F Sadiq

The heterogeneity of the developing brain insulin receptor.

ABSTRACT: Comparison of the adult brain insulin receptor (IR) to other tissue IR demonstrates that the former migrates ∼10 kD faster on sodium dodecyl sulfate-polyacrylamide gel electrophoresis due to deficient sialic acid content of the asparagine N-linked carbohydrate moieties. We studied these receptors in the fetal rat (18-day) brain (∼125 kD) and liver (∼135 kD), and demonstrated that similar differences are present during fetal life. These differences are not modified by hyperglycemia associated with both mild hyperinsulinemia and normoinsulinemia/hypoinsulinemia. We further studied the specific brain cell types: neurons, glial cells, and purified microvessel preparation, and demonstrated a heterogeneity in the N-linked glycosylation of the IR within an organ (brain). The neuronal (∼125 kD) and microvascular (∼125 kD, ∼135 kD) IR are deficient in sialic acid, thus conferring neuraminidase-insensitivity to the whole brain, whereas the glial cell IR, similar to the liver IR, exhibits neuraminidase sensitivity and migrates intermediate (∼128 kD) to the liver and brain IR. The functional significance of this receptor heterogeneity between various tissues and cells within the same organ (brain) remains to be determined.

Effect of simultaneous administration of betamethasone and triiodothyronine (T3) on the development of functional pulmonary maturation in fetal rabbit

Recent experimental evidence suggests that a combination of glucocorticoid and thyroid hormone may be more effective than either hormone alone in accelerating morphologic as well as biochemical mammalian fetal lung maturation. We have demonstrated that IM administration of T3 to the rabbit doe is associated with enhanced functional fetal lung maturation. We investigated the effect of simultaneous administration of T3 and betamethasone on the development of functional fetal lung maturation and the duration of survival after premature delivery. On day 25 and 26 of pregnancy, T3 (175 micrograms/kg/dose) betamethasone (85 micrograms/kg/dose), T3 plus betamethasone or the appropriate amount of the vehicles were injected. The functional fetal pulmonary maturity and the duration of survival after premature delivery were assessed on day 27 of gestation. Although enhanced functional fetal lung maturation was observed after T3 or betamethasone administration, there was no additive effect after simultaneous administration of both. The duration of survival on premature delivery was enhanced in betamethasone but not T3 or T3 plus betamethasone group when compared to control. Further animal experimentation seems necessary before a clinical trial of T3 plus betamethasone therapy is considered.

Transplacental Stimulation of Fetal Lung Maturation: Effect of Triiodothyronine in the Female and Male Rabbit Fetus

We have recently demonstrated that intramuscular administration of triiodothyronine (T3) or thyroxine (T4) to the rabbit doe results in its transfer across the placenta. In this study we investigated the effect of maternally administered T3 upon the functional and morphologic fetal lung maturation. T3 (175 micrograms/kg) or the vehicle was injected intramuscularly into the New Zealand White rabbit does on days 25 and 26 of gestation. On day 27 of pregnancy, the does were killed and the fetuses were delivered. Maternal and fetal plasma T3, glucose and insulin and fetal plasma corticosteroid concentrations were determined. The functional pulmonary maturity was assessed by performing the pressure-volume hysteresis while morphologic maturity was established by histologic techniques. Enhanced functional as well as morphologic fetal lung maturation was observed in female as well as male fetuses in T3-treated animals. However, there was a significant increase in the fetal mortality after T3 treatment, and the duration of survival in the extrauterine environment on premature delivery was not prolonged.

1375 TRANSPLACENTAL STIMULATION OF FUNCTIONAL AND MORPHOLOGIC FETAL (F) LUNG (L) MATURATION: CONCENTRATION DEPENDENT EFFECT OF THYROID HORMONES (TH)

TH influence F L maturation. However, it is not known if in vivo administration of TH enhance functional F L maturation. T4 (150 or 250μg/kg) or vehicle were injected IM to the rabbit doe on d 25 & 26. Functional & morphologic F L maturation was assessed on d 27 by pressure(P)-volume curve & histology. F plasma free T4 & T3 were measured by RIA. All data X+SEM (*P <0.05 vs con.) n=No. of does. UD=undetectable.F wt & mortality were similar in all groups. Morphologic maturation was enhanced in T3-175 or 225 group only. In the T3-175 ♂ & ♀ F had more mature L.Conclusion: Functional & morphologic acceleration of F L development from TH stimulation is concentration dependent & can be achieved transplacentally in ♂ & ♀ without affecting F growth or mortality.

