OKLAHOMA CITY — During the first 1,000 days — from the point of conception to a child’s second year of life — there are critical windows of development where metabolic conditions are established that affect a person’s health across the life span.

To better understand those influences, Jed Friedman, Ph.D., director of the OU Health Harold Hamm Diabetes Center and Chickasaw Professor of Physiology at the OU Health Sciences Center College of Medicine, is leading two studies funded by federal grants worth a combined $10 million. One grant focuses on how the diabetes drug metformin, used by millions of pregnant women, affects developing babies and their future risk for obesity, and the other seeks to understand how maternal obesity and a high-fat diet alter the development of a child’s immune system to be predisposed to obesity and diabetes.

“The first 1,000 days is one of our three pillars toward a cure for the diabetes epidemic in Oklahoma and beyond,” Friedman said. “The American Diabetes Association estimates that over 554,400 Oklahoma adults, representing 14.3% of the state’s population, have diabetes, and 1.1 million people, or 36.9%, have pre-diabetes. A mother who develops gestational diabetes (15% of pregnancies), for example, is two times more likely to have a child with obesity and diabetes, and she herself is likely to convert to Type 2 diabetes within seven years. In these studies, we are asking two important questions: Is metformin, when used to treat diabetes in pregnancy, helpful or harmful to infants at risk for obesity? And how does a mother’s obesity and diet impact the development of obesity and inflammation in her offspring?”

Metformin is prescribed to 50 million Americans and is in widespread use both in pre-pregnancy and during pregnancy. Because women with diabetes often give birth to newborns with excessive birth weight, metformin is frequently prescribed to lower the expectant mother’s blood sugar and slow the growth of the fetus, Friedman said. While metformin is beneficial in that regard, researchers lack understanding about the long-term safety of the drug in pregnancy.

“Our concern is that metformin on the maternal side crosses the placenta and creates an adult dose of the drug in a developing fetus,” he said. “The fetus is not accustomed to experiencing this drug at a high level, and it doesn’t have a way to clear it. Even though these babies are not overgrown when they are born, we have epidemiological evidence that, as teenagers, they start to develop obesity. We think that whatever sets that in motion probably occurs with their exposure to metformin. We just don’t know how or under what conditions that happens.”

Using an animal research model of mothers taking metformin, Friedman and his team will study the offspring at various stages. In the womb, fetuses will be examined to see what tissues metformin is targeting. In offspring that are several years old, researchers will look for early signs of obesity. The team at Harold Hamm Diabetes Center is part of a cadre of five academic health centers across the nation providing analysis.
In the second study, Friedman is investigating how a mother’s obesity and high-fat diet may change the way her offspring’s genes work in the stem cells that control immunity. His experiments center on the bone marrow, which is where the immune system originates in a stem cell and sets the stage for inflammatory cells going forward. His hypothesis is that a mother’s obesity and high-fat diet are changing the expression of the genes that control immunity and, therefore, inflammation in the future can be changed by improving the maternal diet.

“We know from prior epidemiological studies that maternal obesity begets obesity in the next generation. We’re not sure how that works on our genes, but believe it could start in the womb due to environmental exposures, including a mother’s diet,” he said. “We’re looking at how diet and obesity in mothers impact inflammation pathways in the offspring. Researchers haven’t always thought about why inflammation, from the time you are born, is playing a role in disease. One of my goals is to tease out, When does that start? Does it start in the bone marrow before you’re born? And how can we turn this down using nutritional or other interventions that protect the next generation? We’ll also find out what happens when mothers who are obese and on a high-fat diet are switched to a healthy diet for the next pregnancy. That will provide insight about how much offspring are affected by a mother’s diet vs. her obesity.”

Because 50% of pregnant women are now overweight or obese at the time of pregnancy, finding answers is becoming more important, Friedman said. “It’s a huge public health concern, as it predisposes the next generation to a risk for obesity and diabetes, thus completing a vicious cycle from mother to infant. It’s not feasible to ask women to lose weight during their pregnancy, but if we can make their diet healthier, or target the switch that causes immunological misfiring in obesity and diabetes in the next generation, we can turn it off. That’s the evidence we are searching for.”

Research reported in this news release is supported by the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health, under the award numbers 1R01DK128187-01A1 and 1R01DK128416-01A1.