Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Apr 15, 2015; 6(3): 412-422
Published online Apr 15, 2015. doi: 10.4239/wjd.v6.i3.412
Some of the experimental and clinical aspects of the effects of the maternal diabetes on developing hippocampus
Javad Hami, Fatemeh Shojae, Saeed Vafaee-Nezhad, Nasim Lotfi, Hamed Kheradmand, Hossein Haghir
Javad Hami, Fatemeh Shojae, Saeed Vafaee-Nezhad, Nasim Lotfi, Department of Anatomy, School of Medicine, Birjand University of Medical Sciences, Birjand 97178, Iran
Nasim Lotfi, Hossein Haghir, Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad 91857, Iran
Hamed Kheradmand, Hazrat Rasoul Hospital, Tehran University of Medical Sciences, Tehran 19168, Iran
Hossein Haghir, Medical Genetic Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad 91857, Iran
Author contributions: All authors contributed to this manuscript.
Conflict-of-interest: All authors claim no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Hossein Haghir, MD, PhD, Department of Anatomy and Cell Biology, School of Medicine, Mashdad University of Medical Sciences, Azadi Square, Mashhad 91857, Iran.
Telephone: +98-513-8002486 Fax: +98-513-8002486
Received: August 27, 2014
Peer-review started: August 31, 2014
First decision: October 14, 2014
Revised: December 22, 2014
Accepted: January 9, 2015
Article in press: January 12, 2015
Published online: April 15, 2015


Diabetes mellitus during pregnancy is associated with an increased risk of multiple congenital anomalies in progeny. There are sufficient evidence suggesting that the children of diabetic women exhibit intellectual and behavioral abnormalities accompanied by modification of hippocampus structure and function. Although, the exact mechanism by which maternal diabetes affects the developing hippocampus remains to be defined. Multiple biological alterations, including hyperglycemia, hyperinsulinemia, oxidative stress, hypoxia, and iron deficiency occur in pregnancies with diabetes and affect the development of central nervous system (CNS) of the fetus. The conclusion from several studies is that disturbance in glucose and insulin homeostasis in mothers and infants are major teratogenic factor in the development of CNS. Insulin and Insulin-like growth factor-1 (IGF-1) are two key regulators of CNS function and development. Insulin and IGF-1 receptors (IR and IGF1R, respectively) are distributed in a highly specific pattern with the high density in some brain regions such as hippocampus. Recent researches have clearly established that maternal diabetes disrupts the regulation of both IR and IGF1R in the hippocampus of rat newborn. Dissecting out the mechanisms responsible for maternal diabetes-related changes in the development of hippocampus is helping to prevent from impaired cognitive and memory functions in offspring.

Key Words: Maternal diabetes, Cognition complications, Teratogenic factor, Hippocampus

Core tip: Diabetes mellitus is the most seriously metabolic condition in pregnancy that affects the hippocampal development and function of the offspring. Multiple biological alterations, including hyperglycemia and hyperinsulinemia are occurring in maternal diabetes and impair the neurodevelopment of the fetus. Insulin-like growth factor-1 (IGF-1) and insulin are important regulators of development of central nervous system. It has clearly showed that maternal diabetes disturb the regulation of both insulin receptors and IGF-1 receptors in the hippocampus of rat newborn. This article is a brief review of the literatures that suggests a probable mechanism of how diabetes during pregnancy affects the hippocampus development in the offspring.

Citation: Hami J, Shojae F, Vafaee-Nezhad S, Lotfi N, Kheradmand H, Haghir H. Some of the experimental and clinical aspects of the effects of the maternal diabetes on developing hippocampus. World J Diabetes 2015; 6(3): 412-422

Diabetes mellitus (DM) is a chronic common metabolic illness characterized by hyperglycaemia associated with insulin deficiency or insulin resistance. There are two major types of DM: type 1 DM (T1DM) results from chronic and progressive destruction of the beta-cells of the islets of Langerhans in the pancreas. T2DM is primarily characterized by both insulin resistance and relative insulin deficiency[1,2].

DM is one of the most common and most important metabolic condition affecting up to 7% of pregnancies. Several population studies show that the diabetes during pregnancy affects the health of both mothers and their infants[3-6].

There are two main types of DM occurs in pregnancy period: pregestational DM (PGDM) and gestational DM (GDM)[7]. GDM accounts for approximately 90% of all cases of diabetes in pregnancy. Of the remaining cases, 60% have preexisting T2DM before pregnancy, while 40% have a diagnosis of pre-conceptual T1DM[8].

In a study in the United Kingdom, it was found that PGDM occurs in approximately 1 out of 250 pregnancies, with two-thirds of them having T1DM and the remaining one-third having T2DM[9]. At present, type 2 diabetes is the most prevalent form of diabetes affecting women of reproductive age in the developed countries, with a mean prevalence of 27.6% in United Kingdom[10]. Last data from Australia also showed that T2DM affected about 55% of pregnancies[11]. Overall, GDM complicated from 2% to 12% of all pregnancies. So, however, the incidence of T1DM appears to be relatively constant and similar to the rate in young adults throughout the world; the incidence of T2DM is specially rising in developed world[9,12]. Furthermore, the overall numbers of children born to mothers with diabetes will significantly rise in the next decades.


An increasing number of evidence clearly showed that infants born to diabetic mothers are in increased risk of fetal and neonatal anomalies which results in increased infant mortality and morbidity rates. Although, the wide spectrum of the effects of diabetes in pregnancy on the fetus development are determined by the time of onset and the severity of DM[6,13,14].

Despite considerable progress in the clinical management of pregnant women who have diabetes, the prevalence of major congenital anomalies is approximately 3 times more in infants of diabetic women in comparison to the offspring of normal mothers[12,15,16].

According to previous works, diabetes in pregnancy has been accompanied by increased risk of a wide range of fetal complications and malformations, including respiratory distress syndrome, macrosomia, organomegaly, obstetric, metabolic and hematological complications[13,14,16,17].

The overall rate of major congenital anomalies in infants born to diabetic mothers is about 6% to 13%, which is approximately 2-3 times higher than that of the normal condition. However, the prevalence of major structural malformations in the children born to mothers with diabetes are to 10 times greater in comparison to the general population. The frequencies of perinatal mortality are also five-fold higher in women with diabetes compared with normal women[12,14,16,18].

The prevalence of Minor congenital anomalies in infants born to 802 mothers with GDM, 117 mothers with PGDM, and 380 normal mothers were assessed by Hod et al[19] (1992). They found a range between 19.4% and 20.5% in prevalence of minor congenital anomalies in their infant in all groups studied without any marked difference between groups. In their study, there was no correlation between the type and prevalence of minor congenital anomalies with the severity and the time of onset of the diabetes in mothers. Neither there was any relationship between the type or prevalence of minor congenital anomalies with the type or appearance of major congenital anomalies[19].

Overall, the defects in central nervous system, heart, kidney, and skeletal system are among the commonest congenital malformations in the offspring of diabetic pregnancies[3,14,16,18].


As yet, the exact mechanisms by which maternal diabetes alters the development of growing fetuses are not completely understood, and no distinct teratogenic mechanism has been identified to clearly explain a reason for this range of congenital anomalies observed in the infants born to diabetic mothers[20,21].

Many of the developmental effects of diabetic pregnancies on the fetus can be attributed to maternal glucose (metabolic) control. In normal pregnancies, the blood glucose level in women remains within a tight range. Consequently, the blood glucose concentration in the fetus is fairly constant as the glucose in the mother’s blood crosses the placenta freely. Nevertheless, in pregnancies complicated by DM, there are great variations in the maternal blood glucose level[12,14,22]. Pedersen et al[23] (1954) emphasized the correlation between high blood glucose concentration in pregnant women with hyperglycemia during fetal period[23], which stimulated the pancreas of the fetuses, leads to beta-cell hyperplasia and hypertrophy with increased insulin secretion and content[23,24].

