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. 1981 Dec;68(6):1605–1609. doi: 10.1172/JCI110417

3,5-Dimethyl-3'-isopropyl-l-thyronine therapy in diabetic pregnancy: stimulation of rabbit fetal lung phospholipids.

N Neufeld, S Melmed
PMCID: PMC370967  PMID: 7033290

Abstract

Diabetes mellitus in pregnancy is associated with neonatal respiratory distress syndrome due to impaired synthesis of fetal lung surfactant. Pharmacologic agents that promote fetal lung maturity are diabetogenic and have limited use in the management of diabetic pregnancy for prevention of respiratory distress syndrome. Maternal administration of a thyroid analog 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) results in significant enhancement of fetal lung phospholipid synthesis and accelerated lung maturity. We therefore studied the effects of DIMIT (0.5 mg/kg per d, s.c.) administration to pregnant alloxan-diabetic rabbits on days 25 and 26 of gestation. DIMIT treatment of diabetic maternal rabbits (DD) was associated with reduction of maternal blood glucose (115 +/- 13 vs. 275 +/- 72 mg/dl, P less than 0.05) and fetal glucose (64 +/- 6 vs. 274 +/- 47 mg/dl, P less than 0.001) compared with saline-injected diabetic (D) mothers. Reduction of fetal insulin levels was also associated with maternal DIMIT therapy in diabetic rabbits (56 +/- 5 (D) vs. 24 +/- 4 microunits/ml, P less than 0.001). Maternal diabetes resulted in significant reduction of fetal lung weight (370 +/- 20 vs. 520 +/- 30 mg, P less than 0.005) and lung protein content (6.5 +/- 0.7 vs. 8.7 +/- 0.7 mg/gm, P less than 0.005), which were restored to normal in offspring of DIMIT-treated diabetic rabbits. Maternal DIMIT administration caused significant reduction in fetal lung glycogen content in control (62 +/- 5.8 vs. 25 +/- 5.9 micrograms/mg protein, P less than 0.001) and diabetic (56 +/- 7 vs. 34 +/- 5 micrograms/mg protein, P less than 0.02) offspring. Whereas maternal diabetes was associated with reduction of all major phospholipid species in fetal lung-comprising surfactant, these were restored with DIMIT therapy. The results demonstrate that short-term maternal administration of DIMIT in pregnant diabetic rabbits not only promotes fetal lung phospholipid synthesis, but also appears to ameliorate maternal hyperglycemia. Thus, DIMIT is of potential benefit in the management of diabetic pregnancy.

