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Monogenic Diabetes: from Genetic Insights to Population Diabetes Care Volume 43, December 2020 3117 DIABETES CARE EXPERT FORUM Matthew C. Riddle,1 Louis H. Philipson,2,3 Monogenic Diabetes: From Stephen S. Rich,4 Annelie Carlsson,5 Paul W. Franks,6,7 Siri Atma W. Greeley,2,3 Genetic Insights to Population- John J. Nolan,8 Ewan R. Pearson,9 Philip S. Zeitler,10 and Based Precision in Care. Andrew T. Hattersley11 Reflections From a Diabetes Care Editors’ Expert Forum Diabetes Care 2020;43:3117–3128 | https://doi.org/10.2337/dci20-0065 Individualization of therapy based on a person’s specific type of diabetes is one key element of a “precision medicine” approach to diabetes care. However, applying such an approach remains difficult because of barriers such as disease hetero- geneity, difficulties in accurately diagnosing different types of diabetes, multiple genetic influences, incomplete understanding of pathophysiology, limitations of current therapies, and environmental, social, and psychological factors. Monogenic 1Division of Endocrinology, Diabetes, & Clinical diabetes, for which single gene mutations are causal, is the category most suited to a Nutrition, Oregon Health & Science University, precision approach. The pathophysiological mechanisms of monogenic diabetes are Portland, OR 2 understood better than those of any other form of diabetes. Thus, this category Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Med- offers the advantage of accurate diagnosis of nonoverlapping etiological subgroups icine, The University of Chicago, Chicago, IL for which specific interventions can be applied. Although representing a small 3Kovler Diabetes Center, The University of Chi- proportion of all diabetes cases, monogenic forms present an opportunity to cago, Chicago, IL 4 demonstrate the feasibility of precision medicine strategies. In June 2019, the Center for Public Health Genomics, University of DiabetesCare Virginia, Charlottesville, VA editorsof convenedapanelofexpertstodiscussthisopportunity. This 5Department of Clinical Sciences, Lund Univer- article summarizes the major themes that arose at that forum. It presents an sity/Clinical Research Centre, Skane˚ University overview of the common causes of monogenic diabetes, describes some challenges Hospital, Lund, Sweden 6 in identifying and treating these disorders, and reports experience with various Harvard T.H. Chan School of Public Health, Bos- ton, MA approaches to screening, diagnosis, and management. This article complements a 7Lund University Diabetes Center, Department of larger American Diabetes Association effort supporting implementation of pre- Clinical Sciences, Lund University, Malmo,¨ Sweden cision medicine for monogenic diabetes, which could serve as a platform for a 8School of Medicine, Trinity College Dublin, Dub- broader initiative to apply more precise tactics to treating the more common forms lin, Ireland 9Division of Population Health and Genomics, of diabetes. Ninewells Hospital and School of Medicine, Uni- versity of Dundee, Dundee, Scotland, U.K. 10 ’ fi Children s Hospital Colorado and University of Diabetes mellitus is a common disease de ned by hyperglycemia but including other Colorado School of Medicine, Aurora, CO metabolic disturbances. It can cause serious medical complications that reduce life 11Institute of Biomedical and Clinical Science, expectancy and quality of life and poses a major public health challenge. The lifetime University of Exeter Medical School, Exeter, U.K. risk of developing diabetes is estimated to be at least one in three for people born in Corresponding author: Matthew C. Riddle, riddlem@ the U.S. (1). ohsu.edu Diabetes is commonly divided into categories (2). These include autoimmune- Received 14 September 2020 and accepted 14 mediatedtype1diabetes leadingtoinsulindeficiency; diabetessecondaryto pancreatic September 2020 injury;diabetesrelatedtospecificgeneticdisorders;andabroadcategorytermedtype2 © 2020 by the American Diabetes Association. diabetes, in which insulin secretion is impaired and resistance to insulin’s actions is Readers may use this article as long as the work is properly cited, the use is educational and not for usually, but not always, present (3). Growing understanding of crucial differences in the profit, and the work is not altered. More infor- pathophysiology underlying these distinct categories has the potential to improve mation is available at https://www.diabetesjournals outcomes by allowing for the application of specific therapeutic approaches (4). Such .org/content/license. 