Brain Structure and Function

, Volume 218, Issue 1, pp 73–84

The effects of maternal diabetes on expression of insulin-like growth factor-1 and insulin receptors in male developing rat hippocampus

  • Javad Hami
  • Ariane Sadr-Nabavi
  • Mojtaba Sankian
  • Mehdi Balali-Mood
  • Hossein Haghir
Original Article


Diabetes during pregnancy causes neurodevelopmental and neurocognitive abnormalities in offspring. Insulin and insulin-like growth factor-1 (IGF-1) are important regulators of developmental and cognitive functions in the central nervous system. We examined the effects of maternal diabetes on insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (InsR) expression in the developing rat hippocampus. Female rats were maintained diabetic from a week before pregnancy through parturition and male offspring was killed at P0, P7, and P14. We found a significant bilateral upregulation of both IGF-1R and InsR transcripts in the hippocampus of pups born to diabetic mothers at P0, as compared to controls. However, at the same time point, the results of western blot analysis revealed only a slight change in their protein levels. At P7, there was a marked bilateral reduction in mRNA expression and protein levels of IGF-1R, although not of InsR in the diabetic group. We also found a downregulation in IGF1-R transcripts, especially in left hippocampus of the diabetic group at P14. Moreover, at the same time point, InsR expression was significantly decreased in both hippocampi of diabetic newborns. When compared with controls, we did not find any difference in hippocampal IGF-1R or InsR mRNA and protein levels in the insulin-treated group. The present study revealed that diabetes during pregnancy strongly influences the regulation of both IGF-1R and InsR in the right/left developing hippocampi. Furthermore, the rigid control of maternal glycaemia by insulin administration normalized these effects.


Maternal diabetes Insulin-like growth factor-1 receptor Insulin receptor Hippocampus Rat newborn 


  1. Aerts L, van Assche FA (1977) Rat foetal endocrine pancreas in experimental diabetes. J Endocrinol 73:339–346PubMedCrossRefGoogle Scholar
  2. Agrawal R, Tyagi E, Shukla R, Nath C (2011) Insulin receptor signaling in rat hippocampus: a study in STZ (ICV) induced memory deficit model. Eur Neuropsychopharmacol 21:261–273PubMedCrossRefGoogle Scholar
  3. Anlar B, Sullivan KA, Feldman EL (1999) Insulin-like growth factor-I and central nervous system development. Horm Metab Res 31:120–125PubMedCrossRefGoogle Scholar
  4. Bach MA, Shen-Orr Z, Lowe WL Jr, Roberts CT Jr, LeRoith D (1991) Insulin-like growth factor I mRNA levels are developmentally regulated in specific regions of the rat brain. Brain Res Mol Brain Res 10:43–48PubMedCrossRefGoogle Scholar
  5. Banks WA, Jaspan JB, Kastin AJ (1997) Selective, physiological transport of insulin across the blood-brain barrier: novel demonstration by species-specific radioimmunoassays. Peptides 18:1257–1262PubMedCrossRefGoogle Scholar
  6. Baron-Van Evercooren A, Olichon-Berthe C, Kowalski A, Visciano G, Van Obberghen E (1991) Expression of IGF-I and insulin receptor genes in the rat central nervous system: a developmental, regional, and cellular analysis. J Neurosci Res 28:244–253PubMedCrossRefGoogle Scholar
  7. Bartlett WP, Li XS, Williams M, Benkovic S (1991) Localization of insulin-like growth factor-1 mRNA in murine central nervous system during postnatal development. Dev Biol 147:239–250PubMedCrossRefGoogle Scholar
