An interview with Dr. Toni Pollin
Jeanette McCarthy, MPH, PhD
Diabetes is a chronic condition characterized by elevated levels of blood glucose and the inability to properly process food for use as energy. Diabetes is a heterogeneous disease, with several different types and a mostly complex genetic etiology.
Up to 4% of cases of diabetes are Mendelian (monogenic), where a mutation in a single gene is sufficient to cause disease. These Mendelian subtypes include neonatal diabetes, maturity-onset diabetes of the young (MODY), and syndromic forms. Genetics also plays a role in Type 1 and 2 diabetes, the most common types of diabetes, but the etiology is polygenic, with variants in dozens of genes, each with a small effect, collectively increasing a person’s risk of disease.
Genetic testing in diabetes is important because it’s estimated that 80% of patients with MODY are misdiagnosed as having Type 1 or 2 diabetes and would benefit from alternative treatments.
We sat down with Dr. Toni Pollin, an Associate Professor of Medicine and Epidemiology & Public Health from the University of Maryland School of Medicine to ask her about the benefits of genetic testing in diabetes patients.
How do MODY, Type 1 and Type 2 diabetes differ clinically?
Type 1 diabetes generally results from an auto-immune destruction of the pancreatic beta cells, which produce insulin, and usually but not always has an acute onset in young people, and requires treatment with insulin.
Type 2 diabetes is a heterogeneous group of disorders in which there is a combination of insulin resistance, or difficulty responding to insulin, and/or inadequate insulin secretion. Type 2 diabetes usually, but not always, has onset in adulthood, and is more likely in the setting of obesity and/or a sedentary lifestyle.
MODY, which stands for maturity onset diabetes of the young, was first recognized in the 1960s when it was observed that some young people had diabetes that looked like type 2 diabetes, then called maturity onset diabetes, instead of the type 1 diabetes (then called juvenile diabetes) more typical of children. These young people did not have any risk factors for type 2 diabetes, such as obesity, and some could be treated with oral medication instead of insulin. Some did not require any treatment at all to keep the hyperglycemia from progressing and causing complications. They also had a very strong dominant pattern of inheritance.
The most obvious cases of MODY are individuals who are young and lean yet have a non-insulin requiring type of diabetes. However, there is a lot of clinical overlap; for example, in a recent study (Treatment Options for Type 2 Diabetes in Adolescents and Youth, TODAY) we found through genetic testing that at least 4.5% of overweight and obese children and adolescents diagnosed with type 2 diabetes actually had MODY.
Are there clinically valid genetic tests for the different types of diabetes?
Yes, monogenic diabetes can be diagnosed and distinguished from type 1 and type 2 by sequencing the genes involved to see if there is a causal mutation. The most common genes are HNF1A, HNF4A, and GCK for MODY, and KCNJ11, ABCC8, and INS for neonatal diabetes (but also dozens of other genes implicated in a few cases each of MODY, neonatal diabetes, or syndromic diabetes). These tests are available from several academic and commercial laboratories for ordering by a health care provider.
What is the benefit of genetic testing for diabetes?
There are several benefits. Overall, it can mean less invasive and/or more effective treatment. A diagnosis of HNF4A- or HNF1A-diabetes (also called MODY1 and MODY3) indicates that the most effective treatment, especially early in the disease course, is likely to be low dose sulfonylurea pills. This treatment promotes insulin secretion rather than the insulin injections used to treat type 1, or the metformin (which promotes insulin sensitivity) usually tried first for type 2 diabetes.
A diagnosis of GCK-diabetes (also called MODY2), which causes stable mild hyperglycemia, usually indicates that no treatment is needed because this mild hyperglycemia is generally not associated with the complications seen in other types of diabetes.
A diagnosis of potassium channel diabetes, caused by mutations in KCNJ11 or ABCC8, usually allows patients to transition from insulin injections to high dose sulfonylurea pills, often with improvements in glucose control.
A positive result for any form of monogenic diabetes makes it easier to correctly diagnose and accurately predict risk of diabetes in relatives.
Who would you recommend have genetic testing for diabetes?
There are a variety of indications discussed in recent guidelines including:
Diabetes diagnosed in infancy;
Apparent type 2 diabetes diagnosed by age 30 and/or not having typical risk factors;
Type 1 diabetes without diabetes auto-antibodies, especially in a parent and child;
Lean women who develop gestational diabetes with high fasting glucose;
Diabetes accompanied by other non-pancreatic features suggestive of a syndrome;
Other atypical situations described in the resources below
What’s the most important thing to consider when selecting a genetic test/lab for MODY?
Whether the lab will test for genes likely to be implicated in the particular case and the experience the lab has with evaluating these genes. Inclusion of a representative(s) on the NICHD/ClinGen Monogenic Diabetes Expert Panel indicates that the laboratory is working with experts in monogenic diabetes to share data and expertise for the most accurate variant classification and therefore diagnosis possible.
Are there any clinical trials you are aware of to develop treatments based on a person’s genetic profile?
There are a number of studies to understand differences in response in people with type 2 diabetes to older (e.g., metformin, sulfonylureas) and newer (e.g., SGLT2-inhibitors, DPP4-inhibitors) pharmaceutical agents based on common genetic variants, which can be found in Clinicaltrials.gov.
In monogenic diabetes, the focus right now is to identify the individuals who have monogenic diabetes and could benefit from known customizations of treatments. Recent studies suggest that monogenic diabetes is only correctly diagnosed about 5% of the time. Once we do a better job identifying these individuals, it will likely be possible to conduct clinical trials for approaches to improving the health and quality of life of these individuals even more.
There is also a new initiative funded by NIDDK called RADIANT (Rare and Atypical DIAbetes NeTwork) to better understand the causes of unusual types of diabetes and what they can teach us about understanding all diabetes.
Where can health care providers learn more about genetic testing for diabetes?
A clinical practice recommendation position statement from the American Diabetes Association.
Diabetesgenes.org, from the University of Exeter, aims to provide information for patients and professionals on genetic types of diabetes. It includes details of research, clinical care and educational opportunities along with information to aid differential diagnosis of diabetes to ensure correct diagnosis and treatment of these genetic subtypes.
GeneReviews: Maturity-Onset Diabetes of the Young Overview
The purpose of this overview is to increase the awareness of clinicians regarding maturity-onset diabetes of the young (MODY) and its genetic causes and management.
Paper by Stein, Maloney and Pollin. Genetic counselors and clinical geneticists are in a prime position to identify monogenic cases through targeted questions during a family history combined with working in conjunction with diabetes professionals to diagnose and assure proper treatment and familial risk assessment for individuals with monogenic diabetes.
More about Dr. Pollin
Dr. Toni Pollin is an Associate Professor of Medicine and Epidemiology & Public Health from the University of Maryland School of Medicine. She has a PhD in human genetics and is also a board-certified genetic counselor. Her research focuses on identifying genes that influence risk of type 2 diabetes, related diseases, and responses to treatment by studying various populations, from the Old Order Amish to multi-ethnic national and international populations. She is studying how some of those genes affect the body, such as the APOC3 gene, in which her group discovered a variant that lowers triglyceride levels and protects against heart disease. She also works to ensure that people have access to the medical benefits of genomic knowledge, particularly with respect to monogenic diabetes.
Learn about Dr. Pollin’s Monogenic Diabetes Research and Advocacy Project (MDRAP).