Monogenic Diabetes: From Genetic Insights to Population-Based Precision in Care. Reflections From a Diabetes Care Editors’ Expert Forum

Carotid Disease and Retinal Optical Coherence Tomography Angiography Parameters in Type 2 Diabetes: The Fremantle Diabetes Study Phase II

AbstractIndividualization 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 heterogeneity, 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 diabetes, for which single gene mutations are causal, is the category most suited to a precision approach. The pathophysiological mechanisms of monogenic diabetes are understood better than those of any other form of diabetes. Thus, this category offers the advantage of accurate diagnosis of nonoverlapping etiological subgroups for which specific interventions can be applied. Although representing a small proportion of all diabetes cases, monogenic forms present an opportunity to demonstrate the feasibility of precision medicine strategies. In June 2019, the editors of Diabetes Care convened a panel of experts to discuss this opportunity. This article summarizes the major themes that arose at that forum. It presents an overview of the common causes of monogenic diabetes, describes some challenges in identifying and treating these disorders, and reports experience with various approaches to screening, diagnosis, and management. This article complements a larger American Diabetes Association effort supporting implementation of precision medicine for monogenic diabetes, which could serve as a platform for a broader initiative to apply more precise tactics to treating the more common forms of diabetes.IntroductionDiabetes mellitus is a common disease defined by hyperglycemia but including other metabolic disturbances. It can cause serious medical complications that reduce life expectancy and quality of life and poses a major public health challenge. The lifetime risk of developing diabetes is estimated to be at least one in three for people born in the U.S. (1).Diabetes is commonly divided into categories (2). These include autoimmune-mediated type 1 diabetes leading to insulin deficiency; diabetes secondary to pancreatic injury; diabetes related to specific genetic disorders; and a broad category termed type 2 diabetes, in which insulin secretion is impaired and resistance to insulin’s actions is usually, but not always, present (3). Growing understanding of crucial differences in the pathophysiology underlying these distinct categories has the potential to improve outcomes by allowing for the application of specific therapeutic approaches (4). Such evidence-based individualization of therapy is a key component of the current movement toward “precision medicine” (5,6).There are several barriers to implementing precision medicine in diabetes. These include disease heterogeneity, difficulties in accurately diagnosing different types of diabetes, multiplicity and variability of genetic influences, incomplete understanding of pathophysiology, limitations of current therapies, and environmental, social, and psychological factors that affect clinical management (7,8). Therefore, a stepwise approach is needed.Monogenic forms of diabetes, for which single gene mutations are causal, are the ones best suited to more precise interventions. More than 50 genetic subtypes have been described in which the disease-causing mutation appears to be minimally affected by behavioral and environmental factors. Because the etiology of monogenic forms is known, their pathophysiological mechanisms are also understood better than those of other forms of diabetes. Although these disorders account for a relatively small proportion of all cases of diabetes, ranging from 1% to 5% in reports of pediatric and young-adult populations (9–14), they present an opportunity to demonstrate the feasibility of precise diagnostic and therapeutic strategies (15). Despite the demonstrated importance of making a correct diagnosis, it is estimated that at least 80% of all monogenic cases of diabetes remain undiagnosed (16).In June 2019, the editors of Diabetes Care convened a group of experts to discuss this opportunity. The group was asked to consider the present scientific understanding of the main monogenic forms of diabetes, current experience with diagnostic and therapeutic approaches to the management of each of these, and the challenges to applying these insights at a population level. The American Diabetes Association and the European Association for the Study of Diabetes recently established the Precision Medicine in Diabetes Initiative to consider the potential for precision medicine in diabetes more generally (6), and this Diabetes Care Editors’ Expert Forum was intended to complement that initiative. This article summarizes the major themes that arose at the forum.Monogenic Diabetes: An OverviewClinical Subtypes of Monogenic DiabetesAn unusually strong genetic component causing diabetes in certain individuals was suspected decades ago by astute clinicians who observed two main clinical phenotypes that continue to be most suggestive of a possible monogenic