellular pathways of insulin-mediated glucose uptake before and after puberty in conscious rats [Meeting Abstract]
ISI:A1997WK80800006
ISSN: 0031-3998
CID: 3492522
Pseudotumor cerebri in an infant after L-thyroxine therapy for transient neonatal hypothyroidism
ISI:A1997WM26400028
ISSN: 0022-3476
CID: 3492532
Current concepts - Turner's syndrome [Review]
ISI:A1996VW79500007
ISSN: 0028-4793
CID: 3492512
