about his frequent nighttime trips to the bathroom. The problem started seven years ago, around the time he was being treated for a prostate issue. Medication eased the problem, but not completely. Then in 2013, Cohen and his wife started dieting. His wife lost half a pound a week. Cohen’s weight dropped three pounds a week. After six weeks of dieting, Cohen, then age 61, had lost 25 pounds and was urinating constantly — six, seven, eight times per night — and was overly thirsty, as well. He went back to his internist. A finger prick and a blood test revealed that Cohen’s blood sugar levels were 408 mg/dl, more than four times normal levels. His A1C level, which measures the accumulation of blood glucose for the past two to three months, was 13.6, more than twice the normal level.
Cohen was diagnosed with type 2 diabetes, a condition marked by the body’s inability to use insulin, the hormone that helps our cells convert blood sugar into energy. Cohen met with a diabetes educator in his doctor’s office who adjusted the amount of carbohydrates in his diet, since carbohydrate-containing foods can raise blood glucose levels. He also started taking two oral medications, glimepiride and metformin. But the diet change and medications gave Cohen “industrial-grade diarrhea.” His blood glucose levels stayed dangerously high.
Week after week, nothing Cohen did — not taking the oral medications, nor changing his diet — got his blood sugar under control. A month later, the diabetes educator suspected that his initial diagnosis was incorrect, and Cohen actually had type 1, or insulin-dependent diabetes, which is most commonly diagnosed in children. In fact, a specialized blood test revealed that Cohen has what is called latent autoimmune diabetes of adults (LADA). Even though LADA is similar to the young-onset type 1 diabetes, doctors may not suspect that older adults such as Cohen would have the autoimmune diabetes. In addition, the adult version has its own distinct features, making this version of diabetes difficult to diagnose at first.
“I see patients like this all the time,” says Clay F. Semenko-vich, chief of the Division of Endocrinology, Metabolism, and Lipid Research at Washington University School of Medicine in St. Louis. Some members of the medical community have what Semenkovich calls “fixed, false beliefs that if you’re above age 30, you can’t get insulin-dependent diabetes. People can be treated with the wrong agents when they actually needed insulin, but because of a person’s age, physicians assumed patients could not have this type of diabetes.”
Now that Cohen is checking his blood sugar levels and injecting insulin several times a day, his blood sugar and A1C levels have returned to normal. Cohen’s experience also shows how complicated diabetes can be.
Diabetes mellitus can be traced back to Egyptian manuscripts from 1500 B.C. that record a condition describing too much urine, with a sweet or honey-like smell and taste. Diabetes is actually a series of metabolic disorders that reflect how the pancreas senses and reacts to glucose. As the food we eat is processed in the gut, beta cells, nestled in structures called islets in the pancreas, detect the amount of glucose from our meal. Ideally, beta cells churn out just enough insulin to help glucose get inside cells and work as an energy source. People with diabetes have high blood sugar, either because they can’t produce insulin at all or because they can’t use the insulin that’s produced, a condition known as insulin resistance. Although diabetes can’t be cured, the disease can be treated.
In the U.S., more than 29 million people have diabetes. Worldwide there are 382 million people with diabetes. In the U.S. alone, 1 in 3 adults is expected to have diabetes by the year 2050. Researchers have been working to identify the genes involved in diabetes and how best to personalize its treatment and management. Personalized medicine is starting to make advances into diabetes diagnosis and care, ranging from utilizing genetic testing to implementing mobile health technology that monitors a person’s specific blood sugar levels and dispenses medication accordingly (see “Blood Glucose in Real Time,” page 62).
Diabetes is divided into different groups. Type 1 diabetes is an autoimmune disease in which the body makes antibodies to the islets or to insulin, and this type of diabetes is most commonly diagnosed in children. Doctors diagnose type 1 diabetes with a blood test that detects certain antibodies. These antibodies act like friendly fire and destroy the beta cells. Without beta cells, the body can’t produce insulin. For now, the only way to treat the disease is to inject insulin. About 5 percent of Americans with diabetes have type 1. As Cohen learned, it’s marked by excessive thirst, excessive urination, and weight loss.