Several lines of studies also emphasized the direct correlation between high blood glucose concentration in mothers as revealed by increased level of glycosylated hemoglobin (HbA1c) with increased frequency of congenital malformations in offspring[22,25]. Towner et al[26] (1995) found a striking correlation between pregestational elevated HbA1c in early pregnancy with the increased risk of fetal congenital malformations[26]. There is enough evidence accumulates to support this hypothesis that the tight glycaemic control in early and before pregnancy may reduce the frequency of anomalies in the infants born to diabetic mothers[22]. Therefore, the prevalence of congenital abnormalities in children born to mothers with diabetes has decreased in the last three decades probably as a result of the overall progress in monitoring of blood glucose concentrations in diabetic pregnant women[27-29].

In addition, fetal hyperinsulinemia also has been shown in the offspring of diabetic mothers. On separation of the newborn from the mother, the glucose former no longer is supported by placental glucose transfer, may develop neonatal hypoglycemia[30,31].

In earlier works, chronic fetal hyperinsulinemia in the third trimester of pregnancy has been produced in monkeys. The researchers showed that in utero hyperinsulinemia results in an organomegaly and fetal macrosomia, except for kidney and brain[32,33]. Increased plasma erythropoietin levels and body fat content was also evident in infants of diabetic mothers[34].

Insulin is a hormone that primarily functions as an anabolic hormone of fetal development and growth resulting in macrosomia and visceromegaly[14]. On the basis of in vitro and animal studies on the pancreas, the simplified hyperinsulinemia - hyperglycemia hypothesis has been expanded in earlier studies[35,36].

Ketones in the mother’s blood readily cross the placenta, but they cannot be cause fetal hyperinsulinemia; so, they might not influence fetal growth and development[14].

In experimental diabetic rodents, fetal hyperglycemia, neonatal hypoglycemia, and disturbances in prostaglandin and arachidonic acid metabolism have been reported to result in congenital anomalies in their offspring[14,37]. In diabetic pregnancies in rats, it is clearly established that the elevated intracellular free oxygen radicals concentrations have been accompanied by the increased risk of embryopathies[38]. Nevertheless, hyperglycemia-induced fetal malformations in rodents have been demonstrated to associate with the number of genomic DNA mutations[39]. Therefore, there are animal studies showing that the free radical scavengers and antioxidants may decrease the risk of teratogenicity of maternal diabetes[40,41].


Both PGDM and GDM can affect fetal neurodevelopment[42-45]. Although the untoward effects of maternal diabetes on pregnancy outcomes with respect to congenital malformations have generally been appreciated, the effect of maternal diabetes on the development of central nervous system (CNS) in the fetuses and its behavioral sequelae remains to be completely defined. A limited number of long-term follow-up studies of neurodevelopmental outcomes in diabetic pregnancies have been reported[46-50]. Nevertheless, it is demonstrated that children born to diabetic mothers are more likely to have neurodevelopmental abnormalities including impairments in learning ability, activity level, attention span, and motor functioning. Interestingly, some of these deficiencies are well-known as risk factors in children who develop schizophrenia later, but the degree of risk is variable and may be related to the severity of metabolic derangement in the mothers with diabetes[42,46,50,51].

Examination of cognitive functioning and the behavior of the children born to diabetic mothers offers the opportunity to functionally assess the CNS development[52]. Hence the assessment of the behavior and cognition in the offspring of diabetic mothers may clarify the maternal diabetes effects on the development of CNS.

The results of earlier studies clearly demonstrated that the diabetes during pregnancies may results in intellectual and behavioral functioning disturbances in the infants[45,46,49,53]. These data suggest a teratogenic effect of diabetes in pregnancy on the function of CNS in fetuses and provides the earliest indicator of postnatal CNS deficiencies reflected in intellectual and behavioral problems observed in the children of mothers with diabetes[54].

Earlier reports on the neurologic development in infants of diabetic mothers revealed serious CNS deficits, even in the absence of structural malformations. These alterations were significantly less severe when maternal diabetes was medically controlled and treated, but some alterations in cognitive function may persist throughout childhood[6,42,45,48,51].

To elucidate the effects of diabetes during pregnancy period on cognitive functioning in the children, Yamashita et al[45] (1996) studied 33 pregnant women (24 with T2DM, 6 with T1DM, and 3 with GDM). Their long term follow-up research showed that maternal diabetes significantly affects the development of intellectual functioning in infants. Although, they report no differences in IQ score among offspring of three groups[45]. In another study, Churchill et al[55] (1969), found that diabetic mothers had offspring with significantly lower mean IQs than control infants. In a cohort study of fifty infants at 1, 3, and 5 years of age born to diabetic mothers, Stehbens et al[56] (1977) reported an adverse effect of diabetes in pregnancy on CNS structure and function in their children. They also found that three infants born to diabetic mothers had major neurologic anomalies and six of them had IQs less than 80.

Rizzo et al[57] (1991) reported a strikingly correlation between diabetes in mothers during pregnancy and lower IQ in their children. In another study, the same researcher found significant correlations between second- and third-trimester regulation of glycemia and results on the Brazelton Neonatal Behavioral Assessment Scale; they reported an association between increases in maternal glucose levels with poorer infant responses[58].

Other investigators have not found any differences in cognitive scores[59-61]. Children born to diabetic mothers may sustain minor neurological damage which does not necessarily affect their scores in IQ tests[49]. For example, Persson et al[60] reported more encouraging results in 73 infants born either to mothers with T1DM or to mothers with GDM; all subjects available for follow-up at 5 years of age had normal results on neurologic examinations, as well as normal IQs, and there was no relation between maternal diabetes and IQ[60].

In a retrospective study at considerable variance with most other reported studies, Yssing et al[62] (1975) reported a 36% incidence of cerebral dysfunction or related conditions in 740 infants of diabetic pregnancies; 18% had a major cerebral disability. In a study by Haworth et al[63] (1976) on infants of diabetic pregnancies, noted an about 30% increase in the incidence of neurological and intellectual development impairments[63]. No differences in behavioral adjustment and academic achievement between children born to T1DM mothers and children of normal mothers were reported in Hadden et al[64] study.

In addition, poorer habituation performance were also found in fetuses of diabetic pregnancies when compared to fetuses born to normal mothers[65]. Since habituation reflects the fetal CNS performance, the observed habituation abilities differences between the diabetic and normal groups suggests differences in their CNS function or maturation[65,66]. Recent investigations also have been demonstrated that there is a significant correlation between diabetes during pregnancy and increased risk of some psychologic disturbances including schizophrenia in their children[67,68].

Together, these studies suggest a wide-range of teratogenic effects of maternal diabetes on the development and function of fetal CNS[67]. However, no single molecular mechanism can fully explain the effects of maternal diabetes on fetal neurodevelopment because the CNS development is complex and regulated by a number of signaling molecules and transcription factors.


Neurodevelopmental assessment of the offspring born to diabetic dams have been revealed a wide spectrum of behavioral, neurochemical, cellular, and molecular impairments[69-72]. Experimental models subjected to streptozotocin - induced type 1 diabetic pregnancies developed significant deficits in cognitive behaviors[68]. Kinney et al[73] (2003) found that the only female offspring born to diabetic dams showed deficits in long-term memory and learning. These results have suggested that the in utero diabetic condition has gender-specific effects on CNS development[73].

In a study by Plagemann et al[74] (1998), alterations in catecholamines levels in the hypothalamic nuclei of newborns born to diabetic animals were evaluated. They reported an increased hypothalamic dopamine (DA) and norepinephrine (NE) concentrations in the offspring born to diabetic rats at birth. Twenty one-day-old pups born to diabetic mothers, NE levels were strikingly increased in the ventromedial hypothalamic nucleus and the lateral hypothalamic area (LHA), while DA levels were significantly elevated in the paraventricular hypothalamic nucleus and the LHA. The authors concluded that there are strikingly differences in hypothalamic catecholaminergic systems during early development in the rat newborns born to diabetic animals[74].