  8. Baskin DG, Wilcox BJ, Figlewicz DP, Dorsa DM (1988) Insulin and insulin-like growth factors in the CNS. Trends Neurosci 11:107–111PubMedCrossRefGoogle Scholar
  9. Bayer SA (1980) Development of the hippocampal region in the rat. I. Neurogenesis examined with 3H-thymidine autoradiography. J Comp Neurol 190:87–114PubMedCrossRefGoogle Scholar
  10. Becerra JE, Khoury MJ, Cordero JF, Erickson JD (1990) Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case–control study. Pediatrics 85:1–9PubMedGoogle Scholar
  11. Bondy CA (1991) Transient IGF-I gene expression during the maturation of functionally related central projection neurons. J Neurosci 11:3442–3455PubMedGoogle Scholar
  12. Bondy CA, Cheng CM (2004) Signaling by insulin-like growth factor 1 in brain. Eur J Pharmacol 490:25–31PubMedCrossRefGoogle Scholar
  13. Breese CR, D’Costa A, Booze RM, Sonntag WE (1991) Distribution of insulin-like growth factor 1 (IGF-1) and 2 (IGF-2) receptors in the hippocampal formation of rats and mice. Adv Exp Med Biol 293:449–458PubMedCrossRefGoogle Scholar
  14. Brussee V, Cunningham FA, Zochodne DW (2004) Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes 53:1824–1830PubMedCrossRefGoogle Scholar
  15. Cardell BS (1953) Hypertrophy and hyperplasia of the pancreatic islets in new-born infants. J Pathol Bacteriol 66:335–346PubMedCrossRefGoogle Scholar
  16. Castellucci M, Kaufmann P (1995) Basic structure of the villous trees. In: Benirschke K, Kaufmann P (eds) Pathology of the human placenta, 3rd edn. Springer, New York, pp 57–115Google Scholar
  17. Cederberg J, Picard JJ, Eriksson UJ (2003) Maternal diabetes in the rat impairs the formation of neural-crest derived cranial nerve ganglia in the offspring. Diabetologia 46:1245–1251PubMedCrossRefGoogle Scholar
  18. Chang TI, Horal M, Jain SK, Wang F, Patel R, Loeken MR (2003) Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects. Diabetologia 46:538–545PubMedCrossRefGoogle Scholar
  19. Chiu SL, Cline HT (2010) Insulin receptor signaling in the development of neuronal structure and function. Neural Dev 5:7PubMedCrossRefGoogle Scholar
  20. Chu Q, Moreland R, Yew NS, Foley J, Ziegler R, Scheule RK (2008) Systemic Insulin-like growth factor-1 reverses hypoalgesia and improves mobility in a mouse model of diabetic peripheral neuropathy. Mol Ther 16:1400–1408PubMedCrossRefGoogle Scholar
  21. Churchill JA, Berendes HW, Nemore J (1969) Neuropsychological deficits in children of diabetic mothers. A report from the collaborative study of cerebral palsy. Am J Obstet Gynecol 105:257–268PubMedGoogle Scholar
  22. Craner MJ, Klein JP, Black JA, Waxman SG (2002) Preferential expression of IGF-I in small DRG neurons and down-regulation following injury. Neuroreport 13:1649–1652PubMedCrossRefGoogle Scholar
  23. D’Agostino AN, Bahn RC (1963) A histopathologic study of the pancreas of infants of diabetic mothers. Diabetes 12:327–331Google Scholar
  24. de Pablo F, de la Rosa EJ (1995) The developing CNS: a scenario for the action of proinsulin, insulin and insulin-like growth factors. Trends Neurosci 18:143–150PubMedCrossRefGoogle Scholar
  25. DeCarolis NA, Eisch AJ (2010) Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation. Neuropharmacology 58:884–893PubMedCrossRefGoogle Scholar
  26. Dou JT, Chen M, Dufour F, Alkon DL, Zhao WQ (2005) Insulin receptor signaling in long-term memory consolidation following spatial learning. Learn Mem 12:646–655PubMedCrossRefGoogle Scholar