People with type 1 diabetes require insulin because there’s no perfect replacement to do the job of islet cells. They live in fear of dangerously low blood sugar. “A young person will take insulin, forget to eat, or vigorously exercise, and could have dangerous episodes of low blood sugar that could lead to seizures,” says Semenkovich.
A typical way for type 1 diabetes to be diagnosed is for patients to come into the emergency room with ketoacidosis, a condition marked by perilously low insulin levels, says Raghu G. Mirmira, director of the Center for Diabetes and Metabolic Diseases at Indiana University School of Medicine. Ketoacidosis is life-threatening, and these patients often go from the ER to intensive care units. Sometimes, the person is also sick with a viral or bacterial infection. Doctors don’t know what triggers type 1 diabetes, but most patients with this disease have genetic variants in the human leukocyte antigen (HLA) genes, which are immune genes that help the body distinguish its own cells from invaders. Some research is showing that our gut microbes may influence diabetes (see “Gut Reactions,” page 63).
Pregnant women can also get what’s called gestational diabetes, which can jeopardize both the mother’s and the baby’s health. The Centers for Disease Control and Prevention estimates that as many as 9.2 percent of pregnancies can result in gestational diabetes, and it can develop in women who have never had diabetes.
The type of diabetes with the strongest genetic connection is mature onset diabetes of the young (MODY). MODY is relatively rare, accounting for about 1 to 5 percent of diabetes cases in the U.S. Geneticists call it monogenic, because an inherited mutation in a single gene is sufficient to cause the disease. Most typically, people are diagnosed with MODY before age 25. MODY is marked by beta cells’ inability to sense glucose levels properly and secrete insulin at the right time.
With the availability of commercial genetic tests for MODY, doctors can more easily distinguish monogenic diabetes from type 2 diabetes and get people on the correct treatment. “It’s one of the best examples of personalized medicine there is,” says Mark McCarthy, a professor of diabetes at the University of Oxford in England.
There are commercially available genetic diagnostic panels to detect MODY, but not all physicians utilize them. People with MODY may not need any medication, but this condition is often misdiagnosed as type 1 diabetes and people are given lifelong insulin therapy, says Semenkovich. “You can make large differences in someone’s life by keeping them off insulin for 20 years if they don’t need it.”
The advent of next-generation sequencing is helping doctors bring a personalized medicine approach to MODY diagnosis at the University of Maryland School of Medicine in Baltimore. Toni Pollin and her colleagues at the university’s Program in Personalized and Genomic Medicine have recently implemented a survey for people diagnosed with diabetes that is designed to find and diagnose people with other forms of diabetes, such as MODY. Pollin would like to apply the same approach that genetic counselors use to identify patients at increased risk of cancers, so that she can identify patients at increased risk of diabetes. “It’s not always obvious which kind of diabetes someone has,” says Pollin. “We might be able to do more than say ‘your family history puts you at risk.’ ”
Pollin and her colleagues are using a seven-question survey to help patients get the correct diabetes diagnosis. Based on survey results, some people will have their DNA sequenced in a 40-gene panel, which includes genes that could be implicated in MODY, neonatal diabetes, and monogenic forms of obesity. If genetic variants that cause a specific form of diabetes are found, a physician will explain to the patient what the results mean for diagnosis, and the team will track how these results change provider behavior in diagnosis and treatment.
“If we can really figure out how we can apply these tools to a significant number of people with the monogenic forms of diabetes, we’ll take the fundamental first steps towards the goal of personalized medicine,” says Pollin.
For example, Pollin’s approach might help with the diagnosis of neonatal diabetes, a rare condition (estimated at 1 in 100,000 births), that is another monogenic form of diabetes. It is diagnosed in babies less than 6 months old and may be permanent or temporary. The health risks for neonates with the disease can include learning and developmental problems. As with other types of diabetes, doctors use the characteristic symptoms of excess urination and thirst for diagnosis. Although there have been single gene defects linked to this disease, the monogenic form of diabetes is not part of newborn screening tests conducted by states.