It has been shown that PGDM is associated with an increases risk of neural tube defects (NTDs), also known as diabetic embryopathy. The prevalence of NTDs in the offspring of diabetic mothers is 3 to 10-fold higher than that of in general population[75-77]. In earlier studies, the mitochondrial morphological changes has been shown in developing neural tubes subjected to a diabetic environment during the same time period when the NTDs are induced in diabetic pregnancies[72,78]. Altered activity of cytochrome-c oxidase also has been manifested in the rat hippocampus that have iron deficiency in their brains due to fetal hyperglycemia[79]. It has also been hypothesized that dysfunction in energy metabolism of developing brain leads to oxidative stress elevation and abnormal regulation of intracellular calcium[80-82].


Several well-known biological alterations occur in mothers with diabetes that affect fetal neurodevelopment. These biological changes lead to alterations in neurotransmitter systems, synaptic membranes, neuronal integrity, and growth factors expression that have also been implicated in the development of neurodevelopmental and neurocognitive sequelae in offspring born to diabetic mothers[14,42,69,72,74].

The hyperglycemia is the most distinct mechanism by which these predispositions might be mediated. The defining characteristics of diabetes during pregnancy, these are clearly showed to have effects on developing CNS and to induce fetal hyperinsulinemia, chronic tissue hypoxia, decreased in fetal iron levels and increased oxidative stress[20,83-85].

Hyperinsulinemia, hypoxia, polycythemia and iron deficiency

It is revealed that fetal polycythemia induced by DM in pregnancy is likely triggered by the chronic in utero hyperglycemia and hyperinsulinemia and develops in response to higher concentration of blood glucose in mothers[20,42]. A study by Mimouni et al[86] (1986) showed an incidence of 29.4% fetal polycythemia in infants born to diabetic mothers in comparison to 5.9% in normal conditions. One of the reasonable explanations is that in utero hyperglycemia and hyperinsulinemia produces a hypermetabolic state in the developing fetuses, which results in relative tissue hypoxia, leading to polycythemia via excess production of erythropoietin. Elevated fetal plasma erythropoietin concentrations in diabetic pregnancies suggests an increased prevalence of chronic fetal hypoxia during development. Although there are no distinct mechanisms for fetal hypoxia in diabetic pregnancies[34].

Hypoxia affects the fetal CNS development including alterations in myelination, changes in cortical connectivity, excitotoxicity, and neuronal or glial cell death[87-89].

In the hypoxia state, excess erythropoietin and hemoglobin are produced[90]. So, the developing fetuses need for iron exceeds its supply that leads to Iron mobilization from vital tissues including the fetal brain[91,92]. It is showed that human infants born to diabetic women possess brain iron content 40% less than that in normal pregnancies[93].

Several authors have reviewed the role of iron on CNS development and function[94-96]. Iron is one of the key component of the many enzymes involve in essential reduction or oxidation reactions, neuronal replication, synthesis and catabolism of neurotransmitters and myelin production[97-101]. The uptake of Iron into the brain is maximal during the rapid brain development and growth, which coincides with the peak of myelinogenesis[99-101]. In experimental animals, iron deficiency demonstrated to affect the development of neurotransmitter systems in the brain results in behavioral alteration[98,102]. Moreover, iron deficiency in fetuses is also known to manifest as increased negative emotionality and higher levels of irritability in infants and is a predictive factor in the behavioral and developmental problems at 5 age old children[103]. There are studies suggesting that iron deficiency during brain development leads to alterations in the hippocampal structure and function[104].

Moreover, in animal models, hyperinsulinemia during in utero period reduced the fetal amino acid concentrations, including levels of the nonprotein amino acid taurine, which is showed to be involved in the development of the brain[105].

Diabetes during pregnancy as a proinflammatory milieu

Diabetes during pregnancy is associated with the disbalance of pro-inflammatory pathways supported by increased circulating concentrations of inflammatory molecules[106,107]. It is demonstrated that inflammatory cytokines affect the neuronal development and metabolism of neurotransmitters[108]. In experimental models, cytokines reduced the survival of dopaminergic and serotonergic cells[109]. Earlier investigations demonstrated that cytokines, including tumor necrosis factor alpha and interleukin-6, are increased in infants exposed to diabetes in utero and have been implicated in neuronal damage[110,111]. It is also clearly showed that imbalances in the regulation of cytokines have been increasingly associated by a number of prevalent and severe neurodevelopmental disorders[112,113].

Currently, a limited number of human studies demonstrating the effects of inflammatory prenatal environment on neurobehavioural development in children[114]. Evidence from a few studies suggests that immune alterations that occur in prenatal period may persist into postnatal life[115,116]. Therefore, increased inflammatory cytokines in diabetic pregnancies may be relevant to neurodevelopment alterations exhibited by the infants born to diabetic women.

Diabetes in pregnancy and oxidative stress

Enhanced oxidative stress plays important roles in embryo development and implicated in the pathogenesis of some neurodevelopmental disorders observed in infants of diabetic mothers[83-85]. Free radicals can inactivate the biological functions of proteins and lipids and potentially leading to cell death[117,118]. It is showed that GDM is associated with an increased concentration of oxidative stress, due to both defect in the antioxidant defenses and/or overproduction of free radicals[83-85]. Although, there are several studies demonstrating the presence of elevated oxidative stress in PGDM and GDM states. Some works also suggested that this milieu can be shared with the developing fetus[83-85,119].

In experimental animals, it is emphasized that oxygen radicals play crucial roles in the progression and timing of the development and differentiation of neurons, and synaptic plasticity; so, imbalance in these signals can lead to changes in development of CNS[120,121]. On the other hands, the developing CNS is particularly susceptible to increase in oxidative stress, owing to its poor antioxidant defenses and/or high oxygen consumption[122].

Oxidative stress might contribute to the pathogenesis of some of neurodevelopmental disorders via an attenuation with gamma-aminobutyric acid receptor function in the brain, decreased synaptic efficiency in hippocampal cells, and inhibition of dopamine β-hydroxylase[123-125]. On the other hand, there are evidence indicating that maternal diabetes-induced NTDs are associated with some metabolic difficulties such as increase in superoxide dismutase activity and decreased in arachidonic acid level[126]. There are evidence from human models indicating a potential role of elevated oxidative stress in neurodevelopmental diseases[127-131]. Moreover, the incidence of congenital anomalies in infants of diabetic mothers has been reported to be significantly reduced by antioxidants supplements therapy including Ascorbic Acid and vitamin E. These data suggest that elevated oxidative stress is associated with the pathophysiology of fetal dysmorphogenesis[132,133].

Role of insulin-like growth factor-1 and insulin in maternal diabetes - induced neuropathies

Insulin- like growth factor-1 (IGF-1) and insulin belong to the insulin superfamily and exert profound effects in the CNS development and function. Evidence of these peptides actions on CNS comes from a wide variety of in vitro and in vivo experimental data, the latter predominantly derived from rodent studies. In several studies, the authors demonstrated that the insulin and IGF-1 have a wide spectrum of biological actions in the developing CNS including neuronal/glial cell proliferation, differentiation, survival, synaptogenesis, longevity, and neuroregeneration. Most of these biological functions are mediated via two transmembrane receptors: the insulin receptor (IR) and the IGF-1 receptor (IGF1R)[69,70,134-142].

The IR and IGF1R, which are homologus in structure, are composed of two α-subunits and two β-subunits linked by disulphide bonds. The extracellular α- subunit binds to their cognate ligand. The β-subunit comprises an extracellular domain and a cytoplasmic domain that contains intrinsic protein tyrosine kinase activity. The binding of either IGF-1 or insulin to α-subunit of their cognate receptors stimulates phosphorylation of the β subunit on serine and tyrosine residues. The autophosphorylation of the β subunit then results in the phosphorylation of cellular substrates and signal transfer cascade for IGF-1 and insulin[141,143,144].