  27. Eidelman AI, Samueloff A (2002) The pathophysiology of the fetus of the diabetic mother. Semin Perinatol 26:232–236PubMedCrossRefGoogle Scholar
  28. Ekström AR, Kanje M, Skottner A (1989) Nerve regeneration and serum levels of insulin-like growth factor-I in rats with streptozotocin-induced insulin deficiency. Brain Res 496:141–147PubMedCrossRefGoogle Scholar
  29. Entingh-Pearsall A, Kahn CR (2004) Differential roles of the insulin and insulin-like growth factor-I (IGF-I) receptors in response to insulin and IGF-I. J Biol Chem 279:38016–38024PubMedCrossRefGoogle Scholar
  30. Eriksson UJ, Borg LAH (1991) Protection by free oxygen radical scavenging enzymes against glucose-induced embryonic malformations in vitro. Diabetologia 34:325–331PubMedCrossRefGoogle Scholar
  31. Eriksson UJ, Borg LAH (1993) Diabetes and embryonic malformations. Role of substrate-induced free-oxygen radical production for dysmorphogenesis in cultured rat embryos. Diabetes 42:411–419PubMedCrossRefGoogle Scholar
  32. Eriksson UJ, Simán CM (1996) Pregnant diabetic rats fed the antioxidant butylated hydroxytoluene show decreased occurrence of malformations in the offspring. Diabetes 45:1497–1502PubMedCrossRefGoogle Scholar
  33. Eriksson U, Dahlström E, Larsson KS, Hellerström C (1982) Increased incidence of congenital malformations in the offspring of diabetic rats and their prevention by maternal insulin therapy. Diabetes 31:1–6PubMedCrossRefGoogle Scholar
  34. Eriksson RSM, Thunberg L, Eriksson UJ (1989a) Effects of interrupted insulin treatment on fetal outcome of pregnant diabetic rats. Diabetes 38:764–772PubMedCrossRefGoogle Scholar
  35. Eriksson UJ, Bone AJ, Turnbull DM, Baird JD (1989b) Timed interruption of insulin therapy in diabetic BB/E rat pregnancy: effect on maternal metabolism and fetal outcome. Acta Endocrinol 120:800–810PubMedGoogle Scholar
  36. Eriksson UJ, Styrud J, Eriksson RSM (1989c) Diabetes in pregnancy: genetic and temporal relationships of maldevelopment in the offspring of diabetic rats. In: Sutherland HW, Stowers JM, Pearson DWM (eds) Fourth international colloquium on carbohydrate metabolism in pregnancy and the newborn. Springer, Berlin, pp 51–63CrossRefGoogle Scholar
  37. Förster E, Zhao S, Frotscher M (2006) Laminating the hippocampus. Nat Rev Neurosci 7:259–267PubMedCrossRefGoogle Scholar
  38. Fu J, Tay SS, Ling EA, Dheen ST (2006) High glucose alters the expression of genes involved in proliferation and cell-fate specification of embryonic neural stem cells. Diabetologia 49:1027–1038PubMedCrossRefGoogle Scholar
  39. Gao Q, Gao YM (2007) Hyperglycemic condition disturbs the proliferation and cell death of neural progenitors in mouse embryonic spinal cord. Int J Dev Neurosci 25:349–357PubMedCrossRefGoogle Scholar
  40. Gunnell D, Miller LL, Rogers I, Holly JM (2005) Association of insulin-like growth factor I and insulin-like growth factor-binding protein-3 with intelligence quotient among 8- to 9-year-old children in the Avon Longitudinal Study of Parents and Children. Pediatrics 116:681–686CrossRefGoogle Scholar
  41. Hagay ZJ, Weiss Y, Zusman I, Peled-Kamar M, Reece EA, Eriksson UJ, Groner Y (1995) Prevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide dismutase in transgenic mouse embryos. Am J Obstet Gynecol 173:1036–1041PubMedCrossRefGoogle Scholar
