Diabetes Forecast

Genetics, Environment, Lifestyle: Triple Diabetes Threat

See how these factors join together to up your risk for diabetes

By Andrew Curry , ,


Nature, or nurture? When it comes to diabetes, it’s a little bit of both. The genes you inherit from your parents can increase the chance that your body will develop the symptoms of diabetes, namely, the inability to produce enough insulin to move glucose from your bloodstream to fuel your cells, the ability of your cells to respond to insulin, or both.

But genes are only a part of the equation. For most people, environmental factors—from the food they eat to the microbes they’re exposed to—play a much more significant role. That’s certainly the case for type 1, a disease where genetics accounts for up to half of the total risk.

When it comes to type 2 diabetes, tremendous advances in genetics research in the past few decades haven’t uncovered a single “diabetes gene.” Instead, they’ve found dozens, each representing a tiny increase in your overall risk for diabetes.

Yet as the costs of analyzing human DNA drop, researchers are discovering that other kinds of diabetes, such as monogenic (see “All in the Genes,” below) and gestational, can run in families. At the same time, they’re developing new approaches to predicting and treating the disease.

Type 2

Family Ties

Looking back, Keshia Cooper, 39, says she probably should have known type 2 was something to worry about. Her grandmother died of the disease, after losing five fingers and both of her legs to complications. And her mother was diagnosed with type 2 in 1989.

Cooper’s turn came in 2008, when she was diagnosed with type 2 and prescribed metformin after years of overeating and not exercising enough. “I guess I kind of hoped it wouldn’t happen to me,” says Cooper. “I really wasn’t expecting it.”

Cooper’s diagnosis makes her worry for her sons, one of whom is overweight at 14. “I try to be an example when it comes to what we eat,” Cooper says. “I tell him he doesn’t want to end up like me. But it’s tricky.”

Cooper’s story isn’t unusual. Many people with type 2 have family members with the disease, and in the past few decades type 2 diagnoses have skyrocketed around the world. In the United States, type 2 diabetes cases have increased by more than a third in the past 20 years. Nearly 28 million Americans live with the disease today, and experts estimate one in three Americans living today will have type 2 at some point in their lives.

Experts say that while genetics plays a big role in type 2 diabetes, the increase in the number of cases has little to do with heredity. On an evolutionary time scale, the past few decades are barely the blink of an eye. “This epidemic isn’t caused by genes,” says Jose Florez, MD, PhD, a researcher at the Broad Institute and Harvard Medical School and chief of the diabetes unit at Massachusetts General Hospital. “Genes don’t change that fast.”

Homegrown Diabetes

The growth of type 2 cases has to do with the interaction between our genes, the world we live in, and the choices we make. One way to think of the genetic risk for type 2 might be as a seed. A seed by itself won’t grow into a tree. But take that seed, put it in a pot of soil, and add water and sunlight, and it stands a good chance of flourishing.

The modern environment is a lot like that sun-drenched pot of soil, with an ample application of Miracle-Gro mixed in. And the genetic factors that put some people at greater risk for type 2 are the seed—full of dangerous potential but usually harmless unless you add excess calories and lack of exercise.

Seen from that perspective, the type 2 diabetes epidemic makes far more sense. For countless generations, people have been carrying the seeds of type 2 around unnoticed and unrealized. It took our modern lifestyle, heavy on calories and light on exercise, to fertilize and water them. “Everyone placed in our contemporary environment, with high-calorie, nutritionally poor food and a sedentary lifestyle, is more vulnerable,” says Florez. “Genetics just makes some more vulnerable than others.”

Much of the work on the genetics of type 2 has focused on figuring out why some people are more at risk than others. So far, there are about 80 known genes that can put you at greater risk for type 2 diabetes—although some people with no particular genetic risk factors still get diabetes, just as people with higher risk factors often don’t have diabetes.

Some genes make people a little less sensitive to insulin. Some interfere with the body’s ability to make insulin. Others make people more likely to be overweight or obese, both risk factors for type 2. “It’s possible there are so many variants that have a small effect that you’d need to track 500 variants to account for heritability,” says National Institute of Health researcher Clifton Bogardus, MD.

These genes have been discovered mostly thanks to advances in gene sequencing technology in the last decade. As scanning the human genome gets cheaper, researchers are able to analyze hundreds of thousands of people for tiny genetic differences and then compare what they find with diabetes rates. Certain differences line up with higher or lower risk, telling scientists there’s probably a connection. “These big coalitions have worked together to amass huge numbers of cases to see which variants are more common,” says Bogardus.