Using ligand binding autoradiography and in situ hybridization, several line of human and animal investigations have found that IR and IGF1R are irregularly distributed in developing and mature brain with the highest densities in the hippocampus, cerebral cortex, olfactory bulb, cerebellum, and hypothalamus. Interestingly, some of brain regions show a marked difference in the density of InsR and IGF1R between embryonic vs mature brain, implying a key role for these ligands in brain development[145-147].

There are evidence from several researches implicating defects in IR and IGF1R signaling result in congenital developmental defects seen in offspring of diabetic mothers[145,148-150]. Ramsay et al[151] (1994) in their study was found that expression of IGF-1 in the brain were declined in swine newborns born to diabetic dams when compared to that of control animals.

The hippocampal formation subserves important physiological and behavioral functions including spatial learning and memory and is a part of brain that particularly vulnerable to changes in blood glucose level[152-154]. In an investigation by Tehranipour et al[155] (2008) the effects of maternal T1DM on density of hippocampal pyramidal cells immediately after birth were examined. Those study results were clearly indicated that maternal diabetes can decreased the numerical density of pyramidal cells in the hippocampus of rat newborns, especially in CA3[155].

Interestingly, the studies By Hami et al[156] (2012) showed that there are prominent gender-and laterality- differences in expression and distribution pattern of InsR and IGF1R in the developing rat hippocampus. The authors concluded that these differences may be a probable mechanism for the control of sex and laterality differences in development and function of the rat hippocampus[156].

In another study by Hami et al[69] (2013), the effects of diabetes in pregnancy on gene expression and protein concentration of IGF1R and IR in the developing rat hippocampus at postnatal days 0, 7, and 14 were evaluated. In that study, the authors found a markedly upregulation of both IR and IGF1R expression in the hippocampus of diabetic group newborns at first postnatal day. At the same time point, they showed only slight changes in their hippocampal protein transcripts. In 7-d old rats, there was a significant decreased in IGF-1R gene expression and protein levels in the newborns born to diabetic dams. Moreover, they found a down regulation in hippocampal IGF1R transcripts in 14-d old diabetic group offspring. Two weeks after birth, the IR gene expression was significantly declined in the hippocampus of diabetic newborns. The authors claimed that maternal diabetes strongly altered the regulation of both IR and IGF1R during development of rat hippocampus[67].


The Incidence of congenital anomalies in infants born to diabetic women is more common in comparison to children of normal population. There are multiple lines of evidence that suggest the disturbances in intellectual and behavioral functioning observed in the children of diabetic women are accompanied by modification of hippocampus structure and function. The etiology and pathogenesis of these impairments induced by diabetes during pregnancy have spurred considerable efforts for clinically and basically researches. The final goal at these investigations was to find the teratogenic factors, which may enable preventive or protective measures to be taken in pregnancies with diabetes. Nevertheless, the exact mechanism by which diabetes during pregnancy affects the CNS development remains to be defined. Until now, several biological changes are defined to occur in diabetic mothers and to affect development of CNS (i.e., disturbance in glucose and insulin homeostasis, oxidative stress, hypoxia, and iron deficiency). Moreover, the new researches on genetic predisposition involves in teratogenicity of diabetes in pregnancy starts to define new genes and their products involved in the etiology of CNS malfunctions and malformations observed in offspring born to diabetic mothers. Hyperglycaemia and hyperinsulinemia in the mothers and their fetuses are thought to be major factors in teratogenicity of maternal diabetes on the CNS development. There are sufficient evidences for this hypothesis as concise control of glycemia in mothers reduces the incidence of anomalies exhibited with the offspring born to diabetic mothers. Recent evidence clearly indicated that maternal diabetes markedly influences the regulation of both IR and IGF1R - as two important regulators of development and function of CNS - in the developing rat hippocampus. Dissecting out the mechanisms responsible for maternal diabetes-related changes in the development of hippocampus is helping to prevent from impaired cognitive and memory functions in offspring.


P- Reviewer: Budziszewska B, Hernandez SRZ S- Editor: Ji FF L- Editor: A E- Editor: Liu SQ