cause: 1) onset of diabetes in neonates or infants (termed neonatal diabetes mellitus [NDM]) and 2) families with several generations of diabetes occurring in adolescents or young adults suggestive of an autosomal dominant pattern of inheritance (termed maturity-onset diabetes of the young [MODY]) (17). Other subtypes of monogenic diabetes include multisystem syndromes, severe insulin resistance (in the absence of obesity), and lipodystrophy (both full and partial).Evolving Classification SystemsIn the past three decades, the classification of monogenic diabetes disorders has evolved from one based on clinical characteristics (e.g., MODY) to one based on molecular genetics (e.g., glucokinase gene [GCK] status). This evolution has improved the robustness of diagnoses and enhanced our ability to define the etiology, likely clinical course, and best treatment in any given patient.The order in which causative loci and genes were described in the literature was used originally in the nomenclature of MODY subtypes. Thus, a disorder involving the HNF4A gene was termed “MODY1,” one involving GCK was called “MODY2,” and so forth up to at least MODY14 at present (18). This approach has broken down, however, as more genes have been described. In some cases, new MODY numbers have been assigned without convincing rigorous evidence of causality (19), and in others, new genes involved in MODY have been described but not assigned a number (20).A more useful classification combines the standard abbreviation for the gene involved, followed by a term or abbreviation of the clinical phenotype (because the same gene can result in multiple phenotypes). Clinical phenotypes include MODY, PNDM (permanent NDM), TNDM (transient NDM), lipodystrophy, severe insulin resistance, and so forth. Examples of this combined nomenclature, then, are GCK-MODY, KCNJ11-TNDM, and PPARG-partial lipodystrophy (i.e., lipodystrophy caused by mutations in PPARG). When a clinical diagnosis is made but genetic testing has not been performed, the clinical classification can be used without an associated gene (e.g., MODY alone).The term MODY itself can result in confusion with childhood-/young-adult–onset type 2 diabetes, which is typically associated with marked obesity, unlike the familial monogenic form of diabetes for which the term was intended. Still, the term persists in the literature, and most diabetes care providers are familiar with it as a disease entity, even if they may not remember many other details. Hence, it is easiest to continue to use it as the clinical descriptor rather than inventing a new nomenclature.The most common causes of monogenic diabetes (MODY and NDM) are listed in Table 1 and discussed in more detail below.Table 1 Clinical implications of some common and important causes of monogenic diabetesGCK-MODYNonprogressive hyperglycemia related to GCK, or GCK-MODY, is the most common cause of monogenic diabetes, with an estimated incidence as high in 1 in 1,000 individuals (21). It is caused by heterozygous inactivating mutations in the enzyme glucokinase, which acts as the β-cell glucose sensor (22,23). Metabolism of glucose initiated by GCK activity triggers the cascade of events leading to insulin secretion, but impairment of GCK activity causes an increase in the threshold glucose level required for insulin secretion to be initiated, while β-cell function is otherwise completely normal (24,25). The key role of GCK in hepatic regulation of glucose release and storage also results in defects in these processes. The overall result is mild fasting hyperglycemia, usually 97–150 mg/dL (5.4–8.3 mmol/L), and an A1C of ∼5.8–7.6% (40–60 mmol/mol) (26).This pattern is present from birth and remains remarkably stable over time, although there can be an age-related increase in A1C that is parallel to that seen in aging populations (27). Individuals are asymptomatic and are not diagnosed until incidental laboratory testing or routine screening reveals hyperglycemia, often as pediatric incidental hyperglycemia (28–30), during pregnancy, or during incidental illness (21,31,32).Experts advise that no treatment is required, except possibly under certain circumstances during pregnancy in women with GCK-MODY (33,34). Nontreatment is advised because mild hyperglycemia is not sufficient to cause the microvascular or macrovascular complications associated with other forms of diabetes (26), and therapy does not lower glucose as it is regulated at the higher fasting level (35,36). This advice can sometimes be difficult for both people with GCK-MODY and earnest diabetologists to accept, yet the weight of the evidence showing the absence of diabetes complications and a lack of treatment response is clear. The urgent need to improve our recognition of this disorder is seen in the high percentage of individuals who are unnecessarily treated with a variety of medications before genetic diagnosis, for whom cessation of treatment usually has no effect on overall glycemia (35,37,38).HNF1A-MODY and HNF4A-MODYHNF1A-MODY is the most common cause of symptomatic, treatment-requiring MODY (39). Less