No mother would deny that one of the most exciting moments of her life is when she becomes a source of life and a tiny being forms inside her womb. But it can sometimes be stressful too, knowing that that tiny being depends on the mother for life, and that everything the mother does can affect her unborn child.

The placenta is the “home” of the fetus, and the intrauterine environment supports its development and health. Perturbations in this environment can thus have detrimental effects on the fetus. But do you know that these effects can have persistent consequences through adolescence and even adulthood? In other words, how mothers take care of themselves and their unborn child during pregnancy could, at least in part, determine the future health and well-being of their child.

The fetal origins of adult disease was originally proposed by David Barker and colleagues in the United Kingdom. The “Barker Hypothesis” was put forth to describe the increased incidence of chronic disease such as diabetes in humans and animals exposed to a less than ideal intrauterine environment. In this article, we will discuss what intrauterine conditions can predispose an offspring to diabetes, and what we can still do about it.

Fetal malnutrition
The “Thrifty Phenotype Hypothesis” was coined by Hales and Barker and was based on the observation that poor maternal nutrition during the Dutch Hunger Winter during World War II in the 1940’s resulted in increased incidence of obesity, cardiovascular disease, and diabetes.

This hypothesis suggested that when fetal environment is poor, fetal development tries to adapt and this leads to an altered postnatal metabolism. This is designed to make sure the offspring survives under conditions of poor nutrition. However, these adaptations worked to the disadvantage of the offspring when nutrition was more abundant in the postnatal environment. In other words, fetal adaptations to a poor intrauterine environment may have adverse consequences if there is a relative excess of nutrition available in adult life.

In modern times, fetal malnutrition can still occur and is a primary cause of intrauterine growth restriction (IUGR). IUGR occurs in genetically normal fetuses that are restrained from reaching their full growth potential. This usually leads to small-for-gestational-age (SGA) babies. Low birth weight is an important risk factor for impaired glucose tolerance (pre-diabetes) and diabetes later in life. Evidence shows that type 2 diabetes is more common among those that had IUGR during fetal development, indicating that the defects in glucose metabolism start in the womb.

Studies have shown that in IUGR/SGA fetuses, the function of pancreatic beta-cells (the cells that secrete insulin) and insulin secretion are reduced. Insulin is the most important hormone responsible for normalizing our blood sugar. Many SGA children exhibit catch-up growth and reach normal height and weight by 3 years of age. Catch-up growth, especially if the children exceed their genetic target as what happens in overfeeding,

is also associated with increased adiposity or body fat, leading to insulin resistance or decreased effectivity of one’s own insulin on the body. In insulin resistance, more insulin must be secreted by the pancreas to maintain the normal glucose levels. This places a greater burden on the pancreatic beta-cells already compromised by fetal malnutrition, and may accelerate the progression towards beta-cell failure and diabetes.

Maternal overnutrition
Aside from fetal malnutrition, overnutrition may also predispose the offspring to increased fat mass (leading to LGA or large-for-gestational-age babies) and increased incidence of metabolic syndrome (impaired glucose tolerance/diabetes, abnormal cholesterol, hypertension, obesity) as children and adults. This was initially shown in animal studies wherein maternal high-fat feeding during pregnancy in rats produces offspring with phenotype that resembles the human metabolic syndrome. Maternal glucose crosses the placenta easily, and it was also shown in animal studies that high sugar levels in utero increase the risk of abnormal glucose tolerance, diabetes, and obesity in the offspring.

These findings were replicated in human studies, wherein offspring who had been exposed to maternal diabetes during fetal life exhibit higher prevalence of impaired glucose tolerance and insulin resistance. In one study, the risks for developing type 2 diabetes and pre-diabetes for offspring of diabetic mothers were eight- and fourfold increased, respectively, and this was not explained by differences in offspring weight, birth weight, or gestational age. Recent studies also show that a defect in insulin secretion already exists even in adult offspring who still have normal glucose tolerance.