1.  Khan MN, Khan FA, Sultana S, Dilawar M, Ijaz A, Khan MJ, Mahmood T. Impact of new diagnostic criteria of diabetes mellitus. J Coll Physicians Surg Pak. 2007;17:327-330.  [PubMed]  [DOI]
2.  Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26 Suppl 1:S5-20.  [PubMed]  [DOI]
3.  Reece EA. The fetal and maternal consequences of gestational diabetes mellitus. J Matern Fetal Neonatal Med. 2010;23:199-203.  [PubMed]  [DOI]
4.  Fetita LS, Sobngwi E, Serradas P, Calvo F, Gautier JF. Consequences of fetal exposure to maternal diabetes in offspring. J Clin Endocrinol Metab. 2006;91:3718-3724.  [PubMed]  [DOI]
5.  Aerts L, Holemans K, Van Assche FA. Maternal diabetes during pregnancy: consequences for the offspring. Diabetes Metab Rev. 1990;6:147-167.  [PubMed]  [DOI]
6.  Persaud OD. Maternal diabetes and the consequences for her offspring. J Develop Disab. 2007;1:101-134.  [PubMed]  [DOI]
7.  US Preventive Services Task Force (USPSTF). Screening for gestational diabetes mellitus: recommendation and rationale. Am Fam Physician. 2003;68:331-335.  [PubMed]  [DOI]
8.  Reece EA, Homko CJ. Diabetes mellitus in pregnancy. What are the best treatment options? Drug Saf. 1998;18:209-220.  [PubMed]  [DOI]
9.  Chaudry R, Gilby P, Carroll PV. Pre-existing (type 1 and type 2) diabetes in pregnancy. Obst Gyn Repro Med. 2007;17:339-344.  [PubMed]  [DOI]
10.  Health CEiMaC.  Pregnancy in women with type 1 and type 2 diabetes in 2002-03, england, wales and northern ireland. London: CEMACH; 2005;.  [PubMed]  [DOI]
11.  McElduff A, Ross GP, Lagström JA, Champion B, Flack JR, Lau SM, Moses RG, Seneratne S, McLean M, Cheung NW. Pregestational diabetes and pregnancy: an Australian experience. Diabetes Care. 2005;28:1260-1261.  [PubMed]  [DOI]
12.  Meur S, Mann NP. Infant outcomes following diabetic pregnancies. Paediatrics and Child Health. 2007;17:217-222.  [PubMed]  [DOI]
13.  ter Braak EW, Evers IM, Willem Erkelens D, Visser GH. Maternal hypoglycemia during pregnancy in type 1 diabetes: maternal and fetal consequences. Diabetes Metab Res Rev. 2002;18:96-105.  [PubMed]  [DOI]
14.  Schwartz R, Teramo KA. Effects of diabetic pregnancy on the fetus and newborn. Semin Perinatol. 2000;24:120-135.  [PubMed]  [DOI]
15.  Gabbe SG. Congenital malformations in infants of diabetic mothers. Obstet Gynecol Surv. 1977;32:125-132.  [PubMed]  [DOI]
16.  Mills JL. Malformations in infants of diabetic mothers. Teratology. 1982;25:385-394.  [PubMed]  [DOI]
17.  Suevo DM. The infant of the diabetic mother. Neonatal Netw. 1997;16:25-33.  [PubMed]  [DOI]
18.  Bánhidy F, Acs N, Puhó EH, Czeizel AE. Congenital abnormalities in the offspring of pregnant women with type 1, type 2 and gestational diabetes mellitus: a population-based case-control study. Congenit Anom (Kyoto). 2010;50:115-121.  [PubMed]  [DOI]
19.  Hod M, Merlob P, Friedman S, Litwin A, Mor N, Rusecki Y, Schoenfeld A, Ovadia J. Prevalence of minor congenital anomalies in newborns of diabetic mothers. Eur J Obstet Gynecol Reprod Biol. 1992;44:111-116.  [PubMed]  [DOI]
20.  Eidelman AI, Samueloff A. The pathophysiology of the fetus of the diabetic mother. Semin Perinatol. 2002;26:232-236.  [PubMed]  [DOI]
21.  Styrud J, Thunberg L, Nybacka O, Eriksson UJ. Correlations between maternal metabolism and deranged development in the offspring of normal and diabetic rats. Pediatr Res. 1995;37:343-353.  [PubMed]  [DOI]
22.  Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM. 2001;94:435-444.  [PubMed]  [DOI]
23.  Pedersen J. Weight and length at birth of infants of diabetic mothers. Acta Endocrinol (Copenh). 1954;16:330-342.  [PubMed]  [DOI]
24.  Pedersen J.  The pregnant diabetic and her newborn. Baltimore: Williams & Wilkins; 1977;.  [PubMed]  [DOI]
25.  Taylor R, Lee C, Kyne-Grzebalski D, Marshall SM, Davison JM. Clinical outcomes of pregnancy in women with type 1 diabetes(1). Obstet Gynecol. 2002;99:537-541.  [PubMed]  [DOI]
26.  Towner D, Kjos SL, Leung B, Montoro MM, Xiang A, Mestman JH, Buchanan TA. Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care. 1995;18:1446-1451.  [PubMed]  [DOI]
27.  Eriksson U, Dahlström E, Larsson KS, Hellerström C. Increased incidence of congenital malformations in the offspring of diabetic rats and their prevention by maternal insulin therapy. Diabetes. 1982;31:1-6.  [PubMed]  [DOI]
28.  Eriksson UJ, Bone AJ, Turnbull DM, Baird JD. Timed interruption of insulin therapy in diabetic BB/E rat pregnancy: effect on maternal metabolism and fetal outcome. Acta Endocrinol (Copenh). 1989;120:800-810.  [PubMed]  [DOI]
29.  Lapolla A, Dalfrà MG, Fedele D. Insulin therapy in pregnancy complicated by diabetes: are insulin analogs a new tool? Diabetes Metab Res Rev. 2005;21:241-252.  [PubMed]  [DOI]
30.  Salvesen DR, Freeman J, Brudenell JM, Nicolaides KH. Prediction of fetal acidaemia in pregnancies complicated by maternal diabetes mellitus by biophysical profile scoring and fetal heart rate monitoring. Br J Obstet Gynaecol. 1993;100:227-233.  [PubMed]  [DOI]
31.  Schwartz R, Gruppuso PA, Petzold K, Brambilla D, Hiilesmaa V, Teramo KA. Hyperinsulinemia and macrosomia in the fetus of the diabetic mother. Diabetes Care. 1994;17:640-648.  [PubMed]  [DOI]
32.  Susa JB, Neave C, Sehgal P, Singer DB, Zeller WP, Schwartz R. Chronic hyperinsulinemia in the fetal rhesus monkey. Effects of physiologic hyperinsulinemia on fetal growth and composition. Diabetes. 1984;33:656-660.  [PubMed]  [DOI]
33.  Susa JB, Widness JA, Hintz R, Liu F, Sehgal P, Schwartz R. Somatomedins and insulin in diabetic pregnancies: effects on fetal macrosomia in the human and rhesus monkey. J Clin Endocrinol Metab. 1984;58:1099-1105.  [PubMed]  [DOI]
34.  Widness JA, Susa JB, Garcia JF, Singer DB, Sehgal P, Oh W, Schwartz R, Schwartz HC. Increased erythropoiesis and elevated erythropoietin in infants born to diabetic mothers and in hyperinsulinemic rhesus fetuses. J Clin Invest. 1981;67:637-642.  [PubMed]  [DOI]
35.  Freinkel N. Diabetic embryopathy and fuel-mediated organ teratogenesis: lessons from animal models. Horm Metab Res. 1988;20:463-475.  [PubMed]  [DOI]
36.  Milner RD, Hill DJ. Interaction between endocrine and paracrine peptides in prenatal growth control. Eur J Pediatr. 1987;146:113-122.  [PubMed]  [DOI]
37.  Cousins L. Etiology and prevention of congenital anomalies among infants of overt diabetic women. Clin Obstet Gynecol. 1991;34:481-493.  [PubMed]  [DOI]
38.  Eriksson UJ, Borg LA. Diabetes and embryonic malformations. Role of substrate-induced free-oxygen radical production for dysmorphogenesis in cultured rat embryos. Diabetes. 1993;42:411-419.  [PubMed]  [DOI]
39.  Lee AT, Reis D, Eriksson UJ. Hyperglycemia-induced embryonic dysmorphogenesis correlates with genomic DNA mutation frequency in vitro and in vivo. Diabetes. 1999;48:371-376.  [PubMed]  [DOI]
40.  Hagay ZJ, Weiss Y, Zusman I, Peled-Kamar M, Reece EA, Eriksson UJ, Groner Y. Prevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide dismutase in transgenic mouse embryos. Am J Obstet Gynecol. 1995;173:1036-1041.  [PubMed]  [DOI]