444 EFFECT OF T4 OR T3 ON MATERNAL (M)-FETAL (F) GLUCOSE (GLU)-GLYCOGEN (GLY) METABOLISM

A potential for T4 or T3 therapy in prevention of IRDS of the newborn has been recently proposed (J.C.I.74,898,1984). We explored the dose-responsiveness of F/M GLU-GLY metabolism to M administration of T4 or T3. T4 (150 or 250μg/kg), T3 (75,125,175 or 225μg/kg) or vehicle were administered IM on d 25 & 26 of pregnancy to rabbit doe. F & M plasma GLU, insulin (I), free T4 (FT4) & T3 concentration, cardiac (Ca) & hepatic (H) GLY content were quantitated on d 27. All data X±SEM (P*<0.05 vs control (c)). n = No. of litters. UD = undetectable.M GLU, M & F I were similar in all groups.Conclusions:1) T4 or T3 crosses the rabbit placenta from M in a dose dependent manner. 2) M T4 or T3 Rx causes F but not M hyperglycemia without change in I 3) T4 or T3 deplete F Ca & H GLY. 4) M H but not Ca GLY is depleted with higher dose of T3.

254 EFFECT OF BETAMETHASONE (B), TRIIODOTHYRONINE (T3) OR B+T3 ON MATERNAL (M) AND FETAL (F) GLUCOSE (GLU)- GLYCOGEN (GLY) METABOLISM

A potential for B+T3 therapy in prevention of IRDS of the newborn has been recently proposed (J.C.I. 74,898, 1984). Some of the major growth and metabolic effects of B and/or T3 therapy on the M and F were determined. B (85 μg/kg), T3 (175 μg/kg), B+T3 (85 and 175 μg/kg) or the vehicle were administered I.M. on d 25 and 26 of pregnancy to rabbit doe. F wt, F and M plasma GLU, insulin (I) and T3 concentration, F and M cardiac (Ca) and hepatic (H) GLY content were quantitated on d 27. All data X±SEM (*P <0.05 vs control (C)). n = No. of litters.Conclusions: 1) Runting effect of B is prevented when administered with T3 2) Major differences in M and F are noted: (a) T3 and/or B cause F but not M hyperglycemia (b) T3 and/or B deplete F but not M Ca GLY (c) B deplete F but increase M H GLY and (d) T3 deplete M and F H GLY.

EFFECT OF HYPOTHYROIDISM |[lpar]|HP|[rpar]| AND HYPERTHYROIDISM |[lpar]|HT|[rpar]| ON 125I-EPIDERMAL GROWTH FACTOR |[lpar]|EGF|[rpar]| SPECIFIC BINDING |[lpar]|S|[period]|B|[period]||[rpar]| TO NEWBORN |[lpar]|NB|[rpar]| LUNG |[lpar]|L|[rpar]| AND BRAIN |[lpar]|B|[rpar]| PLASMA MEMBRANE |[lpar]|PM|[rpar]|

Receptor mediated role of EGF in fetal/neonatal L development and stimulating multiplication of B glial cells is well established. T4 enhances L maturation and CNS myelination. EGF receptor and T4 interactions were explored by examining the effect of HP and HT on S.B. of 125I-EGF to NB (<24 hours) rabbit LPM and BPM. NB were made HP by administering .05% PTU in drinking water at 24c of pregnancy. HT was achieved by administering 100ug/kg (I.M.) of T4 to the doe on 29th and 30th d. of gestation. LPM and BPM were isolated and characterized by protein % recovery, DNA and 5′-nucleotidase assay. S.B. of 125I-EGF to LPM or BPM was assessed at 37°C, pH 7.45 after 75′ of incubation. (ANOVA,*p<.01)From these preliminary results we suggest that T4 status of the Id. NB may influence the development of B but not L EGF R.