The Effect of Maternal Hypothyroidism on the Carbohydrate Metabolism and Insulin Secretion of Isolated Islets in Adult Male Offspring of Rats

Abstract

Thyroid hormones have crucial developmental effect during fetal life. This study investigates the effects of maternal hypothyroidism on the carbohydrate metabolism and insulin secretion capacity of islets of the adult male offspring of rats. One group of pregnant mothers (fetal hypothyroid) of Wistar rats drank water containing 0.02% of 6-propyl-2-thiouracil during pregnancy, while the control group consumed only tap water. After delivery, survival and weight of the neonates from both groups were followed. In adult male offspring, the intravenous glucose tolerance test was performed and 5–6 weeks later, glucose-stimulated insulin secretion of isolated islets was assessed. Plasma glucose concentration of the fetal hypothyroid group during intravenous glucose tolerance test was significantly higher (p=0.003) at 5–20 min as compared to the control group, whereas plasma insulin concentration was significantly lower (p=0.012) at 5–20 min. Insulin secretion of the isolated islets stimulated with 16 mM glucose of the offspring in the fetal hypothyroid group (376.2±57.1 pmol/islet/60 min) was significantly lower (p=0.02) as compared to the control group (618.1±85.2). Although adult offspring born from hypothyroid mothers were euthyroid, their glucose tolerance and glucose stimulated insulin secretion of islets were altered, which may eventually contribute to the development of diabetes.

Key words

intrauterine growth retardation - fetal hypothyroidism - plasma glucose - adulthood

