Rare and atypical forms of diabetes are frequently misdiagnosed as type 1 or type 2 diabetes, or they are undiagnosed. Ashok Balasubramanyam, MD, professor of medicine in the Division of Endocrinology, Diabetes, and Metabolism at Baylor College of Medicine and a principal investigator for the NIDDK-supported study Rare and Atypical Diabetes Network, or RADIANT, talks about the complexities of diabetes and its rare and atypical forms. He also discusses early lessons from RADIANT and why learning about atypical diabetes is important to the future of precision testing, diagnosis, and treatment.

Q: How do you define rare and atypical diabetes? What role do genes play in these forms of diabetes?

A: First, rare disease in general is clearly defined by the Orphan Drug Act as a disease or condition that affects less than 200,000 people in the United States. Rare forms of diabetes include monogenic diabetes. This affects 1% to 2% of people with diabetes in European populations. People with monogenic diabetes have a single gene that seems to cause the diabetes. There are many monogenic forms of diabetes—currently, about 16 or 17 different forms. Each one is caused by a different single gene defect.

Atypical forms of diabetes are harder to define. Diabetes has gotten really complicated. We’ve had for a long time these imprecise categories of type 1 or type 2 diabetes, but neither one is clearly defined. If there’s a gray area around type 1 and an even bigger gray area around type 2, then where does atypical diabetes start? We are starting to think of diabetes as a spectrum that includes a large number of conditions, some known and many other “atypical” forms waiting to be identified. The only thing they have in common is high blood glucose, which causes chronic complications.

In the RADIANT trial, part of our goal is to define and better understand these rare and atypical forms of diabetes. If we can do this, we are in a much better position to refine treatment and improve the quality of life for our patients.

Q: Why should health care professionals understand these types of diabetes?

A: The history of medicine shows that we treat people better if we diagnose them better. And we diagnose people much better if we classify the disease better.

Let’s take the example of monogenic diabetes. Because these patients tend to be lean and develop diabetes at a relatively young age, health care professionals infer type 1 diabetes. So, they put the patients on insulin, but many of these patients don’t require insulin. They need a genetic test for monogenic diabetes. Through this genetic test, we can get a precise diagnosis. In many cases, if a diagnosis of monogenic diabetes is confirmed, the patient can stop insulin completely, switch to a sulfonylurea pill, and do great.

Another example is ketosis-prone diabetes (KPD), an atypical form of diabetes that is more common in Black, Hispanic, and Asian populations. Middle-aged or older adults with this form of diabetes may come into the emergency room with diabetic ketoacidosis (DKA). Up to that point, they never knew they had diabetes. We’ve always thought that DKA happens exclusively in people with type 1 diabetes, but these patients don’t look like they have type 1 because they are late onset, have overweight or obesity, and don’t have the antibodies or typical features of type 1 diabetes. Yet, they have a propensity to develop DKA. You can’t call them type 1 or type 2. They sit in their own category, KPD, which has several subtypes. Each subtype appears to have a different cause, including novel defects in protein metabolism.

One of the goals with RADIANT is education. How do we transform the practice of managing diabetes to include detecting atypical forms of diabetes, so that we can make the diagnosis more precise? The hope is that when health care professionals are educated about and attuned to these variations in the forms and causes of diabetes, they can make better management decisions for their patients.

Q: What forms of rare and atypical diabetes have researchers identified? How common are these forms of diabetes? Could there be others that we don’t know about?

A: The number of syndromes of monogenic diabetes is increasing. The number of people diagnosed with monogenic diabetes has also been increasing, with improved awareness of the need for genetic testing. Still, the thinking is that if you added up all the people with every kind of monogenic diabetes, this would probably account for about 1% of people with diabetes.

Other rare and atypical forms of diabetes include mitochondrial diabetes, Wolfram syndrome, and lipodystrophies. As the RADIANT study progresses, we will likely discover new monogenic forms of diabetes. We may also find oligogenic forms of diabetes, which involve two or three genes. In addition, we are finding that many patients with atypical diabetes cluster into groups with similar characteristics, even though the cause of the diabetes in each cluster may be complex.

Q: How can health care professionals recognize rare and atypical forms of diabetes in their patients? Are there tests they can use to diagnose these forms of diabetes?

A: Look for anything unusual in your patients. For example, why is your patient with apparent type 2 diabetes lean, or why does your patient with apparent type 1 have obesity? Is there a strong family history of diabetes with onset at a young age? If you see there is a family history, you should be much more alert to the possibility of monogenic diabetes. Clues that may indicate mitochondrial diabetes include deafness or some type of heart or muscle condition, along with high blood glucose.

Health care professionals don’t often test adult patients for islet antibodies or use the C-peptide test to measure how much insulin the body is producing. However, the results of these tests can really help in making treatment decisions.