By far, the most common form of diabetes is type 2. People can have type 2 diabetes for many years without being aware of it. In this form of diabetes, beta cells in the pancreas produce insulin, but the body becomes insulin resistant and can’t use the hormone. Type 2 diabetes is strongly linked to metabolic syndrome, a condition marked by a group of “highs” — high blood sugar, high blood pressure, and high cholesterol levels, three problems most commonly found in men with too much abdominal fat. In fact, type 2 diabetes used to be referred to as “mature onset” or “adult diabetes” because the age at diagnosis was typically between 50 and 60. Although this still holds true, the problem of childhood obesity is now causing teens and younger kids to be diagnosed with type 2 diabetes.
Genes also influence type 2 diabetes but in a less direct way than with MODY. Type 2 diabetes results from a combination of genetics and environmental influences. If you have a family member with diabetes, you are more likely to get the disease; an unhealthy lifestyle — too much dietary fat and too little exercise — contributes as well.
The American Diabetes Association has an online questionnaire for type 2 diabetes that asks about age, weight, family history, and whether you’re physically active. Answers to the questionnaire can then be used to rank your risk of developing the disease from low to high. Jose Florez, an associate professor of medicine at Harvard Medical School, says that using such tools and including other risk factors, such as glucose levels and HDL cholesterol, can give you an accurate picture of whether you will develop diabetes over the next eight to nine years. For now, there’s no commercially available genetic test for type 2 diabetes because the genetics of type 2 diabetes are complex and the genes associated with this disease have little predictive power, says Florez. One of the best ways to find out if you are at risk of diabetes is family history, says Indiana’s Mirmira.
The health consequences of diabetes make this disease the seventh leading cause of death in the U.S. Diabetes can destroy eye tissue, nerves, kidneys, and the vascular system. “This is a disorder that’s going to bankrupt western society,” Semenkovich says. “It’s much more common than cancer or heart disease, and those are complications of diabetes as well.”
The good news is that lifestyle intervention does work to prevent type 2 diabetes. In 2002 the Diabetes Prevention Program research group (DPP) randomly assigned men and women in their 50s and 60s to groups that changed their lifestyles or groups that got medication only. Participants had high blood glucose levels but did not have diabetes. The lifestyle group limited daily caloric intake. They exercised 30 minutes, five days a week, and ate a heart-healthy diet, which limited fat to less than 25 percent of total calorie intake. During the first year, there was a 58 percent reduction in diabetes.
This regimen did better at reducing type 2 diabetes than medication alone. However even with these interventions, some participants still got diabetes. Because DPP included participants who were already at risk for diabetes, some may have already been on an irreversible path to the disease, notes the University of Oxford’s McCarthy.
So far, personalized medicine is still somewhat limited in improving the treatment of diabetes. People with type 1 diabetes need insulin. Currently, there are no genetic tests to help guide treatment to improve efficacy or reduce side effects of diabetes drugs. Nor can we match a gene variant with a specific treatment in much the way some cancers are treated today.
“Even with all that we know about the human genome, we haven’t come up with something that strongly correlates to responses to medication or treatment or risk of complications,” Mirmira says. “We are still very good at saying ‘if you have a strong family history of diabetes, you’ll likely get it,’ or ‘if you have a strong family history of kidney disease because of diabetes, that increases your risk of getting kidney disease if you have diabetes.’ Family history is a better genetic tool than sequencing the genome.”
Cohen does have a family history of the disease. His mother had classic type 2 diabetes that was diagnosed when she was in her early 70s. “My mother was obese throughout my childhood and engaged in no physical activity,” says Cohen. Thus, Cohen himself can understand why his diagnosis was initially made as type 2 diabetes, rather than LADA. “I am overweight and my activity level is nonexistent,” he says. “As a matter of fact, it might be in the negative range.”
Once it became clear that oral medications weren’t working for Cohen, and he was indeed diagnosed with the autoimmune, insulin-dependent LADA, he had to decide when to start insulin injections. The diabetes educator in his physician’s office suspected that Cohen’s pancreas either had already quit making insulin or was very close to failing. After talking it over with his wife, Cohen decided to start the injections. He learned how to count his carbohydrates, test his blood sugar, and calculate the proper dose of insulin to inject. He’s also stopped eating any food that quickly raises blood sugar, such as maple syrup and orange juice.
Today, diabetes care is fully integrated into Cohen’s daily routine. “As long as I do what I’m supposed to do, it’s not a huge imposition on my life,” he says.