Distinguishing Monogenic Diabetes from Polygenic Disease Improves Patient Outcomes
Diabetes develops when the body cannot control the level of sugar circulating in the blood. Type 1 diabetes (T1D), sometimes referred to as autoimmune diabetes, develops as a result of multiple factors, including genetic changes at multiple points in the genome (polygenic variations). People with this form of diabetes have a higher likelihood of other autoimmune diseases including Hashimoto’s disease and celiac disease.
A different and rarer form of autoimmune diabetes, referred to as autoimmune diabetes with a monogenic cause, originates from a single, usually inherited genetic mutation, and is accompanied by a different pattern of related conditions. The distinction between the two causes is key, says Columbia pediatric endocrinology fellow, Virginia Rahming, MD, because unlike polygenic autoimmune diabetes, monogenic causes may be treated with different existing, targeted therapies. Recent reports have shown that treating T1D soon after diagnosis with a therapy that is tailored specifically for the genetic cause can actually reverse the T1D and the need for insulin.
Dr. Rahming has teamed up with Joshua Milner, MD, chief of pediatric allergy, immunology, and rheumatology, in a research project designed to determine the prevalence of autoimmune diabetes with a monogenic cause and the factors that can identify those most likely to have it. This information will enable doctors to diagnose the condition more accurately and earlier in life.
The research team uses family history as a central part of the study to reveal a pattern of disease among the patient’s relatives. Symptoms and disorders they look for include significant atopic disease, conditions in which the body has allergic responses to even low levels of environmental triggers. Such conditions include elevated IgE levels, severe environmental or food allergies, eosinophilic esophagitis, severe eczema, chronic unexplained hives, and others. They also look for other types of significant autoimmune disease such as alopecia, psoriasis, rheumatoid arthritis, juvenile idiopathic arthritis, autoimmune hepatitis, and lupus, to name a few. The researchers also look for severe or recurrent viral, bacterial, or fungal infections, unexplained fevers, or low blood cell counts. “When patients have conditions like these, our suspicions are raised,” says Dr. Rahming, “and we want to find out more.
“We didn't realize how many patients within the large population treated at Columbia’s Naomi Berrie Diabetes Center fit the study criteria until we really started looking for them,” she adds. “Often, when a patient has multiple symptoms that require different types of doctors, it doesn’t become as clear that they might all have a single cause. I believe that more patients may have a monogenic cause of their autoimmune diabetes than the very small percentage we originally thought.”
Once patients enroll in the study, they and additional family members—preferably one or both parents—undergo genetic sequencing (whole exome sequencing). Among those sequenced to date, the researchers have identified several patients with mutations in genes that play critical roles in orchestrating the immune system. Targeted therapies are also in development and/or already FDA-approved for diseases related to mutations in some of these genes.
As Dr. Rahming and others learn more about the underlying causes of different types of diabetes, they hope to alter the future for those with diabetes. “Our whole team is hopeful that we won’t need to have big careers in diabetes, and that we’ll be able to help these patients,” she says. “If I can improve diabetes in even a few patients, or prevent them from developing other immune symptoms that can occur later in life, that would be a success.”
