Diabetes in pregnant women: a population at risk for autism development in the offspring

A large number of epidemiologic studies have linked maternal lifestyle (i.e. diet, stress, exposure to alcohol or tobacco) to a higher risk for abnormal fetal development.
Indeed, maternal metabolic conditions such as diabetes could dramatically impact fetal growth and development including brain formation.

1. What is diabetes?

Diabetes is a chronic, progressive autoimmune disorder characterized by the destruction of a particular set of cells within the pancreas that secrete insulin, an hormone needed to allow glucose (sugar) to enter cells to produce energy. There are three types of diabetes:

  • Type 1 diabetes (T1DM or insulin-dependent) is characterized by a low or an absence of insulin production and occur generally during adolescence.
  • Type 2 diabetes (T2DM or noninsulin-dependent) affects the way your body uses the glucose. Your body starts to be resistant to the effects of insulin.
  • Gestational diabetes (GDM) develops during pregnancy and starts when your body is not able to secrete or use the insulin needed during this highly demanding period. This is generally assumed to be a similar syndrome and part of those with T2DM.

It should be noted that those with a history of PCOS (Polycystic Ovarian Syndrome) are at greater risk for GDM and T2DM and should be followed during their pregnancies very closely as well, even if a diagnosis of GDM or T2DM has not yet been made. It would appear they would have similar risks for autism as those categories discussed above.

2. Maternal diabetes and autism in children: facts

Several studies have presented a significant association between maternal diabetes and autism development in the offspring, regardless of diabetes type.
The CHARGE study ( Childhood Autism Risks from Genetics and the Environment) showed that diabetes was more common among mothers of children with ASD than in healthy control mothers. Several other studies showed that mothers with diabetes are more likely to have autistic children than non-diabetic mothers (1.4 to 2-fold increase risk).
A recent large multiethnic clinical study included 322 323 singleton children and their mothers. They followed children’s development up to 5.5 years-old to detect any autistic behaviors. The study showed a higher prevalence of ASD children in mothers that developed gestational diabetes diagnosed by 26 weeks of gestation.
This highlights accrued risks for autism development with maternal and untreated diabetes as the exposure of fetus to maternal hyperglycemia and the associated inflammatory responses, has deleterious effects on fetal development during this early, critical and sensitive period for fetal brain development.

3. How maternal diabetes can cause autism in the offspring?

The association between maternal diabetes and ASD might be attributable to several factors:

  • Genetics: a common genetic background between ASD and maternal diabetes.

Few common genetic profiles have been found between autism and Type 1 diabetes. Among them, HLA-DR4, an allele present in the DRB1 locus has been associated in different studies, with mothers of autistic children, where they were up to 5.5 times more likely to have HLA-DR4 than control individuals. Moreover, HLA-DR4 is also associated with T1DM. It is also well known that the immune system is involved in brain development and plasticity. HLA-DR4 was proposed to alter the maternal immune system during pregnancy thus impacting brain development.

  • Maternal diabetes alters the fetal cytokine environment.

Maternal diabetes is an autoimmune disease and is very often associated with increased maternal weight that induces chronic inflammation. The production of inflammatory cytokines and autoantibodies by the maternal immune system can pass through the placenta and attack the fetal brain during its development and impair its formation. Moreover, maternal glucose travels freely to the fetus while maternal insulin does not. The fetus is then exposed to higher concentrations of glucose than normal, forcing the fetus to increase its own insulin production. Because insulin can cross the blood-brain barrier, the high level of insulin, produced by the fetus as a result of maternal diabetes, will overstimulate a specific pathway (PI3K/Tor) involved in synaptic plasticity (communication between your neurons) that is implicated in autism development.

New studies have shown that patients with GDM may lose their ability to generate tolerance for paternal genetics, due to a loss in activated “protective” T regulator cells. This loss of tolerance can lead to a chronic immune attack against the pregnancy with its associated elevation in inflammatory cytokines and activated T cells.

Many of the above mechanisms are also associated with the higher rate of miscarriage, stillbirth, and late pregnancy complications in these patients as well.

  • In utero exposure to hyperglycemia disrupt fetal development:

Maternal hyperglycemia could result in hypoxia in the fetus that may impair its neurodevelopment thus leading to a higher risk for autism. It has also been linked to an increase in free radical production (a sign of inflammation) leading to oxidative stress in the cord blood and placenta, which increases risks for autism.
Maternal hyperglycemia could also alter epigenetic modifications (i.e. DNA methylation) on key factors involved in brain formation during the highly susceptible phase of fetal development.

These recent studies clearly demonstrate the role of maternal diabetes in the poor neurodevelopmental outcome of the offspring that is more likely to develop autism.

The early screening for gestational diabetes in addition to an early detection for maternal inflammation by an immune profile screening, could help to detect the 2 mechanisms assumed to be causing autism (i.e. hyperglycemia and altered immune profile) and treat the patients at higher risk for having an autistic child.

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