41.  Wentzel P, Thunberg L, Eriksson UJ. Teratogenic effect of diabetic serum is prevented by supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture. Diabetologia. 1997;40:7-14.  [PubMed]  [DOI]
42.  Georgieff MK. The effect of maternal diabetes during pregnancy on the neurodevelopment of offspring. Minn Med. 2006;89:44-47.  [PubMed]  [DOI]
43.  Ornoy A. Growth and neurodevelopmental outcome of children born to mothers with pregestational and gestational diabetes. Pediatr Endocrinol Rev. 2005;3:104-113.  [PubMed]  [DOI]
44.  Nelson CA, Wewerka S, Thomas KM, Tribby-Walbridge S, deRegnier R, Georgieff M. Neurocognitive sequelae of infants of diabetic mothers. Behav Neurosci. 2000;114:950-956.  [PubMed]  [DOI]
45.  Yamashita Y, Kawano Y, Kuriya N, Murakami Y, Matsuishi T, Yoshimatsu K, Kato H. Intellectual development of offspring of diabetic mothers. Acta Paediatr. 1996;85:1192-1196.  [PubMed]  [DOI]
46.  Sells CJ, Robinson NM, Brown Z, Knopp RH. Long-term developmental follow-up of infants of diabetic mothers. J Pediatr. 1994;125:S9-17.  [PubMed]  [DOI]
47.  Van Assche FA, Holemans K, Aerts L. Long-term consequences for offspring of diabetes during pregnancy. Br Med Bull. 2001;60:173-182.  [PubMed]  [DOI]
48.  Ornoy A. The impact of intrauterine exposure versus postnatal environment in neurodevelopmental toxicity: long-term neurobehavioral studies in children at risk for developmental disorders. Toxicol Lett. 2003;140-141:171-181.  [PubMed]  [DOI]
49.  Ornoy A, Ratzon N, Greenbaum C, Peretz E, Soriano D, Dulitzky M. Neurobehaviour of school age children born to diabetic mothers. Arch Dis Child Fetal Neonatal Ed. 1998;79:F94-F99.  [PubMed]  [DOI]
50.  Ornoy A, Ratzon N, Greenbaum C, Wolf A, Dulitzky M. School-age children born to diabetic mothers and to mothers with gestational diabetes exhibit a high rate of inattention and fine and gross motor impairment. J Pediatr Endocrinol Metab. 2001;14 Suppl 1:681-689.  [PubMed]  [DOI]
51.  Delascio Lopes C, Sinigaglia-Coimbra R, Mazzola J, Camano L, Mattar R. Neurofunctional evaluation of young male offspring of rat dams with diabetes induced by streptozotocin. ISRN Endocrinol. 2011;2011:480656.  [PubMed]  [DOI]
52.  Hepper PG. The behaviour of the foetus as an indicator of neural functioning. Fetal development. A psychobiological perspective. Lawrence Erlbaum: Hillsdale, NJ; 1995;405-417.  [PubMed]  [DOI]
53.  Rizzo TA, Silverman BL, Metzger BE, Cho NH. Behavioral adjustment in children of diabetic mothers. Acta Paediatr. 1997;86:969-974.  [PubMed]  [DOI]
54.  Freinkel N. Banting Lecture 1980. Of pregnancy and progeny. Diabetes. 1980;29:1023-1035.  [PubMed]  [DOI]
55.  Churchill JA, Berendes HW, Nemore J. Neuropsychological deficits in children of diabetic mothers. A report from the Collaborative Sdy of Cerebral Palsy. Am J Obstet Gynecol. 1969;105:257-268.  [PubMed]  [DOI]
56.  Stehbens JA, Baker GL, Kitchell M. Outcome at ages 1, 3, and 5 years of children born to diabetic women. Am J Obstet Gynecol. 1977;127:408-413.  [PubMed]  [DOI]
57.  Rizzo T, Metzger BE, Burns WJ, Burns K. Correlations between antepartum maternal metabolism and child intelligence. N Engl J Med. 1991;325:911-916.  [PubMed]  [DOI]
58.  Rizzo T, Freinkel N, Metzger BE, Hatcher R, Burns WJ, Barglow P. Correlations between antepartum maternal metabolism and newborn behavior. Am J Obstet Gynecol. 1990;163:1458-1464.  [PubMed]  [DOI]
59.  Cummins M, Norrish M. Follow-up of children of diabetic mothers. Arch Dis Child. 1980;55:259-264.  [PubMed]  [DOI]
60.  Persson B, Gentz J. Follow-up of children of insulin-dependent and gestational diabetic mothers. Neuropsychological outcome. Acta Paediatr Scand. 1984;73:349-358.  [PubMed]  [DOI]
61.  Rizzo TA, Dooley SL, Metzger BE, Cho NH, Ogata ES, Silverman BL. Prenatal and perinatal influences on long-term psychomotor development in offspring of diabetic mothers. Am J Obstet Gynecol. 1995;173:1753-1758.  [PubMed]  [DOI]
62.  Yssing M. Long-term prognosis of children born to mothers diabetic when pregnant. Early diabetics in early life. New York: Academic Press; 1975;575-586.  [PubMed]  [DOI]
63.  Haworth JC, McRae KN, Dilling LA. Prognosis of infants of diabetic mothers in relation to neonatal hypoglycaemia. Dev Med Child Neurol. 1976;18:471-479.  [PubMed]  [DOI]
64.  Hadden DR, Byrne E, Trotter I, Harley JM, McClure G, McAuley RR. Physical and psychological health of children of Type 1 (insulin-dependent) diabetic mothers. Diabetologia. 1984;26:250-254.  [PubMed]  [DOI]
65.  Doherty NN, Hepper PG. Habituation in fetuses of diabetic mothers. Early Hum Dev. 2000;59:85-93.  [PubMed]  [DOI]
66.  Gonzalez-Gonzalez NL, Medina V, Padron E, Domenech E, Diaz Gomez NM, Armas H, Bartha JL. Fetal and neonatal habituation in infants of diabetic mothers. J Pediatr. 2009;154:492-497.  [PubMed]  [DOI]
67.  Van Lieshout RJ, Voruganti LP. Diabetes mellitus during pregnancy and increased risk of schizophrenia in offspring: a review of the evidence and putative mechanisms. J Psychiatry Neurosci. 2008;33:395-404.  [PubMed]  [DOI]
68.  Ramanathan M, Jaiswal AK, Bhattacharya SK. Hyperglycaemia in pregnancy: effects on the offspring behaviour with special reference to anxiety paradigms. Indian J Exp Biol. 2000;38:231-236.  [PubMed]  [DOI]
69.  Hami J, Sadr-Nabavi A, Sankian M, Balali-Mood M, Haghir H. The effects of maternal diabetes on expression of insulin-like growth factor-1 and insulin receptors in male developing rat hippocampus. Brain Struct Funct. 2013;218:73-84.  [PubMed]  [DOI]
70.  Haghir H, Rezaee AA, Sankian M, Kheradmand H, Hami J. The effects of induced type-I diabetes on developmental regulation of insulin & amp; insulin like growth factor-1 (IGF-1) receptors in the cerebellum of rat neonates. Metab Brain Dis. 2013;28:397-410.  [PubMed]  [DOI]
71.  Yamano T, Shimada M, Fujizeki Y, Kawasaki H, Onaga A. Quantitative synaptic changes on Purkinje cell dendritic spines of rats born from streptozotocin-induced diabetic mothers. Brain Dev. 1986;8:269-273.  [PubMed]  [DOI]
72.  Yang X, Borg LA, Eriksson UJ. Altered mitochondrial morphology of rat embryos in diabetic pregnancy. Anat Rec. 1995;241:255-267.  [PubMed]  [DOI]
73.  Kinney BA, Rabe MB, Jensen RA, Steger RW. Maternal hyperglycemia leads to gender-dependent deficits in learning and memory in offspring. Exp Biol Med (Maywood). 2003;228:152-159.  [PubMed]  [DOI]
74.  Plagemann A, Harder T, Lindner R, Melchior K, Rake A, Rittel F, Rohde W, Dörner G. Alterations of hypothalamic catecholamines in the newborn offspring of gestational diabetic mother rats. Brain Res Dev Brain Res. 1998;109:201-209.  [PubMed]  [DOI]
75.  Becerra JE, Khoury MJ, Cordero JF, Erickson JD. Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case-control study. Pediatrics. 1990;85:1-9.  [PubMed]  [DOI]
76.  Correa A, Gilboa SM, Besser LM, Botto LD, Moore CA, Hobbs CA, Cleves MA, Riehle-Colarusso TJ, Waller DK, Reece EA. Diabetes mellitus and birth defects. Am J Obstet Gynecol. 2008;199:237.e1-237.e9.  [PubMed]  [DOI]
77.  Ramos-Arroyo MA, Rodriguez-Pinilla E, Cordero JF. Maternal diabetes: the risk for specific birth defects. Eur J Epidemiol. 1992;8:503-508.  [PubMed]  [DOI]