Unequal Risk

It also seems as though different ethnic groups might have different genetic patterns. Scientists, including Bogardus, are studying the Gila River Indian Community, a Pima tribe in Arizona with the highest rates of type 2 diabetes in the world. Nearly three-quarters of the Pima have diabetes at some point in their lives, and researchers have been collaborating with the tribe for decades to understand why.

Bogardus hoped analyzing the Pima’s DNA—a project partially supported by the American Diabetes Association—would reveal a genetic signature for type 2 that could be applied more broadly. “There were two possibilities,” he says. “Either we’d discover something that’s entirely different, or something that’s common in other populations.”

Their most recent results, published last year in the journal Diabetes, suggest that the Pima carry genes that set them apart from the Caucasians represented in most such studies. One gene mutation the genetics team identified, for example, causes an overproduction of insulin early in life, leading to lows, but later in life increases the risk of diabetes significantly. The mutation is found in 1 in 100,000 people worldwide—but in the Pima, the rate is 1 in 33. “Pimas have a gigantically high risk for this,” Bogardus says.

Another gene his team identified seems to increase risk in the Pima, but the same gene doesn’t play much of a role in Caucasian populations. “It looks like there are things specific to the Pima that don’t exist in Caucasians,” he says. “That means this genetic work has to be done separately in isolated populations with these severe health problems.”

Future Applications

Even if researchers could identify all of the genes that increase diabetes risk, it’s not clear that the information would be all that helpful in terms of predicting who will get type 2 diabetes. Mark McCarthy, MB, BS, a geneticist at the University of Oxford in England, says we already have a pretty good set of indicators. “Family history, BMI [body mass index], and ethnicity are all much stronger predictors right now,” he says. “There are many different things that impinge on individual risk, and the prediction we get from genes is not that strong.” (Ethnicity isn’t the same as genetics, McCarthy points out: Ethnic groups sometimes share genes, but also share cultural norms, favorite foods, and other factors that go above and beyond genetics.)

If doctors already have effective ways to predict who’s at higher risk for type 2, why sink more money and time into genetic research? McCarthy says knowing more about genetics will help researchers slice and dice an incredibly complex disease. Because there are so many pathways, researchers say it’s more accurate to think of type 2 as hundreds of different diseases, all with the same symptoms.

One potential benefit of genetics research might be to narrow down the pool of people being prescribed diabetes drugs. “The drug industry is having a really tough time. So many of the drugs they develop don’t work in humans or have really nasty side effects,” McCarthy says. “Genetics can guide pharma to places they should be intervening and where they’re more effective.”

Take metformin, one of the most common drugs prescribed to people with type 2. It’s usually highly effective. Except that in a minority of patients it just doesn’t work. And in others it causes side effects, such as severe diarrhea. If DNA could predict who will benefit from drugs like metformin and who won’t, patients would get the right drugs faster.

In the meantime, doctors say people with a family history of type 2 should be even more conscious of maintaining a healthy diet and exercising regularly. “You’re not doomed based on the bad deck of cards you inherited from your parents. We know you can do something about it: Lifestyle can trump your genes,” Florez says. That’s a comforting thought for people who already have diabetes but worry about their family members’ or children’s risk.

Type 1

Family Tree

Adam Jensen was 27 when his doctor told him he had type 1 diabetes. The diagnosis came as a shock: He was an active adult and had no family history of the disease. “I always thought people with diabetes were overweight, inactive, older,” he says. “I was totally surprised.”

A few months after Jensen’s 2011 diagnosis came more bad news: His 3-year-old son, Max, had type 1 as well. Jensen and his wife, Kara, went to a specialist in Utah, where they live, who assured them the chances of another child having type 1 were less than 5 percent. Fast-forward to August 2015, nine months after the Jensens’ third son, Finn, was born, and they were back at the doctor, who gave them more bad news. Finn, too, had type 1.

It’s made them think twice about having a fourth child. “When I was first diagnosed, I felt like my world was turned upside down,” Jensen says. “My wife’s not sure she wants to put another kid through it.”

Clustered cases like Adam, Max, and Finn are rare. Most type 1 cases seem to occur in isolation. “Only 10 percent of patients have a family history. Type 1 tends to come out of the blue,” says Janelle Noble, PhD, a geneticist at Children’s Hospital Oakland Research Institute. “People don’t expect it, and parents are blindsided—there’s no family history, and all of a sudden their child has a life-threatening chronic disease with no known cure.”

Scientists are increasingly realizing that genes play an outsized role. Take, for instance, the distribution of type 1 diabetes in populations around the world. If type 1 diabetes were truly a random phenomenon, it would be equally distributed: Someone in China would have the same odds as someone in Finland or the United States.