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Selected References

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  1. Avery M. E. Pharmacological approaches to the acceleration of fetal lung matturation. Br Med Bull. 1975 Jan;31(1):13–17. [PubMed] [Google Scholar]
  2. Ballard P. L., Benson B. J., Brehier A., Carter J. P., Kriz B. M., Jorgensen E. C. Transplacental stimulation of lung development in the fetal rabbit by 3,5-dimethyl-3'-isopropyl-L-thyronine. J Clin Invest. 1980 Jun;65(6):1407–1417. doi: 10.1172/JCI109805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Borberg C., Gillmer M. D., Beard R. W., Oakley N. W. Metabolic effects of beta-sympathomimetic drugs and dexamethasone in normal and diabetic pregnancy. Br J Obstet Gynaecol. 1978 Mar;85(3):184–189. doi: 10.1111/j.1471-0528.1978.tb10478.x. [DOI] [PubMed] [Google Scholar]
  4. Comite F., Burrow G. N., Jorgensen E. C. Thyroid hormone analogs and fetal goiter. Endocrinology. 1978 Jun;102(6):1670–1674. doi: 10.1210/endo-102-6-1670. [DOI] [PubMed] [Google Scholar]
  5. Cuestas R. A., Lindall A., Engel R. R. Low thyroid hormones and respiratory-distress syndrome of the newborn. Studies on cord blood. N Engl J Med. 1976 Aug 5;295(6):297–302. doi: 10.1056/NEJM197608052950601. [DOI] [PubMed] [Google Scholar]
  6. Cunningham M. D., Desai N. S., Thompson S. A., Greene J. M. Amniotic fluid phosphatidylglycerol in diabetic pregnancies. Am J Obstet Gynecol. 1978 Aug 1;131(7):719–724. doi: 10.1016/0002-9378(78)90233-8. [DOI] [PubMed] [Google Scholar]
  7. Erenberg A., Omori K., Menkes J. H., O W., Fisher D. A. Growth and development of the thyroidectomized ovine fetus. Pediatr Res. 1974 Sep;8(9):783–789. doi: 10.1203/00006450-197409000-00001. [DOI] [PubMed] [Google Scholar]
  8. FOLCH J., LEES M., SLOANE STANLEY G. H. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957 May;226(1):497–509. [PubMed] [Google Scholar]
  9. Fisher D. A., Dussault J. H., Sack J., Chopra I. J. Ontogenesis of hypothalamic--pituitary--thyroid function and metabolism in man, sheep, and rat. Recent Prog Horm Res. 1976;33:59–116. doi: 10.1016/b978-0-12-571133-3.50010-6. [DOI] [PubMed] [Google Scholar]
  10. Gilden C., Sevanian A., Tierney D. F., Kaplan S. A., Barrett C. T. Regulation of fetal lung phosphatidyl choline synthesis by cortisol: role of glycogen and glucose. Pediatr Res. 1977 Jul;11(7):845–848. doi: 10.1203/00006450-197707000-00014. [DOI] [PubMed] [Google Scholar]
  11. Hallman M., Kulovich M., Kirkpatrick E., Sugarman R. G., Gluck L. Phosphatidylinositol and phosphatidylglycerol in amniotic fluid: indices of lung maturity. Am J Obstet Gynecol. 1976 Jul 1;125(5):613–617. doi: 10.1016/0002-9378(76)90782-1. [DOI] [PubMed] [Google Scholar]
  12. Jorgensen E. C., Murray W. J., Block P., Jr Thyroxine analogs. 22. Thyromimetic activity of halogen-free derivatives of 3,5-dimethyl-L-thyronine. J Med Chem. 1974 Apr;17(4):434–439. doi: 10.1021/jm00250a014. [DOI] [PubMed] [Google Scholar]
  13. Kolins M. D., Epstein E., Civin W. H., Weiner S. Amniotic fluid phospholipids measured by continuous-development thin-layer chromatography. Clin Chem. 1980 Mar;26(3):403–405. [PubMed] [Google Scholar]
  14. Lindenberg J. A., Brehier A., Ballard P. L. Triiodothyronine nuclear binding in fetal and adult rabbit lung and cultured lung cells. Endocrinology. 1978 Nov;103(5):1725–1731. doi: 10.1210/endo-103-5-1725. [DOI] [PubMed] [Google Scholar]
  15. Mashiach S., Barkai G., Sack J., Stern E., Brish M., Goldman B., Serr D. M. The effect of intraamniotic thyroxine administration on fetal lung maturity in man. J Perinat Med. 1979;7(3):161–170. doi: 10.1515/jpme.1979.7.3.161. [DOI] [PubMed] [Google Scholar]
  16. Mason R. J., Nellenbogen J., Clements J. A. Isolation of disaturated phosphatidylcholine with osmium tetroxide. J Lipid Res. 1976 May;17(3):281–284. [PubMed] [Google Scholar]
  17. Melmed S., Harada A., Murata Y., Socol M., Reed A., Carlson H. E., Azukizawa M., Martin C., Jorgensen E., Hershman J. M. Fetal response to thyrotropin-releasing hormone after thyroid hormone administration to the rhesus monkey: lack of pituitary suppression. Endocrinology. 1979 Aug;105(2):334–341. doi: 10.1210/endo-105-2-334. [DOI] [PubMed] [Google Scholar]
  18. Melmed S., Spira O., Gordon A., Gross J., Jorgensen E. C., Hershman J. M. Suppression of thyrotropin by 3,5-dimethyl-3'-isopropyl-L-thyronine in euthyroid and hypothyroid rats. Endocrinology. 1980 Oct;107(4):1050–1054. doi: 10.1210/endo-107-4-1050. [DOI] [PubMed] [Google Scholar]
  19. Neufeld N. D., Corbo L. M., Kaplan S. A. Plasma membrane insulin receptors in fetal rabbit lung. Pediatr Res. 1981 Jul;15(7):1058–1062. doi: 10.1203/00006450-198107000-00017. [DOI] [PubMed] [Google Scholar]
  20. Neufeld N. D., Kaplan S. A., Lippe B. M. Monocyte insulin receptors in infants of strictly controlled diabetic mothers. J Clin Endocrinol Metab. 1981 Mar;52(3):473–476. doi: 10.1210/jcem-52-3-473. [DOI] [PubMed] [Google Scholar]
  21. Neufeld N. D., Sevanian A., Barrett C. T., Kaplan S. A. Inhibition of surfactant production by insulin in fetal rabbit lung slices. Pediatr Res. 1979 Jun;13(6):752–754. doi: 10.1203/00006450-197906000-00006. [DOI] [PubMed] [Google Scholar]
  22. Raheja R. K., Kaur C., Singh A., Bhatia I. S. New colorimetric method for the quantitative estimation of phospholipids without acid digestion. J Lipid Res. 1973 Nov;14(6):695–697. [PubMed] [Google Scholar]
  23. Robert M. F., Neff R. K., Hubbell J. P., Taeusch H. W., Avery M. E. Association between maternal diabetes and the respiratory-distress syndrome in the newborn. N Engl J Med. 1976 Feb 12;294(7):357–360. doi: 10.1056/NEJM197602122940702. [DOI] [PubMed] [Google Scholar]
  24. Schönberger W., Grimm W., Emmrich P., Gempp W. Thyroid administration lowers mortality in premature infants. Lancet. 1979 Dec 1;2(8153):1181–1181. doi: 10.1016/s0140-6736(79)92400-0. [DOI] [PubMed] [Google Scholar]
  25. Sevanian A., Gilden C., Kaplan S. A., Barrett C. T. Enhancement of fetal lung surfactant production by aminophylline. Pediatr Res. 1979 Dec;13(12):1336–1340. doi: 10.1203/00006450-197912000-00007. [DOI] [PubMed] [Google Scholar]
  26. Smith B. T., Giroud C. J., Robert M., Avery M. E. Insulin antagonism of cortisol action on lechithin synthesis by cultured fetal lung cells. J Pediatr. 1975 Dec;87(6 Pt 1):953–955. doi: 10.1016/s0022-3476(75)80916-4. [DOI] [PubMed] [Google Scholar]
  27. Smith B. T., Torday J. S. Factors affecting lecithin synthesis by fetal lung cells in culture. Pediatr Res. 1974 Oct;8(10):848–851. doi: 10.1203/00006450-197410000-00006. [DOI] [PubMed] [Google Scholar]
  28. Van Handel E. Estimation of glycogen in small amounts of tissue. Anal Biochem. 1965 May;11(2):256–265. doi: 10.1016/0003-2697(65)90013-8. [DOI] [PubMed] [Google Scholar]
  29. Wu B., Kikkawa Y., Orzalesi M. M., Motoyama E. K., Kaibara M., Zigas C. J., Cook C. D. The effect of thyroxine on the maturation of fetal rabbit lungs. Biol Neonate. 1973;22(3):161–168. doi: 10.1159/000240550. [DOI] [PubMed] [Google Scholar]

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