78.  Xu C, Li X, Wang F, Weng H, Yang P. Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis. Am J Physiol Endocrinol Metab. 2013;305:E667-E678.  [PubMed]  [DOI]
79.  Reece EA, Pinter E, Leranth CZ, Garcia-Segura M, Sanyal MK, Hobbins JC, Mahoney MJ, Naftolin F. Ultrastructural analysis of malformations of the embryonic neural axis induced by in vitro hyperglycemic conditions. Teratology. 1985;32:363-373.  [PubMed]  [DOI]
80.  Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, Radi E. Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci. 2012;322:254-262.  [PubMed]  [DOI]
81.  Faizi M, Salimi A, Rasoulzadeh M, Naserzadeh P, Pourahmad J. Schizophrenia induces oxidative stress and cytochrome C release in isolated rat brain mitochondria: a possible pathway for induction of apoptosis and neurodegeneration. Iran J Pharm Res. 2014;13:93-100.  [PubMed]  [DOI]
82.  Foster KA, Galeffi F, Gerich FJ, Turner DA, Müller M. Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration. Prog Neurobiol. 2006;79:136-171.  [PubMed]  [DOI]
83.  Zein S, Rachidi S, Hininger-Favier I. Is oxidative stress induced by iron status associated with gestational diabetes mellitus? J Trace Elem Med Biol. 2014;28:65-69.  [PubMed]  [DOI]
84.  Lappas M, Hiden U, Desoye G, Froehlich J, Hauguel-de Mouzon S, Jawerbaum A. The role of oxidative stress in the pathophysiology of gestational diabetes mellitus. Antioxid Redox Signal. 2011;15:3061-3100.  [PubMed]  [DOI]
85.  Chen X, Scholl TO. Oxidative stress: changes in pregnancy and with gestational diabetes mellitus. Curr Diab Rep. 2005;5:282-288.  [PubMed]  [DOI]
86.  Mimouni F, Miodovnik M, Siddiqi TA, Butler JB, Holroyde J, Tsang RC. Neonatal polycythemia in infants of insulin-dependent diabetic mothers. Obstet Gynecol. 1986;68:370-372.  [PubMed]  [DOI]
87.  Curristin SM, Cao A, Stewart WB, Zhang H, Madri JA, Morrow JS, Ment LR. Disrupted synaptic development in the hypoxic newborn brain. Proc Natl Acad Sci USA. 2002;99:15729-15734.  [PubMed]  [DOI]
88.  McQuillen PS, Sheldon RA, Shatz CJ, Ferriero DM. Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia. J Neurosci. 2003;23:3308-3315.  [PubMed]  [DOI]
89.  Johnston MV, Trescher WH, Ishida A, Nakajima W. Neurobiology of hypoxic-ischemic injury in the developing brain. Pediatr Res. 2001;49:735-741.  [PubMed]  [DOI]
90.  Carrapato MR, Marcelino F. The infant of the diabetic mother: The critical developmental windows. Early Pregnancy. 2001;5:57-58.  [PubMed]  [DOI]
91.  Yehuda S, Youdim MB. Brain iron: a lesson from animal models. Am J Clin Nutr. 1989;50:618-625; discussion 625-629.  [PubMed]  [DOI]
92.  Yehuda S. Neurochemical basis of behavioral effects of brain iron deficiency in anemia. Brain, behavior and iron in the infant diet. London: Springer-Verlag; 1990;63-81.  [PubMed]  [DOI]
93.  Petry CD, Eaton MA, Wobken JD, Mills MM, Johnson DE, Georgieff MK. Iron deficiency of liver, heart, and brain in newborn infants of diabetic mothers. J Pediatr. 1992;121:109-114.  [PubMed]  [DOI]
94.  Lozoff B, Georgieff MK. Iron deficiency and brain development. Semin Pediatr Neurol. 2006;13:158-165.  [PubMed]  [DOI]
95.  Beard J. Iron deficiency alters brain development and functioning. J Nutr. 2003;133:1468S-1472S.  [PubMed]  [DOI]
96.  Georgieff MK. The role of iron in neurodevelopment: fetal iron deficiency and the developing hippocampus. Biochem Soc Trans. 2008;36:1267-1271.  [PubMed]  [DOI]
97.  Larkin EC, Rao GA. Mportance of fetal and neonatal iron: Adequacy for normal development of central nervous system. Brain, behavior and iron in the infant diet. London: Springer-Verlag; 1990;43-62.  [PubMed]  [DOI]
98.  Felt BT, Beard JL, Schallert T, Shao J, Aldridge JW, Connor JR, Georgieff MK, Lozoff B. Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats. Behav Brain Res. 2006;171:261-270.  [PubMed]  [DOI]
99.  Rytych JL, Elmore MR, Burton MD, Conrad MS, Donovan SM, Dilger RN, Johnson RW. Early life iron deficiency impairs spatial cognition in neonatal piglets. J Nutr. 2012;142:2050-2056.  [PubMed]  [DOI]
100.  Eden AN. Iron deficiency and impaired cognition in toddlers: an underestimated and undertreated problem. Paediatr Drugs. 2005;7:347-352.  [PubMed]  [DOI]
101.  Walter T. Impact of iron deficiency on cognition in infancy and childhood. Eur J Clin Nutr. 1993;47:307-316.  [PubMed]  [DOI]
102.  Felt BT, Lozoff B. Brain iron and behavior of rats are not normalized by treatment of iron deficiency anemia during early development. J Nutr. 1996;126:693-701.  [PubMed]  [DOI]
103.  Wachs TD, Pollitt E, Cueto S, Jacoby E, Creed-Kanashiro H. Relation of neonatal iron status to individual variability in neonatal temperament. Dev Psychobiol. 2005;46:141-153.  [PubMed]  [DOI]
104.  Siddappa AM, Georgieff MK, Wewerka S, Worwa C, Nelson CA, Deregnier RA. Iron deficiency alters auditory recognition memory in newborn infants of diabetic mothers. Pediatr Res. 2004;55:1034-1041.  [PubMed]  [DOI]
105.  Aerts L, Van Assche FA. Animal evidence for the transgenerational development of diabetes mellitus. Int J Biochem Cell Biol. 2006;38:894-903.  [PubMed]  [DOI]
106.  Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002;106:2067-2072.  [PubMed]  [DOI]
107.  Loukovaara M, Leinonen P, Teramo K, Alfthan H, Stenman UH, Andersson S. Fetal hypoxia is associated with elevated cord serum C-reactive protein levels in diabetic pregnancies. Biol Neonate. 2004;85:237-242.  [PubMed]  [DOI]
108.  Mehler MF, Kessler JA. Hematolymphopoietic and inflammatory cytokines in neural development. Trends Neurosci. 1997;20:357-365.  [PubMed]  [DOI]
109.  Jarskog LF, Xiao H, Wilkie MB, Lauder JM, Gilmore JH. Cytokine regulation of embryonic rat dopamine and serotonin neuronal survival in vitro. Int J Dev Neurosci. 1997;15:711-716.  [PubMed]  [DOI]
110.  Kinalski M, Telejko B, Kuźmicki M, Kretowski A, Kinalska I. Tumor necrosis factor alpha system and plasma adiponectin concentration in women with gestational diabetes. Horm Metab Res. 2005;37:450-454.  [PubMed]  [DOI]
111.  Bo S, Signorile A, Menato G, Gambino R, Bardelli C, Gallo ML, Cassader M, Massobrio M, Pagano GF. C-reactive protein and tumor necrosis factor-alpha in gestational hyperglycemia. J Endocrinol Invest. 2005;28:779-786.  [PubMed]  [DOI]
112.  Deverman BE, Patterson PH. Cytokines and CNS development. Neuron. 2009;64:61-78.  [PubMed]  [DOI]
113.  Zhao B, Schwartz JP. Involvement of cytokines in normal CNS development and neurological diseases: recent progress and perspectives. J Neurosci Res. 1998;52:7-16.  [PubMed]  [DOI]
114.  Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, Perrin M, Gorman JM, Susser ES. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry. 2004;161:889-895.  [PubMed]  [DOI]
115.  Kaan A, Dimich-Ward H, Manfreda J, Becker A, Watson W, Ferguson A, Chan H, Chan-Yeung M. Cord blood IgE: its determinants and prediction of development of asthma and other allergic disorders at 12 months. Ann Allergy Asthma Immunol. 2000;84:37-42.  [PubMed]  [DOI]
116.  Spencer SJ, Hyland NP, Sharkey KA, Pittman QJ. Neonatal immune challenge exacerbates experimental colitis in adult rats: potential role for TNF-alpha. Am J Physiol Regul Integr Comp Physiol. 2007;292:R308-R315.  [PubMed]  [DOI]
