Excerpt
Postnatal management of neonates of diabetic mothers continues to give cause for concern [
1‐
3]. Gestational diabetes is connected with the risk of fetal and neonatal complications that are directly related to inadequate glycemic control during pregnancy [
1,
2]. Insulin does not cross the placenta; therefore, the fetus must secrete insulin independently [
2,
3]. Infants born to diabetic mothers often secrete higher amounts of insulin to accommodate for excess fetal glucose concentrations [
3]. Maternal hyperglycemia leads to fetal hyperglycemia and transient hyperinsulinemia, which in turn leads to fetal overgrowth or macrosomia as stated by the Pedersen hypothesis [
2]. Macrosomia is the principal neonatal adverse effect reported in babies of mothers with gestational diabetes [
1,
2,
4,
5]. Macrosomic newborns are predisposed to selected adverse perinatal outcomes such as birth asphyxia brain damage [
6]. However, there is no evidence for greater incidence of brain damage from perinatal asphyxia in infants of diabetic mothers compared with nondiabetic population [
4,
7]. Moreover, it has been shown that gestational diabetes neither increases the risk for such conditions when it is not treated [
1]. Concordantly, it has been observed that perinatal nerve palsy is rare in the case of gestational diabetes [
1]. Conversely, macrosomic infants of nondiabetic mothers have been demonstrated to be more susceptible to neonatal complications including cerebral palsy and neonatal encephalopathy [
7]. Neonatal hypoxic–ischemic encephalopathy represents a serious cerebral event occurring around birth with high mortality and neurological morbidity linked to long-term invalidating sequelae [
8]. The pathogenic mechanisms underlying neurological damage resulting from neonatal cerebral hypoxia–ischemia prime a cascade of biochemical events leading to cell dysfunction and ultimately to neuronal death through necrosis, apoptosis and autophagia [
8‐
11]. Glutamate excitotoxicity, oxidative stress and inflammation are considered as the central biochemical mechanisms implicated in the pathophysiology of neuronal death after birth asphyxia brain damage [
8‐
11]. Glutamate is a major excitatory neurotransmitter, widely expressed in the central nervous system (CNS) that is highly toxic to neurons due to its property to cause excitotoxicity that is involved in the mediation of neuronal death [
10,
11]. It has recently been assessed that insulin exerts neuroprotective effects [
12]. It has been reported that insulin receptors (IRs) in the brain have unique molecular features and a characteristic pattern of distribution implying a close relationship between insulin and the brain [
13]. Interestingly, it has been highlighted that insulin is able to attenuate glutamate-induced excitotoxic neuronal damage by multiple mechanisms including reduction in glutamate-induced cell loss, prevention of apoptosis and reducing the production of reactive oxygen species [
12]. Mounting data have provided strong evidence for a death-mediating role of enhanced autophagy in neonatal hypoxic–excitotoxic neuronal death [
14]. Interestingly, it has been found that cells undergo autophagic cell death following insulin withdrawal [
15]. Insulin has also been described to increase the survivin expression [
16]. Survivin is a member of the inhibitor of apoptosis protein family that is considered as a key regulator of antiapoptosis against hypoxic–ischemic brain injury [
17]. Taken together into account, we suppose that infants of diabetic mother are at low risk of birth asphyxia as a result of neuroprotection due to transient hyperinsulinemia. We hypothesize that hyperinsulinemia in newborns of diabetic mothers may play the role of guardian of the brain protecting neurons from perinatal asphyxia by reducing glutamate-induced neurotoxicity and promoting both overexpression of survivin and inhibition of excessively activated autophagy. Advances in the knowledge of the impact of fetal hyperinsulinemia on brain in gestational diabetes may be a major stimulus for the development of treatment for preventing the pathogenic events triggering neurological disorders, mainly those focused on inhibiting glutamate excitotoxicity which has been described as a common ground for essentially all forms of brain damage. What’s more, we speculate that the role of insulin in the regulation of survivin and in the signaling pathways associated with autophagy might represent a potential target to implement new neuroprotective strategies against hypoxic–ischemic brain injury from birth to adulthood. …