  42. Hami J, Sadr-Nabavi A, Sankian M, Haghir H (2011) Sex differences and left–right asymmetries in expression of insulin and insulin-like growth factor-I receptors in developing rat hippocampus. Brain Struct Funct. doi:10.1007/s00429-011-0358-1 PubMedGoogle Scholar
  43. Haworth JC, McRae KN, Dilling LA (1976) Prognosis of infants of diabetic mothers in relation to neonatal hypoglycaemia. Dev Med Child Neurol 18:471–479PubMedCrossRefGoogle Scholar
  44. Higgins M, Mc Auliffe F (2010) A review of maternal and fetal growth factors in diabetic pregnancy. Curr Diabetes Rev 6(2):116–125PubMedCrossRefGoogle Scholar
  45. Hill JM, Lesniak MA, Pert CB, Roth J (1986) Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience 17:1127–1138PubMedCrossRefGoogle Scholar
  46. Hine RJ, Das GD (1974) Neuroembryogenesis in the hippocampal formation of the rat. An autoradiographic study. Z Anat Entwicklungsgesch 144:173–186PubMedCrossRefGoogle Scholar
  47. Humphrey T (1967) The development of the human hippocampal fissure. J Anat 101:655–676PubMedGoogle Scholar
  48. Jawerbaum A, White V (2010) Animal models in diabetes and pregnancy. Endocr Rev 31:680–701PubMedCrossRefGoogle Scholar
  49. Jian-bo L, Cheng-ya W, Jia-wei C, Xiao-lu L, Zhen-qing F, Hong-tai M (2010) The preventive efficacy of methylcobalamin on rat peripheral neuropathy influenced by diabetes via neural IGF-1 levels. Nutr Neurosci 13:79–86PubMedCrossRefGoogle Scholar
  50. Kar S, Chabot JG, Quirion R (1993) Quantitative autoradiographic localization of [125I] insulin-like growth factor I, [125I]insulin-like growth factor II, and [125I]insulin receptor binding sites in developing and adult rat brain. J Comp Neurol 333:375–397PubMedCrossRefGoogle Scholar
  51. Karunanayake EH, Hearse DJ, Mellows G (1976) Streptozotocin: its excretion and metabolism in the rat. Diabetologia 12:483–488PubMedCrossRefGoogle Scholar
  52. Kervran A, Guillaume M, Jost A (1978) The endocrine pancreas of the fetus from diabetic pregnant rat. Diabetologia 15:387–393PubMedCrossRefGoogle Scholar
  53. Klugmann M, Schwab MH, Pühlhofer A, Schneider A, Zimmermann F, Griffiths IR, Nave KA (1997) Assembly of CNS myelin in the absence of proteolipid protein. Neuron 18:59–70PubMedCrossRefGoogle Scholar
  54. Kruis T, Klammt J, Galli-Tsinopoulou A, Wallborn T, Schlicke M, Müller E, Kratzsch J, Körner A, Odeh R, Kiess W, Pfäffle R (2010) Heterozygous mutation within a kinase-conserved motif of the insulin-like growth factor I receptor causes intrauterine and postnatal growth retardation. J Clin Endocrinol Metab 95:1137–1142PubMedCrossRefGoogle Scholar
  55. Lapolla A, Dalfrà MG, Fedele D (2005) Insulin therapy in pregnancy complicated by diabetes: are insulin analogs a new tool? Diabetes Metab Res Rev 21(3):241–252PubMedCrossRefGoogle Scholar
  56. Lauszus FF (2007) The clinical significance of IGF-I in maternal serum during pregnancy in type 1 diabetes. Curr Diabetes Rev 3:194–197PubMedCrossRefGoogle Scholar
  57. Leinninger GM, Vincent AM, Feldman EL (2004) The role of growth factors in diabetic peripheral neuropathy. J Peripher Nerv Syst 9:26–53PubMedCrossRefGoogle Scholar
  58. Lewis SW, Owen MJ, Murray RM (1989) Obstetric complications and schizophrenia: methodology and mechanisms. In: Schulz SC, Tamminga CA (eds) Schizophrenia: scientific progress. Oxford University Press, New York, pp 56–68Google Scholar
  59. Li ZG, Sima AA (2004) C-peptide and central nervous system complications in diabetes. Exp Diabesity Res 5:79–90PubMedCrossRefGoogle Scholar
