Objective:The type 1 insulin-like growth factor receptor (IGF-R1), which resembles the insulin receptor (INS-R), is expressed abundantly in the placenta. The regulation of fetal growth by IGFs and insulin might reflect their actions on the placenta. This study compared the placental expression of IGF-R1 and INS-R in growth-restricted and normal pregnancies.
Methods:Fetal growth restriction was produced in Sprague-Dawley rats by bilateral ligation of the uterine artery on day 19 (term = 21.5 days). Fetuses were delivered by hysterotomy on day 20, and placental samples were frozen. Fetuses that had been subjected to a sham operation of maternal laparotomy without uterine artery manipulation were studied as matched controls. IGF-R1 and INS-R message was assessed by reverse transcription and polymerase chain reaction amplification of extracted placental RNA. The receptors also were assessed by Western blotting of extracted placental protein. Measurements for the growth-restricted group were expressed as a multiple of that of the matched sham litter.
Results:Placental IGF-R1 messenger RNA (mRNA) level was significantly lower in the growth-restricted fetuses (0.66 × sham [0.47-0.93], P < .05), but INS-R mRNA was not different (0.89 × sham [0.63-1.3], P > .5). IGF-R1 protein transcript was similarly reduced in the growth-restricted fetuses (0.78 × sham [0.69-0.88], P < .005), but the INS-R protein transcript was not (0.98 × sham [0.69-1.4], P > .8). Birth weights were significantly less in the growth-restricted group (3.06 ± 0.07 versus 3.29 ± 0.06 g, P = .016); placental weights were not (0.54 ± 0.02 versus 0.54 ± 0.02 g, P = .90).
Conclusion:The placenta responds to decreased nutrient delivery with decreased expression of IGF-R1. This would reduce the growth-promoting effects of insulin-like growth factors, which include augmentation of placental lactogen production and glucose and amino acid transport. INS-R was unaffected, which suggests that placental response to insulin is less important than its response to insulin-like growth factors in growth restriction.
1. Rechler MM, Nissley SP. The nature and regulation of the receptors for insulin-like growth factors. Ann Rev Physiol1985;47:425-442.
2.
2. Kiess W, Yang Y, Kessler U, Hoeflich A. Insulin-like growth factor II (IGF-II) and the IGF-II/manose-6-phosphate receptor: The myth continues. Horm Res1994;41(Suppl 2):66-73.
3.
3. Liu J, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I and (IGF-I) and the type 1 IGF receptor. Cell1993;75:59-72.
4.
4. D'Ercole AJ, Ye P, Gutierrez-Ospina G. Use of transgenic mice for understanding the physiology of insulin-like growth factors. Horn Res1996;45:5-7.
5.
5. Kniss DA, Schubert PJ, Zimmerman PD, London MB, Gabbe SG. Insulin-like growth factors. Their regulation of glucose and amino acid transport in placental trophoblasts isolated from first-trimester chorionic villi. J Reprod Med1994;39:249-256.
6.
6. Karl PI. Insulin-like growth factor-1 stimulates amino acid uptake by the cultured human placental trophoblast. J Cell Physiol1995;165:83-88.
7.
7. Karl PI, Alpy KL, Fisher SE. Amino acid transport by the cultured placental trophoblast: Effect of insulin on AIB transport. Am J Physiol1992;262(4 Pt 1):C834-C839.
8.
8. Jodarski GD, Shanahan MF, Rankin JH. Fetal insulin and placental 3-O-methyl glucose clearance in the near-term sheep. J Dev Physiol1985;7:251-258.
9.
9. Bhaumick B, Dawson EP, Bala RM. The effects of insulin-like growth factor-I and insulin on placental lactogen production by human term placental explants. Biochem Biophys Res Comm1987;144:674-682.
10.
10. Nestler JE. Insulin and insulin-like growth factor-I stimulate the 3B-hydroxysteroid dehydrogenase activity of the human placental cytotrophoblasts. Endocrinology1989;125:2127-2133.
11.
11. Lane RH, Flozak AS, Simmons RA. Measurement of GLUT mRNA in liver of fetal and neonatal rats using a novel method of quantitative polymerase chain reaction. Bichem Mol Med1996;59:192-199.
12.
12. Laemmli UK. Cleavage of structural proteins during the assembly of the head of the bacteriophage T. Nature1970;227:680-685.
13.
13. Garofalo RS, Rosen OM. Insulin and insulin-like growth factor I (IGR-I) receptors during central nervous system development: Expression of two immunologically distinct IGF-1 receptor β subunits. Mol Cell Biol1989;9:2806-2817.
14.
14. Ogata ES, Bussey ME, Finley S. Altered gas exchange, limited glucose and branch chain amino acids, and hypoinsulinism retard fetal growth in the rat. Metabolism1986;35:970-977.
15.
15. Unterman TG, Simmons RA, Glick RP, Ogata ES. Circulating levels of insulin, insulin-like growwth factor-I (IGF-I) IGF-II, and IGF-binding proteins in the small for gestational age fetal rat. Endocrinology1993;132:327-336.
16.
16. Lueder FL, Ogata ES. Uterine artery ligation in fetal rat alters fetal tissue glucose utilization. Pediatr Res1990;28:464-468.
17.
17. Price WA, Liu R, Stiles AD, D'Ercole AJ. Changes in IGF-I and -II, IGF binding protein and IGF receptor transcript abundance after uterine artery ligation. Pediatr Res1992;32:291-295.
18.
18. Matsumura Y, Domeki M, Sugahara K, et al. Nutritional regulation of insulin growth factor-I receptor mRNA levels in growing chickens. Biosci Biotechnol Biochem1996;69:979-982.
19.
19. Hernandez-Sanchez C, Werner H, Roberts CT Jr, et al. Differential regulation of insulin-like growth factor-I (IGF-I) receptor gene expression by IGF-I and basic fibroblasts growth factor. J Biol Chem1997;272:4663-4670.
20.
20. Averbukh E, Weiss O, Halpert M, et al. Gene expression of insulin-like growth factor-I, its receptor and binding proteins in retina under hypoxic conditions. Metabolism1998;47:1331-1336.
21.
21. Gluckman PD, Guan J, Williams C, et al. Asphyxial brain injury-the role of the IGF system. Mol Cell Endocrinol1998;140:95-99.
22.
22. Giussi G, Vinacur J, Ballejo G, Garofalo EG, Martino I. Human chorionic somatomammotropin, estriol and oxytocinase as indexes of fetal growth. J Perinat Med1979;7:235-242.
23.
23. Kleinman D, Karas M, Roberts CT, et al. Modulations of insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins in endometrial cancer cells by estradiol. Endocrinology1995;136:2532-2537.
24.
24. Huynh H, Nickerson T, Pollak M, Yang X. Regulation of insulin-like growth factor I receptor expression by the pure antiestrogen ICI 182780. Clin Cancer Res1996;2:2037-2042.
25.
25. Siiteri PK, MacDonald PC. Placental estrogen biosynthesis during human pregnancy. J Clin Endocrinol Metab1995;26:751-761.
26.
26. Abu-Amero SN, Ali Z, Bennett P, Vaughan JI, Moore GE. Expression of the insulin-like growth factors and their receptors in term placentas: A comparison between normal and IUGR births. Mol Reprod Dev1998;49:229-235.
27.
27. Siddle K, Soos MA, Field CE, Nave BT. Hybrid and atypical insulin/insulin-like growth factor I receptors. Horm Res1994:41(Suppl 2):56-65.
28.
28. Soos MA, Field CE, Siddle K. Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin with high affinity. Biochem J1993;290:419-426.