3118 Monogenic Diabetes as a Model for Precision Care Diabetes Care Volume 43, December 2020 evidence-based individualization of ther- MONOGENIC DIABETES: AN GCK-MODY, KCNJ11-TNDM, and PPARG- apy is a key component of the current OVERVIEW partial lipodystrophy (i.e., lipodystrophy movement toward “precision medicine” Clinical Subtypes of Monogenic caused by mutationsin PPARG).Whena (5,6). Diabetes clinical diagnosis is made but genetic There are several barriers to imple- An unusually strong genetic component testing has not been performed, the menting precision medicine in diabetes. causingdiabetes in certain individuals was clinical classification can be used without These include disease heterogeneity, dif- suspecteddecades ago byastuteclinicians an associated gene (e.g., MODY alone). ficulties in accurately diagnosing differ- who observed two main clinical pheno- The term MODY itself can result in ent types of diabetes, multiplicity and types that continue to be most suggestive confusion with childhood-/young-adult– variability of genetic influences, incom- of a possible monogenic cause: 1) onset of onset type 2 diabetes, which is typically plete understanding of pathophysiology, diabetes in neonates or infants (termed associated with marked obesity, unlike limitations of current therapies, and en- neonatal diabetes mellitus [NDM]) and 2) the familial monogenic form of diabetes vironmental, social, and psychological families with several generations of di- for which the term was intended. Still, factors that affect clinical management abetes occurring in adolescents or young the term persists in the literature, and (7,8). Therefore, a stepwise approach is adults suggestive of an autosomal dom- most diabetes care providers are familiar needed. inant pattern of inheritance (termed with it as a disease entity, even if they Monogenic forms of diabetes, for maturity-onset diabetes of the young may not remember many other details. which single gene mutations are causal, [MODY]) (17). Other subtypes of mono- Hence, it is easiest to continue to use it are the ones best suited to more precise genic diabetes include multisystem syn- as the clinical descriptor rather than interventions. More than 50 genetic sub- dromes, severe insulin resistance (in the inventing a new nomenclature. types have been described in which the absence of obesity), and lipodystrophy The most common causes of mono- disease-causing mutation appears to be (both full and partial). genic diabetes (MODY and NDM) are minimally affected by behavioral and listed in Table 1 and discussed in more environmental factors. Because the eti- Evolving Classification Systems detail below. ology of monogenic forms is known, their In the past three decades, the classifica- pathophysiological mechanisms are also tion of monogenic diabetes disorders has GCK-MODY understood better than those of other evolved from one based on clinical char- Nonprogressive hyperglycemia related forms of diabetes. Although these dis- acteristics (e.g., MODY) to one based on to GCK,orGCK-MODY, is the most com- orders account for a relatively small pro- molecular genetics (e.g.,glucokinase gene mon cause of monogenic diabetes, with portion of all cases of diabetes, ranging [GCK]status).This evolutionhasimproved an estimated incidence as high in 1 in from 1% to 5% in reports of pediatric and the robustness of diagnoses and enhanced 1,000 individuals (21). It is caused by young-adult populations (9–14), they our ability to define the etiology, likely heterozygous inactivating mutations in present an opportunity to demonstrate clinical course, and best treatment in any the enzyme glucokinase, which acts as the feasibility of precise diagnostic and given patient. the b-cell glucose sensor (22,23). Me- therapeutic strategies (15). Despite the The order in which causative loci and tabolism of glucose initiated by GCK ac- demonstrated importance of making a genes were described in the literature tivity triggers the cascade of events correct diagnosis, it is estimated that at was used originally in the nomenclature leading to insulin secretion, but impair- least 80% of all monogenic cases of of MODY subtypes. Thus, a disorder in- ment of GCK activity causes an increase in diabetes remain undiagnosed (16). volving the HNF4A gene was termed the threshold glucose level required for In June 2019, the editors of Diabetes “MODY1,” oneinvolvingGCK was called insulin secretion to be initiated, while Care convened a group of experts to “MODY2,” andsoforthuptoatleast b-cell function is otherwise completely discuss this opportunity. The group was MODY14 at present (18). This approach normal (24,25). The key role of GCK in asked to consider the present scientific has broken down, however, as more hepatic regulation of glucose release and understanding of the main monogenic genes have been described. In some storage also results in defects in these forms of diabetes, current experience cases, new MODY numbers have been processes. The overall result
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