  60. Lindsay RS, Westgate JA, Beattie J, Pattison NS, Gamble G, Mildenhall LF, Breier BH, Johnstone FD (2007) Inverse changes in fetal insulin-like growth factor (IGF)-1 and IGF binding protein-1 in association with higher birth weight in maternal diabetes. Clin Endocrinol (Oxf) 66:322–328CrossRefGoogle Scholar
  61. Liu W, Ye P, O’Kusky JR, D’Ercole AJ (2009) Type 1 insulin-like growth factor receptor signaling is essential for the development of the hippocampal formation and dentate gyrus. J Neurosci Res 87:2821–2832PubMedCrossRefGoogle Scholar
  62. Loeken MR (2005) Current perspectives on the causes of neural tube defects resulting from diabetic pregnancy. Am J Med Genet C Semin Med Genet 135:77–87Google Scholar
  63. Lopes CD, Sinigaglia-Coimbra R, Mazzola J, Camano L, Mattar R (2011) Neurofunctional evaluation of young male offspring of rat dams with diabetes induced by streptozotocin. ISRN Endocr. doi:10.5402/2011/480656
  64. Marks JL, Porte D Jr, Stahl WL, Baskin DG (1990) Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127:3234–3236PubMedCrossRefGoogle Scholar
  65. Marks JL, Porte D Jr, Baskin DG (1991) Localization of type I insulin-like growth factor receptor messenger RNA in the adult rat brain by in situ hybridization. Mol Endocrinol 5:1158–1168PubMedCrossRefGoogle Scholar
  66. McNay EC, Gold PE (1999) Extracellular glucose concentrations in the rat hippocampus measured by zero-net-flux: effects of microdialysis flow rate, strain, and age. J Neurochem 72:785–790PubMedCrossRefGoogle Scholar
  67. McNay EC, Fries TM, Gold PE (2000) Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc Natl Acad Sci USA 97:2881–2885PubMedCrossRefGoogle Scholar
  68. Meur S, Mann NP (2007) Infant outcomes following diabetic pregnancies. Pediatr Child Health 17:217–222CrossRefGoogle Scholar
  69. Migdalis IN, Kalogeropoulou K, Kalantzis L, Nounopoulos C, Bouloukos A, Samartzis M (1995) Insulin-like growth factor-I and IGF-I receptors in diabetic patients with neuropathy. Diabet Med 12:823–827PubMedCrossRefGoogle Scholar
  70. Muller AP, Fernandez AM, Haas C, Zimmer E, Portela LV, Torres-Aleman I (2011) Reduced brain insulin-like growth factor I function during aging. Mol Cell Neurosci. doi:10.1016/j.mcn.2011.07.008 PubMedGoogle Scholar
  71. Nakae J, Kido Y, Accili D (2001) Distinct and overlapping functions of insulin and IGF-I receptors. Endocr Rev 22:818–835PubMedCrossRefGoogle Scholar
  72. Navarro I, Leibush B, Moon TW, Plisetskaya EM, Baños N, Méndez E, Planas JV, Gutiérrez J (1999) Insulin, insulin-like growth factor-I (IGF-I) and glucagon: the evolution of their receptors. Comp Biochem Physiol B Biochem Mol Biol 122:137–153PubMedCrossRefGoogle Scholar
  73. Nelson CA, Wewerka S, Thomas KM, Tribby-Walbridge S, deRegnier R, Georgieff M (2000) Neurocognitive sequelae of infants of diabetic mothers. Behav Neurosci 114:950–956PubMedCrossRefGoogle Scholar
  74. Nelson TJ, Sun MK, Hongpaisan J, Alkon DL (2008) Insulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair. Eur J Pharmacol 585:76–87PubMedCrossRefGoogle Scholar
  75. Novitskaya T, Baserga M, de Caestecker MP (2011) Organ-specific defects in insulin-like growth factor and insulin receptor signaling in late gestational asymmetric intrauterine growth restriction in Cited1 mutant mice. Endocrinology 152:2503–2516PubMedCrossRefGoogle Scholar
  76. Ornoy A (2005) Growth and neurodevelopmental outcome of children born to mothers with pregestational and gestational diabetes. Pediatr Endocrinol Rev 3:104–113PubMedGoogle Scholar
