How many types of diabetes are there? Most people have heard of Type 1 and Type 2 diabetes, which together account for most cases and are caused by a complex interplay between genetic and environmental factors, such as obesity. However, a less common but significant number of patients has what is called monogenic diabetes. This relatively rare subset of diabetes is caused by a mutation of a single gene, and can be difficult to distinguish from the more common forms of diabetes.
The team of clinicians and researchers at the University of Chicago Medicine Comer Children’s Hospital and Kovler Diabetes Center are recognized as international experts on monogenic diabetes. They take great care to ensure that every patient receives an accurate diagnosis, since treatment and prognosis of each form of diabetes can be vastly different.
Working together with colleagues from around the world, the teams helped link more than 30 out of the roughly 25,000 genes in the human body to the many sub-types of monogenic diabetes. An error in any one of these genes can cause a child or adult to develop, and pass down, monogenic diabetes. A positive test in one patient should also prompt genetic testing in other family members with diabetes, since monogenic diabetes is commonly found in multiple generations.
“Genetic testing is essential for not only clinching a diagnosis but guiding treatment,” said Siri Greeley, MD, PhD, Associate Professor of Pediatrics and Medicine and Associate Director for Pediatrics at Kovler.
“The majority of patients with monogenic diabetes will never receive a correct diagnosis and unfortunately undergo unnecessary or inappropriate treatments as a result,” Greeley said. “For example, a child diagnosed at 12 years of age may have been assumed to have Type 1 diabetes because that is the most common type of diabetes in that age group. But even if the patient’s diabetes was eventually noted to be different than usual for Type 1 diabetes, it can be difficult and expensive to obtain the genetic testing needed to reveal the real cause of diabetes.”
A ‘go-to’ center for monogenic diabetes diagnosis and care
Greeley and his colleagues, including Louis Philipson, MD, PhD, Director of Kovler, have cemented UChicago Medicine as the “go-to” center for monogenic diabetes diagnosis and care in this country. Rochelle Naylor, MD, Assistant Professor of Pediatrics and Medicine, co-manages the NIH-funded Monogenic Diabetes Registry, which serves as an invaluable resource for patients, families, practitioners and researchers. The registry includes more than 3,000 participants from over 1,600 families across the U.S. and beyond.
“The data contributed by each participant in our registry is invaluable in building up aggregate information on these rare disorders,” Greeley said, “We can pass on this information to help improve the diagnosis and long-term management of similar individuals now and in the future, not just in Chicago but across the world.”
There are two main categories of monogenic diabetes. Neonatal or congenital diabetes occurs in the first six to 12 months of life, and affects about one in every 100,000 infants worldwide. Maturity Onset Diabetes of the Young, or MODY, describes a more common group of variations of monogenic diabetes. Together, these forms account for as much as 3% of diabetes diagnosed under 30 years of age and about 0.5% of all diabetes cases. No single feature can definitively identify patients with MODY, but it generally develops in patients who are under 30 years old and runs in families from one generation to the next.
Distinguishing an underlying monogenic cause is essential for appropriate treatment. For example, MODY2, or GCK-MODY, is caused by mutations in the glucokinase (GCK) gene and requires the beta cells in the pancreas to process a higher level of glucose before they start making insulin.
“Even though these patients have slightly higher levels of glucose,” Greeley said, “the research has made it clear that most GCK-MODY patients don’t need any treatment since the small increase in blood sugar levels is not associated with the same consequences associated with other forms of diabetes.” Studies also show that the mutation may be present in as many as one in 1,000 people, though it is often silent because these individuals do not develop any symptoms.
For patients with MODY3 and MODY1, mutations impair the development of beta cells and prevent them from producing sufficient insulin. These patients respond well to inexpensive generic oral sulfonylurea medications, as do infants with the most common cause of neonatal diabetes.
Raising awareness and improving care
Since relatively few clinicians are familiar with monogenic diabetes, patients are often misdiagnosed with Type 1 or Type 2 diabetes and treated with insulin injections or other treatments that may be unnecessary or less effective. Greeley says this is why it’s crucial to continue leveraging resources like the Monogenic Diabetes Registry and related multi-center studies being led by the Kovler team that are helping raise awareness and improve care for these patients.
“Monogenic diabetes represents a wonderful opportunity for implementation of precision medicine that allows treatment to be tailored to individual genetics,” he said. “Although many patients unfortunately have not yet been able to benefit from the knowledge we have been accumulating, we are helping to change that every day, one patient at a time.”
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