common mutations in another β-cell transcription factor (HNF4A) have a similar clinical presentation and treatment requirement (40). These genes encode transcription factors present in many tissues. Although originally named as hepatocyte nuclear factors after being identified as transcription factors in a liver cDNA library, these genes play more important roles in the β-cell and are also expressed in multiple other organs such as the kidney.Individuals with either HNF1A-MODY or HNF4A-MODY usually have an excellent glucose-lowering response to low doses of inexpensive oral sulfonylurea medications, but there are key differences in other associated clinical features of these two subtypes. Before a genetic diagnosis, patients are often treated with a variety of less effective medications such as metformin or insulin, and switching to a sulfonylurea is not only cheaper but also tends to improve glycemic control (41–44). The response to sulfonylurea treatment can be so dramatic that hypoglycemia can cause a provider to switch to a different treatment, when in fact this response could be recognized as a reason to adjust dosing and pursue genetic testing.A reduction in HNF1A regulation of sodium–glucose cotransporter 2 (SGLT2) levels in the kidney results in glycosuria despite near-normal blood glucose levels (45). This response means that glycosuria can be an early marker of children who have inherited an HNF1A mutation (46). Given the effects of HNF1A on SGLT2 expression, caution should be observed in administering SGLT2 inhibitor medications to such individuals (46).HNF4A-MODY has a similar diabetes phenotype to HNF1A-MODY with one clinically very important difference: fetuses and newborns with an HNF4A mutation have excessive insulin secretion. The increased fetal insulin secretion results in a marked increase in birth weight (∼800 g) and a very high risk of macrosomia even when a fetus has inherited the mutation from the father (47). The neonatal hyperinsulinism can result in persistent and prolonged hypoglycemia in some patients (47,48). The management of HNF4A-MODY in pregnancy is discussed later in this article. The mechanisms underlying neonatal hyperinsulinemia but subsequent diabetes resulting from reduced β-cell function in HNF4A-MODY remain unexplained.HNF1B-MODYHNF1B-MODY is typically characterized by renal cysts and diabetes but can feature developmental anomalies in multiple systems (49). This form of diabetes typically starts in adolescence or early adulthood, is usually insulin-requiring, and may be insulin-dependent because the etiology is a reduced number of β-cells in development. Frequently, there is also reduced pancreatic exocrine function, which may require treatment. Reduced pancreatic tail size or low fecal elastase can aid diagnosis of exocrine pancreatic insufficiency. Although renal cysts are typical, multiple subtypes of developmental kidney disease have been described. HNF1B-MODY is the most common genetic etiology of childhood kidney disease, accounting for 20–30% of cases (49).KCNJ11-NDM and ABCC8-NDMActivating heterozygous mutations in either gene encoding the subunits of the β-cell KATP channel (KCNJ11 or ABCC8) are the most common cause of PNDM and a major cause of TNDM (50–55). Mutated channels maintain membrane hyperpolarization even in the face of extreme hyperglycemia, but treatment with high doses of a sulfonylurea can overcome these defects, enabling transition off insulin (56) and restoring meal-stimulated insulin secretion (57) with minimal hypoglycemia (58). Excellent glycemic control commonly persists even after >10 years of treatment (59).The clinical phenotype is correlated with the severity of mutation, with more damaging variants also causing a spectrum of neurodevelopmental disabilities that can be at least partially ameliorated by early initiation of sulfonylurea treatment once a genetic diagnosis is revealed (60–62). More mildly activating mutations are a common cause of TNDM (ABCC8 more often than KCNJ11) or may present as a rare form of MODY in individuals or family members who are not known to have had neonatal hyperglycemia but later in life develop MODY-like diabetes that is also usually responsive to a sulfonylurea (63,64). Other rare causes of NDM from KATP mutations include biallelic mildly activating mutations (usually homozygous), as well as compound heterozygous mutations, in which one is activating and the other is a loss-of-function (LOF) variant (65). However, homozygous LOF variants in either gene cause congenital hyperinsulinism (66).Imprinted Locus at Chromosome 6q24Overexpression of maternally methylated genes at chromosome 6q24 is the most common cause of TNDM, in which the diabetes spontaneously resolves within the first year of life but usually recurs in adolescence or young adulthood (67). When diabetes recurs, clinicians must recognize the significance of the TNDM history because these patients will often respond to oral medications and not require insulin (68).INS-NDM and INS-MODYWith certain subtypes of monogenic diabetes, a genetic diagnosis may not lead to changes