  77. Ornoy A, Ratzon N, Greenbaum C, Peretz E, Soriano D, Dulitzky M (1998) Neurobehaviour of school age children born to diabetic mothers. Arch Dis Child Fetal Neonatal Ed 79:94–99CrossRefGoogle Scholar
  78. Parnas J, Schulsinger F, Teasdale TW, Schulsinger H, Feldman PM, Mednick SA (1982) Perinatal complications and clinical outcome within the schizophrenia spectrum. Br J Psychiatry 140:416–420PubMedCrossRefGoogle Scholar
  79. Persaud OD (2007) Maternal diabetes and the consequences for her offspring. J Develop Disab 1:101–134Google Scholar
  80. Pierson CR, Zhang W, Murakawa Y, Sima AA (2003) Insulin deficiency rather than hyperglycemia accounts for impaired neurotrophic responses and nerve fiber regeneration in type 1 diabetic neuropathy. J Neuropathol Exp Neurol 62:260–271PubMedGoogle Scholar
  81. Pitkin RM, Van Orden DE, Reynolds WA (1970) Plasma insulin response and glucose tolerance in pregnant rhesus monkeys. Endocrinology 86:435–437PubMedCrossRefGoogle Scholar
  82. Plum L, Schubert M, Brüning JC (2005) The role of insulin receptor signaling in the brain. Trends Endocrinol Metab 16:59–65PubMedCrossRefGoogle Scholar
  83. Popken GJ, Hodge RD, Ye P, Zhang J, Ng W, O’Kusky JR, D’Ercole AJ (2004) In vivo effects of insulin-like growth factor-I (IGF-I) on prenatal and early postnatal development of the central nervous system. Eur J Neurosci 19:2056–2068PubMedCrossRefGoogle Scholar
  84. Pulford BE, Ishii DN (2001) Uptake of circulating insulin-like growth factors (IGFs) into cerebrospinal fluid appears to be independent of the IGF receptors as well as IGF-binding proteins. Endocrinology 142:213–220PubMedCrossRefGoogle Scholar
  85. Ramsay TG, Wolverton CK, Steele NC (1994) Alteration in IGF-I mRNA content of fetal swine tissues in response to maternal diabetes. Am J Physiol 267:1391–1396Google Scholar
  86. Reagan LP, Magariños AM, Lucas LR, van Bueren A, McCall AL, McEwen BS (1999) Regulation of GLUT-3 glucose transporter in the hippocampus of diabetic rats subjected to stress. Am J Physiol 276:879–886Google Scholar
  87. Reinhardt RR, Bondy CA (1994) Insulin-like growth factors cross the blood–brain barrier. Endocrinology 135:1753–1761PubMedCrossRefGoogle Scholar
  88. Riikonen R (2006) Insulin-like growth factor delivery across the blood-brain barrier. Potential use of IGF-1 as a drug in child neurology. Chemotherapy 52:279–281PubMedCrossRefGoogle Scholar
  89. Rizzo T, Metzger BE, Burns WJ, Burns K (1991) Correlations between antepartum maternal metabolism and child intelligence. N Engl J Med 325:911–916PubMedCrossRefGoogle Scholar
  90. Rizzo TA, Ogata ES, Dooley SL, Metzger BE, Cho NH (1994) Perinatal complications and cognitive development in 2- to 5-year-old children of diabetic mothers. Am J Obstet Gynecol 171:706–713PubMedGoogle Scholar
  91. Rizzo TA, Dooley SL, Metzger BE, Cho NH, Ogata ES, Silverman BL (1995) Prenatal and perinatal influences on long-term psychomotor development in offspring of diabetic mothers. Am J Obstet Gynecol 173:1753–1758PubMedCrossRefGoogle Scholar
  92. Rizzo TA, Silverman BL, Metzger BE, Cho NH (1997) Behavioral adjustment in children of diabetic mothers. Acta Paediatr 86:969–974PubMedCrossRefGoogle Scholar
  93. Russo VC, Gluckman PD, Feldman EL, Werther GA (2005) The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev 26:916–943PubMedCrossRefGoogle Scholar
