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Gestational Diabetes: The Effects Don’t Stop at Birth

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Mice born to diabetic mothers were prone to obesity even though they exercised as much as normal mice and even ate less. Image: iStockphoto

By Sue Mei Lau & Jenny Gunton

Jenny Gunton is a Senior Research Fellow with the Garvan Institute of Medical Research’s Diabetes and Transcription Factors Group.

New research explains why the children of mothers who develop diabetes during pregnancy have increased risks of obesity and diabetes themselves.

Diabetes is a condition characterised by high blood glucose levels. The hormone insulin, produced by the β cells of the pancreas, makes glucose move out of the blood and into the cells of the body, where it is used for fuel. Diabetes occurs when there is not enough insulin to control blood glucose adequately.

There are three main types of diabetes.

1. Type 1 diabetes, which often occurs in children, occurs when the immune system becomes confused and attacks the β cells of the pancreas.

2. Type 2 diabetes usually involves the development of insulin resistance, so that insulin doesn’t cause blood glucose levels to fall as well as normal. Furthermore, the β cells can’t make and release enough insulin to compensate for insulin resistance.

3. Gestational diabetes is brought about by hormonal changes that occur during pregnancy. During a normal pregnancy, the placenta produces hormones that cause insulin resistance. Gestational diabetes occurs when the β cells are unable to secrete enough insulin to overcome this insulin resistance. Risk factors for gestational diabetes include a family history of Type 2 or gestational diabetes, a maternal age over 35 and obesity, and non-Caucasian ethnicity.

Our research has found that mice born to mothers with gestational diabetes become fat in adulthood even though they have the same genetic makeup as mice whose mothers did not have diabetes in pregnancy. We found that the higher the mother’s sugar levels in pregnancy, the fatter the offspring became.

The brain centres that control body weight were different in the obese offspring. Thus obesity was programmed by exposure to diabetes in the womb.

Our results stress the need for meticulous blood sugar control in women with gestational diabetes because of the impact of high maternal sugars on offspring obesity in later life.

Risks of Exposure to Maternal Diabetes
Babies born to mothers with diabetes of any sort have a high risk of becoming overweight or obese. The babies are also at increased risk of developing diabetes or other health problems including heart disease.

In North American Pima Indians, who are particularly prone to diabetes, babies born to mothers before they develop diabetes have a risk of elevated blood sugar levels of less than 1 in 50 at ~8 years of age. This risk increases to 22 in 50 when babies are born to the same mothers after they have developed diabetes. Since the parents are the same and the mother hasn’t changed her genetic makeup, this increase in risk must be due to changes in the womb.

To figure out how and why this occurs, we needed a mouse model of human diabetes in pregnancy. Studies in people take decades, and we cannot look at how and why the changes happen because we cannot look at their brains, pancreas and muscles.

We bred mice that lack a “master regulator” of gene expression called ARNT, which is only active in the cells that make insulin – the β cells in the pancreas. We used these β-ARNT mice because we know that people who have Type 2 diabetes produce only one-tenth of normal levels of ARNT in their insulin-secreting β cells. We also know from our studies that women with Type 2 diabetes and a past-history of gestational diabetes also have decreased ARNT in their β cells.

Normal pregnancy places a lot of stress on β cells because a lot more insulin is needed to keep blood sugar levels normal, especially in the last trimester of pregnancy. Gestational diabetes develops if the β cells cannot make and release more insulin.

Because of the lack of ARNT in their β cells, β-ARNT mice cannot cope with the β cell stress during pregnancy and their blood sugar levels deteriorate: they develop gestational diabetes.

Effects on the Offspring
We used β-ARNT mice and their normal sisters as mothers to look at the effects of having a mother with gestational diabetes on the offspring. The mouse pups had higher insulin levels, and when they were born they were slightly heavier and tended to have slightly lower blood sugar levels. These are all effects seen in the babies of women with gestational diabetes.

The mouse pups were allowed to eat as much normal food as they liked, and we followed their growth and development over time to look at weight gain, the development of insulin resistance and obesity. By early adulthood both β-ARNT and normal mice born to β-ARNT mothers were heavier than the offspring of normal mothers.

Interestingly β-ARNT mice born to β-ARNT mothers were even heavier than normal mice born to β-ARNT mothers, showing that if you are unlucky enough to have both a mother with gestational diabetes and inherit the genetic risk of diabetes, then you ended up even bigger. The increased body weight was due to increased fat, mostly in the abdomen.

As well as being fatter, we found that mice exposed to maternal diabetes were insulin resistant. Insulin resistance in combination with β cell stress predicts future risk of Type 2 diabetes.