117.  Stadtman ER. Protein oxidation and aging. Science. 1992;257:1220-1224.  [PubMed]  [DOI]
118.  Ames BA, Shingenaga MK, Park EM. Oxyradicals and DNA damage. Oxidation damage and repair: Chemical, biological and medical aspects. Elmsford: Pergamon Press; 1991;181-187.  [PubMed]  [DOI]
119.  Bis-Głuchowska M, Marciniak B, Szpringer-Boguń E, Rola R, Leszczyńska-Gorzelak B, Oleszczuk J. [Determination of antioxidative-peroxidative balance in the cord blood of newborns delivered to mothers with diabetes type G1]. Ginekol Pol. 2001;72:1255-1258.  [PubMed]  [DOI]
120.  Allen RG, Venkatraj VS. Oxidants and antioxidants in development and differentiation. J Nutr. 1992;122:631-635.  [PubMed]  [DOI]
121.  Rafalowska U, Liu GJ, Floyd RA. Peroxidation induced changes in synaptosomal transport of dopamine and gamma-aminobutyric acid. Free Radic Biol Med. 1989;6:485-492.  [PubMed]  [DOI]
122.  Mahadik SP, Mukherjee S. Free radical pathology and antioxidant defense in schizophrenia: a review. Schizophr Res. 1996;19:1-17.  [PubMed]  [DOI]
123.  Schwartz RD, Skolnick P, Paul SM. Regulation of gamma-aminobutyric acid/barbiturate receptor-gated chloride ion flux in brain vesicles by phospholipase A2: possible role of oxygen radicals. J Neurochem. 1988;50:565-571.  [PubMed]  [DOI]
124.  Pellmar T. Electrophysiological correlates of peroxide damage in guinea pig hippocampus in vitro. Brain Res. 1986;364:377-381.  [PubMed]  [DOI]
125.  LEVIN EY, KAUFMAN S. Studies on the enzyme catalyzing the conversion of 3,4-dihydroxyphenylethylamine to norepinephrine. J Biol Chem. 1961;236:2043-2049.  [PubMed]  [DOI]
126.  Dheen ST, Tay SS, Boran J, Ting LW, Kumar SD, Fu J, Ling EA. Recent studies on neural tube defects in embryos of diabetic pregnancy: an overview. Curr Med Chem. 2009;16:2345-2354.  [PubMed]  [DOI]
127.  De Felice C, Signorini C, Leoncini S, Pecorelli A, Durand T, Valacchi G, Ciccoli L, Hayek J. The role of oxidative stress in Rett syndrome: an overview. Ann N Y Acad Sci. 2012;1259:121-135.  [PubMed]  [DOI]
128.  Rossignol DA, Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol. 2014;5:150.  [PubMed]  [DOI]
129.  Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiology. 2006;13:171-181.  [PubMed]  [DOI]
130.  Flatow J, Buckley P, Miller BJ. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013;74:400-409.  [PubMed]  [DOI]
131.  Tylec A, Jarzab A, Stryjecka-Zimmer M, Wójcicka A. [Stress oxidative in schizophrenia]. Pol Merkur Lekarski. 2007;23:74-77.  [PubMed]  [DOI]
132.  Cederberg J, Simán CM, Eriksson UJ. Combined treatment with vitamin E and vitamin C decreases oxidative stress and improves fetal outcome in experimental diabetic pregnancy. Pediatr Res. 2001;49:755-762.  [PubMed]  [DOI]
133.  Cederberg J, Eriksson UJ. Antioxidative treatment of pregnant diabetic rats diminishes embryonic dysmorphogenesis. Birth Defects Res A Clin Mol Teratol. 2005;73:498-505.  [PubMed]  [DOI]
134.  Anlar B, Sullivan KA, Feldman EL. Insulin-like growth factor-I and central nervous system development. Horm Metab Res. 1999;31:120-125.  [PubMed]  [DOI]
135.  Baron-Van Evercooren A, Olichon-Berthe C, Kowalski A, Visciano G, Van Obberghen E. Expression of IGF-I and insulin receptor genes in the rat central nervous system: a developmental, regional, and cellular analysis. J Neurosci Res. 1991;28:244-253.  [PubMed]  [DOI]
136.  Dou JT, Chen M, Dufour F, Alkon DL, Zhao WQ. Insulin receptor signaling in long-term memory consolidation following spatial learning. Learn Mem. 2005;12:646-655.  [PubMed]  [DOI]
137.  Haghir H, Rezaee AA, Nomani H, Sankian M, Kheradmand H, Hami J. Sexual dimorphism in expression of insulin and insulin-like growth factor-I receptors in developing rat cerebellum. Cell Mol Neurobiol. 2013;33:369-377.  [PubMed]  [DOI]
138.  Hami J, Kheradmand H, Haghir H. Gender differences and lateralization in the distribution pattern of insulin-like growth factor-1 receptor in developing rat hippocampus: an immunohistochemical study. Cell Mol Neurobiol. 2014;34:215-226.  [PubMed]  [DOI]
139.  Popken GJ, Hodge RD, Ye P, Zhang J, Ng W, O’Kusky JR, D’Ercole AJ. 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. 2004;19:2056-2068.  [PubMed]  [DOI]
140.  Rother KI, Accili D. Role of insulin receptors and IGF receptors in growth and development. Pediatr Nephrol. 2000;14:558-561.  [PubMed]  [DOI]
141.  Zhao WQ, Chen H, Quon MJ, Alkon DL. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol. 2004;490:71-81.  [PubMed]  [DOI]
142.  Nelson TJ, Sun MK, Hongpaisan J, Alkon DL. Insulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair. Eur J Pharmacol. 2008;585:76-87.  [PubMed]  [DOI]
143.  Zhao WQ, Alkon DL. Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol. 2001;177:125-134.  [PubMed]  [DOI]
144.  Navarro I, Leibush B, Moon TW, Plisetskaya EM, Baños N, Méndez E, Planas JV, Gutiérrez J. Insulin, insulin-like growth factor-I (IGF-I) and glucagon: the evolution of their receptors. Comp Biochem Physiol B Biochem Mol Biol. 1999;122:137-153.  [PubMed]  [DOI]
145.  Chiu SL, Cline HT. Insulin receptor signaling in the development of neuronal structure and function. Neural Dev. 2010;5:7.  [PubMed]  [DOI]
146.  Zemva J, Schubert M. Central insulin and insulin-like growth factor-1 signaling: implications for diabetes associated dementia. Curr Diabetes Rev. 2011;7:356-366.  [PubMed]  [DOI]
147.  Zhang J, Moats-Staats BM, Ye P, D’Ercole AJ. Expression of insulin-like growth factor system genes during the early postnatal neurogenesis in the mouse hippocampus. J Neurosci Res. 2007;85:1618-1627.  [PubMed]  [DOI]
148.  Lauszus FF. The clinical significance of IGF-I in maternal serum during pregnancy in type 1 diabetes. Curr Diabetes Rev. 2007;3:194-197.  [PubMed]  [DOI]
149.  Brussee V, Cunningham FA, Zochodne DW. Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes. 2004;53:1824-1830.  [PubMed]  [DOI]
150.  Russo VC, Gluckman PD, Feldman EL, Werther GA. The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev. 2005;26:916-943.  [PubMed]  [DOI]
151.  Ramsay TG, Wolverton CK, Steele NC. Alteration in IGF-I mRNA content of fetal swine tissues in response to maternal diabetes. Am J Physiol. 1994;267:R1391-R1396.  [PubMed]  [DOI]
152.  Thompson CL, Pathak SD, Jeromin A, Ng LL, MacPherson CR, Mortrud MT, Cusick A, Riley ZL, Sunkin SM, Bernard A. Genomic anatomy of the hippocampus. Neuron. 2008;60:1010-1021.  [PubMed]  [DOI]
153.  Förster E, Zhao S, Frotscher M. Laminating the hippocampus. Nat Rev Neurosci. 2006;7:259-267.  [PubMed]  [DOI]
154.  McNay EC, Fries TM, Gold PE. Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc Natl Acad Sci USA. 2000;97:2881-2885.  [PubMed]  [DOI]
155.  Tehranipour M, Khakzad MR. Effect of maternal diabetes on hippocampus neuronal density in neonatal rats. J Biol Sci. 2008;6:1027-1032.  [PubMed]  [DOI]
156.  Hami J, Sadr-Nabavi A, Sankian M, Haghir H. Sex differences and left-right asymmetries in expression of insulin and insulin-like growth factor-1 receptors in developing rat hippocampus. Brain Struct Funct. 2012;217:293-302.  [PubMed]  [DOI]