Cambodia’s diabetes clinics are overflowing. On its surface, it looks like little more than another country’s growing pains as it rapidly industrializes, shifting from a lifestyle of hard labor and scant food to motorbikes and cheap snacks. But endocrinologist Lim Keuky, president of the Cambodian Diabetes Association, isn’t just seeing the typical sufferers of Type 2 diabetes: the middle aged and overweight. Instead, a startling number of Keuky’s patients are in their early 30s, with relatively normal weights. Like so much of modern Cambodia, these individuals appear to be haunted by their past.
The brutal Khmer Rouge regime has left physical and mental scars across Cambodia. During the regime’s time in power from 1975 to 1979, more than 1.5 million people perished out of the country’s 7 million. Many were executed and left in mass graves, hundreds of thousands of which still dot the countryside. Many more died of starvation and disease.
“If you want to maintain your power, the best way is to keep the people hungry,” Keuky said.
The scars of this famine can still be seen today, especially in Keuky’s diabetes clinics. Keuky believes that this famine has etched itself into the DNA of the Cambodians conceived and born during this time, leaving them profoundly vulnerable to obesity, heart disease, high blood pressure, and diabetes.
By the time the famine finally ended in May 1945, the residents of Amsterdam were surviving on a little more than 500 calories per day.
“It’s become clear that malnutrition while your mother is pregnant can affect your health later in life,” said Robert Lane, a pediatrician and expert in epigenetics at the Medical College of Wisconsin.
Every species has learned to cope with food shortages. Millions of years of evolution have equipped human bodies with the ability to adapt to starvation. Increased thoughts about food encourage us to look harder to find something to eat. As time passes, the body begins to conserve its resources, lowering its heart rate and blood pressure, even as it cannibalizes its own muscle, fat, and internal organs for fuel. Deficiencies in vital nutrients cause skin to dry, lips to crack, and hair to fall out. The body’s ability to adapt to this long-term food scarcity requires that some genes be switched on and others turned off.
This process, known as epigenetics, involves the addition of small chemical tags known as methyl groups to the DNA double helix. The addition of methyl groups can switch a gene off, either by physically impeding gene transcription machinery or by burying the gene deep in the chromosome, where the transcription machinery can’t find it. Whereas some epigenetic changes are temporary, others can be permanent, and even passed on to the next generation.
Despite the physical and mental insults of starvation, some women can still become pregnant and carry a child to term, even during extreme famine. Survival during times of starvation requires a person to conserve as much energy as possible, and if the mother is facing profound food shortages, it was historically likely that the child would, too. By epigenetically changing which genes are turned on and off, a person could make their metabolism as efficient as possible and maximize his or her chances of survival when food is scarce.
“As mammals, we try to anticipate our environment. The problems tend to occur when you program yourself for an environment that no longer exists,” Lane said, such as children who were conceived in famine and now live in a world where calorie-dense food is available 24/7.
When many adults died in their 20s and 30s, an increased risk of diabetes later in life was irrelevant. Until recently, an over-abundance of food was not a problem many people struggled with. So the advantages of being able to extract and store the most energy out of the minimum of calories far outweighed any risks. All of that began to change after World War II.
In the winter of 1944-45, the Netherlands were struggling to free itself from the grip of Nazi Germany. At an impasse with Allied troops, the Germans blockaded all food entering the Netherlands, and the country plunged into starvation during one of the coldest winters on record. By the time the famine finally ended in May 1945, the residents of Amsterdam were surviving on a little more than 500 calories per day, and more than 20,000 had died of malnutrition.
The well-defined start and end dates of the Dutch Hunger Winter, along with the country’s well-organized medical records, made it ideal to study the long-term effects of famine. Starting in the 1990s, scientists began studying those individuals who were in utero during the Hunger Winter. The first study, published in The Lancet in 1998, found that these individuals had significantly higher than expected levels of blood glucose, a precursor to diabetes. Further studies found that these individuals had higher BMIs and were more likely to develop coronary heart disease. Each of these studies found that exposure to starvation during the first trimester of pregnancy appeared to do the most harm.
“The impact of over-nutrition appears to be greater on people who had poor nutrition in utero, perhaps because their genes were programmed to prepare for a poor food environment later in life,” said Lambert Lumey, an epidemiologist at Columbia University who has studied the Dutch Hunger Winter for much of his career.
Nor is it calorie deprivation alone that can harm the developing fetus. A study published last week in Nature Communications led by Andrew Prentice, a nutritionist at the London School of Hygiene and Tropical Medicine, and colleagues looked at the epigenetic effects of seasonal variations in nutrition in a village in rural Gambia. During the plentiful dry season, women consumed more calories and more energy-rich lipids. In the lean rainy season, the women switched out meat and oily sauces for vegetables.
Prentice was expecting that babies who were conceived at the height of the dry season would carry the epigenetic signs of being at greater risk for diseases like heart disease and diabetes. Instead, he found the exact opposite. Methyl groups are synthesized from vitamins like folate, riboflavin, B6, and B12, so without enough vitamins, genes can’t be turned on and off properly.
“During the dry season, women ate more green leafy vegetables,” Prentice said. “In this case, famine wasn’t only about energy, it was also about micronutrients.”
The researchers were also able to show that it was the mother’s diet at or immediately before conception that led to these epigenetic changes. Prentice and colleagues focused on six genes that were known to have methyl groups added during the last day or two of ovum development to within the first 48 hours after conception. They found that the number of methyl groups added to these genes were higher in all six genes in the children who were conceived during the rainy season, and corresponded to nutrient levels in their mothers during pregnancy.
“This is why this study is so important—it nails these effects [on DNA methylation] to the very early days after conception. So now we can say that these very early changes in nutrition affect the methylation of the babies,” said Prentice.
Indeed, many of the individuals in Cambodia that have recently developed diabetes and cardiovascular diseases are in their mid-30s, and were conceived during the famine brought about by the Khmer Rouge. Many of these adults are now having children of their own, and Keuky is interested in how their grandmothers’ starvation may have affected this newest generation.
Scientists warn against taking an overly fatalistic approach to these studies, however. Maternal nutrition definitely plays a role in the health, they say, but it’s not the only factor.
“You can’t say that you have high blood pressure because of a famine,” Lumey says.
Although recognizing the potential sources of the diabetes epidemic is helpful, Keuky needs blood sugar meters and test strips to screen people for diabetes. He would like to screen 100,000 Cambodians by 2016.
“People are waiting too long for diagnosis. By the time somewhat starts to show symptoms of diabetes, they are very close to developing complications,” Keuky said.
He also needs money and resources to help treat existing patients. Members of Parliament in Cambodia don’t think about spending $5 for a cup of coffee, an amount of money that would pay for Keuky’s services for one month for a Cambodian.
“The international community calls me a barefoot soldier in the fight against diabetes,” Keuky said. “I don’t mind being barefoot, but how can I fight when no one will give me any bullets?”