We also measured β cell function, and found that all of the β-ARNT mice secreted less insulin. After all, that is what the genetic change in β-ARNT mice is meant to do!

But we were excited to see that normal mice born to mothers with diabetes also had poor insulin secretion. This shows that if you are born to a mother with diabetes in pregnancy, it can give you all of the major risk factors for developing diabetes: β cells that don’t secrete insulin well, obesity and insulin resistance.

Why Were the Mice Fat?
Obesity is due to a lack of balance between the energy taken in and the energy burned in daily life. Weight gain occurs if more energy is taken in than burned, while weight is lost if more energy is burned. This very simple equation is unavoidable, and applies whatever your diet or medical conditions.

To find out why mice exposed to maternal diabetes gained more weight, we first looked at energy intake by measuring how much food they ate. This was to see whether the obesity was as simple as them eating more food. It wasn’t. In fact, the mice tended to eat less food, and at some points in their life it was significantly less. This should have made them lighter, but didn’t. So, these mice ate less food but got fatter. Very unfair!

Then we measured their metabolic rate by putting them in sealed cages for a known amount of time and measuring how much oxygen they used and how much carbon dioxide and heat they produced. When we did this we found that both normal mice and β-ARNT mice exposed to maternal diabetes used significantly less energy. Energy expenditure was even lower in β-ARNT mice than the normal mice exposed to diabetes.

To see if the mice were using less of energy because they were exercising less or had a slower metabolic rate, we measured their activity and movement using 3-D infrared beam arrays in their cages. Whenever the mice moved through a beam, the machine would count it. The mice couldn’t see the beams, so it didn’t upset them as they moved around the cage.

We found that the activity levels were not different in the mice, even though the energy burned by mice born to diabetic mothers was lower. So, despite moving around the same amount, the mice with mothers that had diabetes burned fewer calories. This was the cause of their weight gain.

A small part of the brain called the hypothalamus puts together many of the signals from the body to control appetite, activity, body temperature and metabolic rate. We reasoned that it was likely that changes in the levels of important factors in the hypothalamus must cause the changes in metabolism that we were seeing.

We set up some new mice to breed, and studied the brains of offspring at 6 weeks of age before the onset of obesity. It was important to study the mice before they developed obesity so that we could know that any changes that we saw were not a response to obesity. If a change was in the brain before the mice became fat, then it was likely that it was causing obesity.

We looked at two of the major appetite and energy regulating proteins in the hypothalamus called NPY and POMC. NPY increases food intake and tends to cause obesity. POMC decreases food intake and tends to cause weight loss. In the β-ARNT offspring of diabetic pregnancy there was significantly more NPY and a trend to less POMC. Both of these changes indicate a tendency for weight gain.

What Was the “Causing Factor” in Mothers?
From a research point of view, all of this was really exciting to us; the offspring of mothers with diabetes get all of these effects, and it is due to decreased metabolic rate combined with insulin resistance and poor insulin secretion. The effects for most of the findings were much worse if the pups inherited the risk of diabetes (i.e. were β-ARNT mice rather than normal). This suggests that people are at even higher risk if they are exposed to diabetes in pregnancy and also inherit the susceptibility genes that led to their mother having diabetes in pregnancy in the first place.

But as endocrinologists we wondered whether we could extract any hints of clinically useful information. There has been quite heated debate for many years about which nutrient or nutrients in gestational diabetes are responsible for short-term and potentially long-term effects on offspring. Various researchers have suggested maternal glucose, weight, circulating triglycerides (fats related to cholesterol) and a number of other factors. We examined our data to see whether there were any correlations between the changes in the offspring and these factors in the mother.

Maternal glucose in pregnancy correlated very strongly with the outcomes for the pups – weight, fat mass, insulin resistance, hypothalamic NPY expression and others – but maternal weight and triglycerides did not correlate at all. This strongly suggests that, at least in our model, the prime driver of all of the changes is as straightforward as the mother’s glucose levels during pregnancy.

What Does it Mean for Women with Gestational Diabetes?
All women with Type 1 and most with Type 2 diabetes take insulin during pregnancy. But it is hard work for pregnant women to watch their diets, measure blood sugar levels and, for women with gestational diabetes, to take insulin.

The close correlations in our study give us extra hope that the better we can control blood sugar levels in pregnancy, the better the outcomes for the babies. And by giving women the hope that it may help to prevent their babies growing up to become fat kids and adults, and may decrease their children’s risk of diabetes, it may help to keep them motivated when the going is tough.

Jenny Gunton is a Senior Research Fellow with the Garvan Institute of Medical Research’s Diabetes and Transcription Factors Group.