  94. Salehi Z, Mashayekhi F, Naji M (2008) Insulin like growth factor-1 and insulin like growth factor binding proteins in the cerebrospinal fluid and serum from patients with Alzheimer’s disease. Biofactors 33:99–106PubMedCrossRefGoogle Scholar
  95. Schulingkamp RJ, Pagano TC, Hung D, Raffa RB (2000) Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev 24:855–872PubMedCrossRefGoogle Scholar
  96. Schwartz R, Teramo KA (2000) Effects of diabetic pregnancy on the fetus and newborn. Semin Perinatol 24:120–135PubMedCrossRefGoogle Scholar
  97. Sells CJ, Robinson NM, Brown Z, Knopp RH (1994) Long-term developmental follow-up of infants of diabetic mothers. J Pediatr 125:9–17CrossRefGoogle Scholar
  98. Shin BC, Fujikura K, Suzuki T, Tanaka S, Takata K (1997) Glucose transporter GLUT3 in the rat placental barrier: a possible machinery for the transplacental transfer of glucose. Endocrinology 138:3997–4004PubMedCrossRefGoogle Scholar
  99. Sima AA, Li ZG, Zhang W (2003) The insulin-like growth factor system and neurological complications in diabetes. Exp Diabesity Res 4:235–256PubMedCrossRefGoogle Scholar
  100. Sima AA, Zhang W, Grunberger G (2004) Type 1 diabetic neuropathy and C-peptide. Exp Diabesity Res 5:65–77PubMedCrossRefGoogle Scholar
  101. Simán CM, Eriksson UJ (1997a) Vitamin C supplementation of the maternal diet reduces the rate of malformation in the offspring of diabetic rats. Diabetologia 40:1416–1424PubMedCrossRefGoogle Scholar
  102. Simán CM, Eriksson UJ (1997b) Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats. Diabetes 46:1054–1061PubMedCrossRefGoogle Scholar
  103. Singh BS, Westfall TC, Devaskar SU (1997) Maternal diabetes-induced hyperglycemia and acute intracerebral hyperinsulinism suppress fetal brain neuropeptide Y concentrations. Endocrinology 138:963–969PubMedCrossRefGoogle Scholar
  104. Sivan E, Reece EA, Wu YK, Homko CJ, Polansky M, Borenstein M (1996) Dietary vitamin E prophylaxis and diabetic embryopathy: morphologic and biochemical analysis. Am J Obstet Gynecol 175:793–799PubMedCrossRefGoogle Scholar
  105. Som S, Basu S, Mukherjee D, Deb S, Choudhury PR, Mukherjee S, Chatterjee SN, Chatterjee IB (1981) Ascorbic acid metabolism in diabetes mellitus. Metabolism 30:572–577PubMedCrossRefGoogle Scholar
  106. Stehbens JA, Baker GL, Kitchell M (1977) Outcome at ages 1, 3, and 5 years of children born to diabetic women. Am J Obstet Gynecol 127:408–413PubMedGoogle Scholar
  107. Stenninger E, Flink R, Eriksson B, Sahlèn C (1998) Long-term neurological dysfunction and neonatal hypoglycaemia after diabetic pregnancy. Arch Dis Child Fetal Neonatal Ed 79:174–179CrossRefGoogle Scholar
  108. Stenvers KL, Lund PK, Gallagher M (1996) Increased expression of type 1 insulin-like growth factor receptor messenger RNA in rat hippocampal formation is associated with aging and behavioral impairment. Neuroscience 72:505–518PubMedCrossRefGoogle Scholar
  109. Styrud J, Thunberg L, Nybacka O, Eriksson UJ (1995) Correlations between maternal metabolism and deranged development in the offspring of normal and diabetic rats. Pediatr Res 37:343–353PubMedCrossRefGoogle Scholar
  110. Sullivan KA, Kim B, Feldman EL (2008) Insulin-like growth factors in the peripheral nervous system. Endocrinology 149:5963–5971PubMedCrossRefGoogle Scholar
  111. Takata K, Fujikura K, Shin BC (1997) Ultrastructure of the rodent placental labyrinth: a site of barrier and transport. J Reprod Develop 43:13–24CrossRefGoogle Scholar
