Raghu G. Mirmira, MD, PhD

The incidence and prevalence of diabetes is rising worldwide. The International Diabetes Federation estimates that the world population with diabetes is around 463 million.¹ Although individuals with type 1 or type 2 diabetes represent the largest percentage of this population, it is becoming increasingly clear that some of these individuals are miscategorised and may have other distinct forms of diabetes whose aetiologies could alter risk of complications and approach to treatment. 

Monogenic forms of diabetes, often referred to as maturity-onset diabetes of the young (MODY), are uncommon – but not as rare as once thought. Some estimates suggest that MODY represents approximately 2.5% of all forms of diabetes in youth,² but because these data come from analysis of Caucasian European populations, this prevalence may be an underestimate. The majority of genes shown to be mutated in MODY affect – at one level or another – the development and/or function of β cells. As such, a major goal of therapy for most patients with MODY is the augmentation of β cell function utilising agents such as sulfonylureas, meglitinides, and GLP-1 receptor agonists. In the case of Glucokinase (GCK)-MODY – one of the two most common forms³ – no treatment is required unless pregnancy intervenes. These approaches differ substantially from first-line therapeutic approaches for traditional forms of diabetes, which include insulin or metformin. 

The Approach to the Patient article by Broome et al. discusses a practical approach to identifying and treating patients with MODY. The authors emphasise features that should trigger consideration of MODY, including onset of disease at a young age (before the age of 35 years, but classically before the age of 25), a history of multiple family members (particularly parents) with diabetes and clinical characteristics atypical of type 1 or type 2 diabetes, and/or extra-pancreatic features (e.g., kidney, liver, gastrointestinal). These features in combination increase the likelihood of underlying MODY, and a MODY calculator is available online through the University of Exeter⁴ that estimates the probability that any given individual might have MODY. In general, a probability >25% should trigger further assessments. Laboratory testing is focused on assessments of β cell autoimmunity (autoantibodies) and function (C-peptide levels), the former of which should be absent and the latter of which should show impairment – followed by genetic testing. 

The diagnosis of MODY represents one example of how greater scrutiny of our patients with diabetes might significantly alter our approach to management. As our understanding of diabetes endotypes increase, it is likely that the traditional categorisation of individuals as having one of perhaps a few distinct forms of diabetes will give way to a more practical and personalised approach based on genetic and clinical characteristics – and which will ultimately change treatment paradigms.

 

References

1. International Diabetes Federation. IDF Diabetes Atlas [Internet]. 9th Edition. Brussels, Belgium: International Diabetes Federation; 2019:150.
2. Shepherd M, Shields B, Hammersley S, et al on behalf of the UNITED Team. Systematic Population Screening, Using Biomarkers and Genetic Testing, Identifies 2.5% of the U.K. Pediatric Diabetes Population With Monogenic Diabetes. Diabetes Care 2016;39(11):1879–88. 
3. Shields BM, Hicks S, Shepherd MH, et al. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 2010;53(12):2504–8. 
4. Shields BM, McDonald TJ, Ellard S, et al. The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes. Diabetologia 2012;55(5):1265–72.