But while type 1 diabetes rates have been climbing worldwide, they’re uneven. If you’re Chinese, for example, your risk for type 1 is one in a million. Finland, on the other hand, has the highest rates of type 1 in the world: For every 100,000 Finns, about 60 people have type 1. (In the United States, the rate is about 23 cases per 100,000 people.) That suggests there must be something in the genetic makeup of different ethnic groups that either protects them from type 1 or puts them at higher risk.

Still stronger evidence comes from studies of identical twins. Identical, or monozygotic, twins share all of their DNA. It stands to reason that if type 1 were purely genetic, identical twins would always share diabetes, or at least develop it at the same time. But they don’t—sometimes one twin will have type 1 while the other is spared, a big clue that more than genes are at play.

Joined Forces

So what explains cases like the Jensens’? Blame it on HLA genes. Unlike type 2, where dozens of different genes can all make small contributions to increased diabetes risk, in type 1 a dozen specific genes play a huge role. Together, these genes make proteins called human leukocyte antigens, or HLA. Each of these genes can have thousands of more than 13,000 possible variants, and some of these variants can have a profound effect in raising or lowering the risk for type 1 diabetes, whether there’s a family connection or not. It makes sense that these genes, which help regulate the immune system, would be involved in type 1, a condition in which the immune system reacts against and destroys insulin-producing pancreatic beta cells.

Noble has spent most of her career trying to untangle HLA. Calling it a gene does its complexity a disservice. HLA, which was first identified almost 40 years ago, is far more complex than a simple on-off switch. It has thousands of possible variations that can raise or lower the odds of type 1.

To put it in perspective, Noble compares variations of HLA genes to frozen desserts: Ice cream, sorbet, and frozen yogurt are all cold, and each can come in many flavors. Altogether there are 13,000 possibilities—and everyone has two “scoops,” one from their father and one from their mother. “Your diabetes risk has a lot to do with which two flavors out of those 13,000 you have in this particular gene,” Noble says.

Some HLA “flavors” protect you from diabetes, and others put you at higher risk. Some ethnic groups have more protective flavors. That helps explain why type 1 diabetes is relatively rare in some populations and more common in others.

It’s possible to test for risk factors that are strong, and several research groups are trying to do just that. When Begoña Lozano’s son, Max, was diagnosed with type 1 at the age of 15, she worried that his younger sister might be at risk, too. The Burlingame, California, intercultural trainer enrolled both kids in the University of California–San Francisco arm of a global study called TrialNet (“Predictive Testing,” below).

TrialNet is one of several programs around the country searching for the small percentage of people with a family history of type 1 diabetes. By closely following people at high genetic risk before and after their diagnoses, they’re hoping to find ways to predict who will get type 1. (Lozano’s daughter, recent tests showed, doesn’t have the “flavors” of HLA genes that would put her at a particularly elevated risk.)

The next step would be to find ways to catch and halt type 1 in the earliest stages, before the immune system has destroyed the body’s insulin-producing beta cells. “The Holy Grail is stopping it before it starts,” says Noble. Genetic testing can help researchers find high-risk candidates for new treatments.

For Adam Jensen and two of his three sons, it’s too late. But Jensen says he hasn’t let that stop him. He recently finished a half marathon and says he’s become a pro at the daily regimen of insulin injections and blood tests needed to keep him and his sons healthy. “I tell my oldest kid that with diabetes you can still do anything,” he says. “Even if the genetic deck’s stacked against you.”

All in the Genes

In some rare cases, diabetes can be purely genetic. When a single mutation causes insulin resistance or makes the body stop producing enough insulin, researchers call it monogenic diabetes. Examples include neonatal diabetes and maturity onset diabetes of the young, or MODY.

Monogenic diabetes has been connected to mutations in about 20 genes; a mutation in any of them can cause a child or adult to develop diabetes. Because genetic mutations can be passed down to children or run in families, if doctors suspect a patient’s diabetes is monogenic they may recommend genetic testing to better evaluate the risks. One sign of MODY, for example, is three or more generations of people with diabetes in a given family.

Predictive Testing

National Institutes of Health–sponsored TrialNet is a network of some 150 medical centers, doctors’ offices, and organizations—including the American Diabetes Association—that support the screening of people who might be at risk for type 1 diabetes. Using blood tests and other measurements (such as oral glucose tolerance tests), they look for signs that the immune system is beginning to react against the beta cells that produce insulin. The goal is to find people about to develop type 1 and test new therapies that might slow or halt the disease’s appearance. Learn more at trialnet.org or by calling 1-800-888-4187.



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