The data from animal and human studies therefore clearly demonstrate that intrauterine exposure to diabetes or high blood sugar is associated with increased risk of abnormal glucose metabolism in the offspring, beyond that attributable to genetic factors.

Maternal stress
A less-studied but nevertheless potentially significant contributing factor to development of diabetes is maternal stress. In addition to consumption of high-calorie, high-fat foods coupled with little physical activity, modern day lifestyle now includes increased stress stemming from work and social environments. A growing body of literature strongly suggests that stress has adverse effects on humans and animals. Human studies indicate that stressful situations activate the hypothalamic-pituitary-adrenal (HPA) axis, the network in our body responsible for the regulation of hormones, causing high levels of cortisol, commonly known as the “stress hormone”. Prenatal exposure to increased cortisol has been linked to abnormal glucose tolerance and diabetes, hypertension, and metabolic syndrome in the adults. The mechanisms responsible for these occurrences, however, remain to be investigated.

Prevention of Diabetes: Role of the mother and the offspring
With the increasing incidence of diabetes worldwide, targeting preventive strategies is crucial. With evidence showing that diabetes may already be “programmed” early in the mother’s womb, it gives us an opportunity to prevent the development of diabetes at a very early stage. For those who were born to diabetic mothers or who had poor intrauterine nutrition, we cannot change the past. But there’s still time to prevent the development of diabetes. The developmental origin of diabetes follows the “two-hit hypothesis”. The “first hit” disruptions that occur during early development (i.e. fetal malnutrition or maternal hyperglycemia) set the stage for long-term vulnerability to a “second hit” (e.g. obesity/ poor diet) which occurs later in life that would precipitate a pathological condition. Therefore, the intrauterine disruption may not be the direct cause of the development of diabetes, but it instead increases future susceptibility.

Here is a list of the things that mothers and offspring can do to prevent diabetes:

For the mothers:

1. Eat a healthy diet. This should consist mainly of complex carbohydrates, protein source (lean meat, fish, chicken), fruits and vegetables. Remember not to overbinge on fruits, though, since they also contain sugars. Three to four fruit servings per day may be enough. Avoid sweets, processed food, and junk food since these will just give you empty calories. Following a healthy diet will ensure a healthy intrauterine environment as well.
2. Have regular pre-natal check-ups so your obstetrician can check and monitor your weight gain as well as the estimated weight of your unborn child. Regular ultrasound as recommended by your OB may also detect IUGR or other fetal problems early.
3. Do an oral glucose tolerance test at the 20th-24th week of gestation. Your doctor may recommend this at an earlier stage of your pregnancy if you are deemed at higher risk of developing gestational diabetes (e.g. obese, family history of diabetes, previous gestational diabetes, previous history of large babies). This test is the best way to check if you have gestational diabetes.
4. Stop smoking and drinking alcohol. Both can lead to fetal malnutrition. Remember that these are toxins not just to you but to your baby as well.
5. If you already have diabetes prior to pregnancy, make sure to tell your doctor once you become pregnant. If you have been on oral medications for diabetes, your doctor will need to shift you to insulin at least while you are pregnant and breastfeeding, and may refer you to an endocrinologist if you don’t have one yet. Follow up regularly with your doctor to ensure good sugar control.
6. Avoid stress. If this is not possible, at least learn some stress management techniques.

For the offspring who had poor intrauterine conditions (you probably have to ask your mother if you fit in this category):

1. Maintain a healthy lifestyle, which includes regular exercise (at least 4x/week) and a healthy diet (see advise for mothers above).
2. Try to maintain your ideal body weight. Obesity can lead to insulin resistance which will overwhelm the function of your pancreas.
3. Consider checking your fasting blood sugar regularly. This is usually done every year for those who have risk factors for diabetes.

Remember that the development of diabetes involves interplay between genetic and environmental factors. Although some things may have happened in the past beyond our control, there are still other things that we can do to prevent diabetes from manifesting.

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