In RADIANT, we’ve found that routinely applying these two tests to patients with atypical features is key. We find many adults who appear to have type 2 diabetes, but they have antibodies. We also find children who appear to have type 1 diabetes, but they don’t have the antibodies. Both are atypical, but you wouldn’t know unless you did the antibody and C-peptide tests.

In addition, health care professionals should understand the criteria for genetic testing in patients with clinical suspicion of monogenic diabetes. We shouldn’t use genetic tests indiscriminately, of course, because there’s a cost involved. But genetic tests are accurate and less expensive than in the past.

Q: How does a health care professional know when to order genetic testing?

A: Health care professionals can use prescreening questionnaires or algorithms to help make decisions about genetic testing. For example, they can ask some simple questions such as, did the diabetes begin before age 30? If yes, was the patient lean when diagnosed? If they were, you can test for antibodies. If there are no antibodies, then do the genetic test.

Some tools are available in publications and online. For example, we have the maturity-onset diabetes of the young (MODY) and diabetes subtypes calculator from the University of Exeter—a leader in MODY diagnosis. A health care professional inputs four or five pieces of information and gets a likelihood percentage. If the calculator says the likelihood of MODY is more than 50%, you should order the genetic test.

These predictive calculators are not perfect, but they are helpful. As we learn more in RADIANT, our goal is to develop an even better calculator. We will discover more genes and thus more atypical and rare forms of diabetes.

Q: How do we treat patients with rare and atypical forms of diabetes?

A: Right now, treatment options guided by a precise diagnosis of a rare or atypical form of diabetes are relatively limited. The diagnosis can influence a decision regarding the need for insulin therapy. Earlier I talked about patients who come into the emergency room with DKA. The textbooks tell you that if anyone has ever had DKA, they require lifelong insulin. But remember that these patients are ultimately diagnosed with an atypical form of diabetes called KPD. With some subtypes of KPD, you can have a single episode of DKA and then come off insulin without relapsing into DKA or prolonged hyperglycemia. Also, in two types of monogenic diabetes that we know of, you can take your patients off insulin and prescribe sulfonylureas, oral medications that may work better for them than insulin.

We’ve gone from having a few medications for type 2 diabetes to about a dozen. I’m sure we’re going to find subsets of people with atypical diabetes for whom specific glucose-lowering agents should be the first line of treatment, and others for whom the same medications might not work well. I think we don’t necessarily have to discover or design new medications, although that is also likely to be a useful downstream benefit of discoveries in RADIANT. We can find more precise uses for the medications and avoid the wrong treatments when we understand the disease process better.

Q: How might more precisely diagnosing different forms of diabetes help prevent and treat long-term health problems?

A: I’m going to use the example of type 2 diabetes. Everyone with type 2 diabetes gets a medication to prevent or slow kidney disease and everyone gets an eye exam. But we now know from preliminary studies with large populations that there may be as many as five or six different clusters of type 2 diabetes. Understanding these clusters, or the heterogeneity of type 2 diabetes, is important. The reason this matters is because it turns out that the consequences of retinopathy and neuropathy are more prevalent in one cluster than in the others. And the risk of chronic kidney disease and some aspects of cardiovascular disease are more prevalent in a different cluster.

So, if we have a patient with type 2 diabetes—even if they’re not atypical in the way I’ve described earlier—and we’re able to identify which cluster they belong to, we can focus our treatment and prevention plans to avoid specific long-term health problems. Right now, we treat everyone the same. This is an expensive and burdensome approach.

Q: What lessons are we learning, or hoping to learn, from research on rare and atypical forms of diabetes? How will the research affect how these forms of diabetes are diagnosed and managed?

A: The focus of RADIANT is to bring precision diagnosis and precision medicine to the field of diabetes. To do this, we’re identifying new forms of rare and atypical diabetes that have not been previously known. We’re using a very wide range of discovery tools, including whole-genome sequencing, metabolomics, RNA sequencing, and environmental questionnaires.

Many people who’ve applied to join the study have a known atypical form of monogenic diabetes, but no one ever ordered the genetic test, and they remained undiagnosed. So, we’ve helped those people by doing these tests and giving them a diagnosis, which they can take back to a health care professional for an appropriate treatment.

Educating health care professionals is a very important practical aspect of what we’re doing in RADIANT. This includes informing them about the value of antibody and C-peptide tests, screening algorithms and questionnaires, and access to genetic tests. We also are working to develop an app to diagnose atypical diabetes and refined calculators for conditions like monogenic diabetes and lipodystrophies. We want to be a valuable and cutting-edge source of information for practice today, not 10 years from now.

Have you seen patients who don’t fit the diagnostic criteria for type 1 or type 2 diabetes? Share below in the comments.