References

• 1 Fowden AL, Giussani DA, Forehead AJ. Intrauterine programming of physiological systems: Causes and consequences.  Physiology (Bethesda). 2006;  21 29-37
• 2 Newsome CA, Shiell AW, Fall CH, Phillips DI, Shier R, Law CM. Is birth weight related to later glucose and insulin metabolism? – a systematic review.  Diabet Med. 2003;  20 339-348
• 3 Kuh D, Mishra GD, Black S, Lawlor DA, Davey Smith G, Okell L, Wadsworth M, Hardy R. Offspring birth weight, gestational age and maternal characteristics in relation to glucose status at age 53 years: Evidence from a national birth cohort.  Diabe Med. 2008;  25 530-535
• 4 Remacle C, Dumortier O, Bol V, Goosse K, Romanus P, Theys N, Bouckenooghe T, Reusens B. Intrauterine programming of the endocrine pancreas.  Diabetes Obes Metab. 2007;  9 (S 02) 196-209
• 5 Alpert S, Hanahan D, Teitelman G. Hybrid insulin genes reveal a developmental lineage for pancreatic endocrine cells and imply a relationship with neurons.  Cell. 1988;  53 295-308
• 6 Kaung HL. Growth dynamics of pancreatic islet cell populations during fetal and neonatal development of the rat.  Dev Dyn. 1994;  200 163-175
• 7 Schwitzgebel VM, Somm E, Klee P. Modeling intrauterine growth retardation in rodents: Impact on pancreas development and glucose homeostasis.  Mol Cell Endocrinol. 2009;  304 78-83
• 8 Incerpi S, Scapin S, D’Arezzo S, Spagnuolo S, Leoni S. Short-term effects of thyroid hormone in prenatal development and cell differentiation.  Steroids. 2005;  70 434-443
• 9 Fisher DA. Thyroid system immaturities in very low birth weight premature infants.  Semin Perinatol. 2008;  32 387-397
• 10 Chidakel A, Mentuccia D, Celi FS. Peripheral metabolism of thyroid hormone and glucose homeostasis.  Thyroid. 2005;  15 899-903
• 11 Bates PC, Holder AT. The anabolic actions of growth hormone and thyroxine on protein metabolism in snell dwarf and normal mice.  J Endocrinol. 1988;  119 31-41
• 12 Laurberg P, Andersen S, Karmisholt J. Cold adaptation and thyroid hormone metabolism.  Horm Metab Res. 2005;  37 545-549
• 13 Barbagallo CM, Averna MR, Liotta A, La Grutta S, Maggio C, Casimiro L, Cefalù AB, Notarbartolo A. Plasma levels of lipoproteins and apolipoproteins in congenital hypothyroidism: effects of L-thyroxine substitution therapy.  Metabolism. 1995;  44 1283-1287
• 14 Annunziata P, Federico A, D’Amore I, Corona RM, Guazzi GC. Impairment of human brain development: glycoconjugate and lipid changes in congenital athyroidism.  Early Hum Dev. 1983;  8 269-278
• 15 Leger J, Forest MG, Czernichow P. Thyroid hormones influences sex steroid binding protein levels in infancy: study in congenital hypothyroidism.  J Clin Endocrinol Metab. 1990;  71 1147-1150
• 16 Kala N, Ravisankar B, Govindarajulu P, Aruldhas MM. Impact of foetal-onset hypothyroidism on the epididymis of mature rats.  Int J Androl. 2002;  25 139-148
• 17 Pickard MR, Leonard AJ, Ogilvie LM, Edwards PR, Evans IM, Sinha AK, Ekins RP. Maternal hypothyroidism in the rat influences placental and liver glycogen stores: Fetal growth retardation near term is unrelated to maternal and placental glucose metabolic compromise.  J Endocrinol. 2003;  176 247-255
• 18 Khaksari M, Shafiee M, Ghasemi A, Zahediasl S. Effect of orally administered propylthiouracil in pregnant and lactating rats on isolated aorta contractility of their adult male offspring.  Med Sci Monit. 2009;  15 123-127
• 19 Tourrel C, Bailbe D, Meile MJ, Kergoat M, Portha B. Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age.  Diabetes. 2001;  50 1562-1570
• 20 Lanza RP, Butler DH, Borland KM, Staruk JE, Faustman DL, Solomon BA, Muller TE, Rupp RG, Maki T, Monaco AP. Xenotransplantation of canine, bovine, and porcine islets in diabetic rats without immunosuppression.  Proc Natl Acad Sci USA. 1991;  88 11100-11104
• 21 Song HK, Han DH, Song JH, Ghee JY, Piao SG, Kim SH, Yoon HE, Li C, Kim J, Yang CW. Influence of sirolimus on cyclosporine-induced pancreas islet dysfunction in rats.  Am J Transplant. 2009;  9 2024-2033
• 22 Zardooz H, Zahediasl S, Naseri M. Effect of chronic psychological stress on insulin release from rat isolated pancreatic islets.  Life Sci. 2006;  79 57-62
• 23 Gault VA, Irwin N, Green BD, McCluskey JT, Greer B, Bailey CJ, Harriott P, O’Harte FP, Flatt PR. Chemical ablation of gastric inhibitory polypeptide receptor action by daily (pro3)gip administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-related diabetes.  Diabetes. 2005;  54 2436-2446
• 24 Gatford KL, Mohammad SN, Harland ML, De Blasio MJ, Fowden AL, Robinson JS, Owens JA. Impaired beta-cell function and inadequate compensatory increases in beta-cell mass after intrauterine growth restriction in sheep.  Endocrinology. 2008;  149 5118-5127
• 25 Boujendar S, Arany E, Hill D, Remacle C, Reusens B. Taurine supplementation of a low protein diet fed to rat dams normalizes the vascularization of the fetal endocrine pancreas.  J Nutr. 2003;  133 2820-2825
• 26 Boujendar S, Reusens B, Merezak S, Ahn MT, Arany E, Hill D, Remacle C. Taurine supplementation to a low protein diet during foetal and early postnatal life restores a normal proliferation and apoptosis of rat pancreatic islets.  Diabetologia. 2002;  45 856-866
• 27 Garofano A, Czernichow P, Breant B. Impaired beta-cell regeneration in perinatally malnourished rats: A study with STZ.  FASEB J. 2000;  14 2611-2617
• 28 MacGregor RR, Williams SJ, Tong PY, Kover K, Moore WV, Stehno-Bittel L. Small rat islets are superior to large islets in in vitro function and in transplantation outcomes.  Am J Physiol Endocrinol Metabol. 2006;  290 E771-E779
• 29 Lehmann R, Zuellig RA, Kugelmeier P, Baenninger PB, Moritz W, Perren A, Clavien PA, Weber M, Spinas GA. Superiority of small islets in human islet transplantation.  Diabetes. 2007;  56 594-603
• 30 Decaux JF, Juanes M, Bossard P, Girard J. Effects of triiodothyronine and retinoic acid on glucokinase gene expression in neonatal rat hepatocytes.  Mol Cell Endocrinol. 1997;  130 61-67
• 31 Garcia-Flores M, Blazquez E, Zueco JA. Effects of triiodothyronine and bovine growth hormone on glucose transporter isoform-2 (glut-2) and glucokinase (gk) gene expression in pancreatic islets of fetal and adult rats.  Pflugers Arch. 2001;  442 662-667
• 32 Kohler B, Schnabel D, Biebermann H, Gruters A. Transient congenital hypothyroidism and hyperthyrotropinemia: Normal thyroid function and physical development at the ages of 6–14 years.  J Clin Endocrinol Metabol. 1996;  81 1563-1567
• 33 Vincent MA, Rodd C, Dussault JH, Van Vliet G. Very low birth weight newborns do not need repeat screening for congenital hypothyroidism.  J Pediatr. 2002;  140 311-314
• 34 Brosvic GM, Taylor JN, Dihoff RE. Influences of early thyroid hormone manipulations: delays in pup motor and exploratory behavior are evident in adult operant performance.  Physiol Behav. 2002;  75 697-715
• 35 Parija SC, Raviprakash V, Telang AG, Varshney VP, Mishra SK. Influence of hypothyroid state on 45 Ca(2+) influx and sensitivity of rat uterus to nifedipine and diltiazem.  Eur J of Pharmacol. 2001;  421 207-213
• 36 Kirby JD, Arambepola N, Porkka-Heiskanen T, Kirby YK, Rhoads ML, Nitta H, Jetton AE, Iwamoto G, Jackson GL, Turek FW, Cooke PS. eonatal hypothyroidism permanently alters follicle-stimulating hormone and luteinizing hormone production in the male rat.  Endocrinology. 1997;  138 2713-2721
• 37 Gravina FS, da Silveira CK, de Assis AM, Rieger DK, Guerini C, Müller AP, Farina M, Rotta LN, Perry ML. Experimental hypothyroidism inhibits delta-aminolevulinate dehydratase activity in neonatal rat blood and liver.  Exp Biol Med (Maywood). 2007;  232 1021-1026
• 38 Hamouli-Said Z, Tahari F, Hamoudi F, Hadj-Bekkouche F. Comparative study of the effects of pre and post natal administration of a thyroid drug on testicular activity in adult rat.  Folia Histochem Cytobiol. 2007;  45 (S 01) S51-S57
• 39 Holt J, Canavan JP, Goldspink DF. The influence of thyroid hormones on the growth of the lungs in perinatal rats.  Int J Dev Biol. 1993;  37 467-472

Correspondence