  112. Tehranipour M, Khakzad MR (2008) Effect of maternal diabetes on hippocampus neuronal density in neonatal rats. J Biol Sci 6:1027–1032CrossRefGoogle Scholar
  113. Thompson CL, Pathak SD, Jeromin A, Ng LL, MacPherson CR, Mortrud MT, Cusick A, Riley ZL, Sunkin SM, Bernard A, Puchalski RB, Gage FH, Jones AR, Bajic VB, Hawrylycz MJ, Lein ES (2008) Genomic anatomy of the hippocampus. Neuron 60:1010–1021PubMedCrossRefGoogle Scholar
  114. Van Lieshout RJ, Voruganti LP (2008) Diabetes mellitus during pregnancy and increased risk of schizophrenia in offspring: a review of the evidence and putative mechanisms. J Psychiatry Neurosci 33:395–404PubMedGoogle Scholar
  115. Venkatasubramanian G, Chittiprol S, Neelakantachar N, Naveen MN, Thirthall J, Gangadhar BN, Shetty KT (2007) Insulin and insulin-like growth factor-1 abnormalities in antipsychotic-naive schizophrenia. Am J Psychiatry 164:1557–1560PubMedCrossRefGoogle Scholar
  116. Viana M, Herrera E, Bonet B (1996) Teratogenic effects of diabetes mellitus in the rat. Prevention with vitamin E. Diabetologia 39:1041–1046PubMedCrossRefGoogle Scholar
  117. Wentzel P, Thunberg L, Eriksson UJ (1997) Teratogenic effect of diabetic serum is prevented by supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture. Diabetologia 40:7–14PubMedCrossRefGoogle Scholar
  118. Werther GA, Abate M, Hogg A, Cheesman H, Oldfield B, Hards D, Hudson P, Power B, Freed K, Herington AC (1990) Localization of insulin-like growth factor-I mRNA in rat brain by in situ hybridization—relationship to IGF-I receptors. Mol Endocrinol 4:773–778PubMedCrossRefGoogle Scholar
  119. Yamashita Y, Kawano Y, Kuriya N, Murakami Y, Matsuishi T, Yoshimatsu K, Kato H (1996) Intellectual development of offspring of diabetic mothers. Acta Paediatr 85:1192–1196PubMedCrossRefGoogle Scholar
  120. Zemva J, Schubert M (2011) Central insulin and insulin-like growth factor-1 signaling—implications for diabetes associated dementia. Curr Diabetes Rev 7(5):356–366PubMedCrossRefGoogle Scholar
  121. Zhang J, Moats-Staats BM, Ye P, D’Ercole AJ (2007) Expression of insulin-like growth factor system genes during the early postnatal neurogenesis in the mouse hippocampus. J Neurosci Res 85:1618–1627PubMedCrossRefGoogle Scholar
  122. Zhao WQ, Alkon DL (2001) Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 177:125–134PubMedCrossRefGoogle Scholar
  123. Zhao WQ, Chen H, Quon MJ, Alkon DL (2004) Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 490:71–81PubMedCrossRefGoogle Scholar
  124. Zhou J, Wang L, Ling S, Zhang X (2007) Expression changes of growth-associated protein-43 (GAP-43) and mitogen-activated protein kinase phosphatase-1 (MKP-1) and in hippocampus of streptozotocin-induced diabetic cognitive impairment rats. Exp Neurol 206(2):201–208PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Javad Hami
    • 1
  • Ariane Sadr-Nabavi
    • 2
  • Mojtaba Sankian
    • 3
  • Mehdi Balali-Mood
    • 4
  • Hossein Haghir
    • 1
  1. 1.Department of Anatomy and Cell Biology, School of MedicineMashhad University of Medical SciencesMashhadIran
  2. 2.Department of Medical Genetics, School of MedicineMashhad University of Medical SciencesMashhadIran
  3. 3.Immunology Research Center, Bu-Ali Research Institute, School of MedicineMashhad University of Medical SciencesMashhadIran
  4. 4.Department of Clinical Toxicology, Medical Toxicology Research Center, School of MedicineMashhad University of Medical SciencesMashhadIran

Personalised recommendations