in treatment of diabetes but could still allow for a precision-based approach. For example, heterozygous mutations in the proinsulin gene (INS) are the second most common cause of PNDM, stemming from a progressive loss of β-cell functional capacity resulting from accumulation of misfolded proinsulin protein (69). Although treatment is currently limited to insulin, minimizing the stimulus for excessive production of the mutated protein by minimizing hyperglycemia through early intensive insulin management may allow for slowing of the progressive loss of β-cell function and better long-term outcomes (70).Recessive nonsense or promoter INS variants preventing or greatly reducing insulin secretion also cause PNDM or TNDM (71,72). Rare INS variants also cause a form of MODY through distinct mechanisms such as reduced binding at the insulin receptor, but the best therapeutic options for these rare patients have not yet been established (73,74).Less Common Causes of Monogenic DiabetesMonogenic diabetes can result in multisystem syndromes that are usually congenital and hence cause NDM (50,75) but can also result in a later onset of diabetes. The most common multisystem syndromes that present later in life are HNF1B (discussed earlier), mitochondrial diabetes, and Wolfram syndrome. These syndromes frequently present with diabetes, which may not be recognized as a first manifestation of a multisystem disease.Cardinal features of mitochondrial diabetes syndromes, most commonly caused by m.3243A>G mutation, include maternally inherited diabetes (typically diagnosed in the third or fourth decades of life), sensorineural deafness (typically diagnosed before the diabetes), and several other possible problems such as renal manifestations, cardiomyopathy, myopathy, and central neurological features (76). Wolfram syndrome is a rare, severe, multisystem condition characterized by insulin-dependent diabetes (diagnosed in the first decade of life), optic atrophy, diabetes insipidus, and sensorineural deafness. It is usually caused by recessive mutations in WFS1 (77).Other subcategories of monogenic diabetes include a growing list of genes causing monogenic autoimmune syndromes in which diabetes is a common feature (78). Lipodystrophies and other syndromes of severe insulin resistance often go unrecognized as clinically distinct from type 2 diabetes even though optimal management may entail vastly different therapeutic approaches (79,80). The heterogeneity of phenotypic presentation and age of onset can hinder recognition of such patients as candidates for genetic testing, but, even if the diabetes can only be treated with insulin, a correct diagnosis can still guide monitoring and treatment of associated features, clarify the long-term prognosis, and lead to testing in family members.Current Experience With Screening, Diagnosis, and ManagementPhysician-Based ApproachesThe study of monogenic diabetes is a relatively new field. At present, monogenic diabetes is not generally diagnosed via systematic population screening, but rather by investigation of cases referred by individual physicians based on a likely clinical presentation. This approach is still missing as many as 80% of monogenic diabetes cases, which are instead being misdiagnosed as type 1 or type 2 diabetes (16,102).Studies of physician referrals to specialist centers for genetic diagnosis have shown that there is a marked degree of regional variation in referral for (and therefore in diagnosis of) monogenic diabetes (16,102). Factors that contribute to this problem include differences in awareness of monogenic forms of diabetes among clinicians and differences in access to appropriate screening and genetic testing services. The existence of specialist networks and the geographic distribution of expert centers have clear effects on identification of new cases (16,101). For these reasons, the reported prevalence of monogenic diabetes as a percentage of all cases varies widely among different regions and countries.A more systematic screening approach using a predefined protocol to examine consecutive pediatric cases was reported by an Italian group who conducted a retrospective analysis (101). This study was conducted through a network of pediatric centers providing good coverage and access throughout Italy, and it followed a sequence of investigations from type 1 diabetes–associated autoantibodies through to genetic testing based on presenting “metabolic phenotype.” This method identified a higher proportion of monogenic cases, 6.3% of the total (101), than has been reported elsewhere in similar age-groups.Education of clinical providers has been shown to greatly improve the effectiveness of the physician-based approach to the diagnosis of monogenic diabetes. In one ongoing project, the monogenic diabetes specialist team at the Royal Devon and Exeter National Health Service Foundation Trust and University of Exeter Medical School trained a cohort of 52 diabetes nurse specialists across the U.K. to serve as genetic diabetes nurses (103). This project has been highly effective at spreading the necessary clinical expertise from specialist testing centers to routine clinical care settings. Such a nurse-led approach to clinician education seems ideal for translation to other countries and regions in support of a more precise approach to diabetes care.Systematic Population-Based ScreeningAn alternative approach used in the UNITED trial (81) is systematic population-based screening to identify young patients for possible MODY sequencing, using low C-peptide and positive autoantibodies to exclude likely type 1 diabetes. This approach has been shown to be highly effective and cost-effective (97). Applied at scale, it should ensure that there are no inequities in screening and diagnosis of monogenic diabetes in the population tested.A similar strategy of C-peptide testing in individuals with >3 years’ duration of assumed type 1 diabetes and autoantibody testing at diagnosis, with monogenic gene sequencing then performed in those who are autoantibody-negative or have a persistently robust C-peptide level, is now being implemented in Scotland, making it the first country to implement population-wide testing for monogenic diabetes.Screening in the Pediatric PopulationMaking a correct diagnosis of MODY in pediatric diabetes is important because these patients will spend almost their whole life living with diabetes, and increasing attention is directed to this problem. However, the correct diagnosis often is made years after an incorrect initial diagnosis, when assumed type 1 diabetes fails to progress. Making a MODY diagnosis close to the initial diagnosis of diabetes is a priority.Currently, recognition of possible MODY cases is based on clinical features at follow-up rather than on any sort of assessment at the time of diabetes diagnosis. There is clear evidence of the need for systematic testing; the multicenter SEARCH for Diabetes in Youth study in the U.S. (11) showed that HNF1A, HNF4A, and GCK mutations accounted for 1.2% of diabetes cases in the pediatric population, but the vast majority of these patients with MODY were misdiagnosed and inappropriately treated with insulin. Screening procedures or algorithms based on islet autoantibodies that are reliable discriminatory factors at diagnosis (104) could be used to direct genetic testing for MODY sooner. Using such protocols would reduce delays in recommended treatment and potentially reduce both personal and clinical costs.Comprehensive autoantibody testing close to the time of diagnosis to guide testing for MODY has been performed in pediatric populations in a large multicenter study in the U.S. (11) and in national studies in Sweden (13) and Norway (100). Testing for MODY was systematically performed in the 12–15% in whom islet antibodies were not detected. The overall prevalence of MODY in these three studies was 0.8–1.2%. No cases were reported when patients were autoantibody positive (13). In these studies, the absence of autoantibodies was the strongest predictor of MODY in these populations, being more discriminatory than any clinical criteria. Because MODY is detected in 7–15% of all autoantibody-negative children, 85–93% of these patients do not have MODY; the majority have type 1 diabetes, but some have type 2 diabetes, and this proportion varies depending on the population studied (11).In the most comprehensive study at diagnosis to date (13), individuals with MODY had lower random plasma glucose and A1C levels than those without MODY and did not present with diabetic ketoacidosis. These indications of severity of presentation discriminated better than the other good predictor—a parental history of diabetes. Using this information could reduce the number of autoantibody-negative patients who need testing for MODY near the time of diabetes diagnosis in pediatric populations, but this reduction will be at the cost of missing some cases.Diagnosis and Management of MODY in PregnancyMODY patients, especially those with GCK-MODY, are often identified during pregnancy. Monogenic disorders account for 1–2% of all cases of diabetes diagnosed during pregnancy, with GCK-MODY being found in one in three patients with a fasting glucose ≥100 mg/dL (5.5 mmol/L) and normal weight (BMI <25 kg/m2) (21). It is important to correctly identify patients with GCK-MODY because its clinical course and management differ substantially from those of other types of diabetes in pregnancy.In GCK-MODY, the primary determinant of fetal growth is the fetal genotype, with affected fetuses having normal birth weight and unaffected fetuses being ∼500–600 g heavier than normal (33). Fetal genotype is not usually known, although an exciting new development is the use of noninvasive testing using cell-free DNA in maternal blood to assess whether a fetus is affected (105). In the absence of cell-free DNA testing, serial fetal ultrasound measurements can help determine likely fetal genotype. If accelerating fetal abdominal circumference—a sign of macrosomia—is present on serial ultrasounds, it can be assumed that the fetus does not have the GCK mutation. Insulin therapy is usually recommended to reduce the risk of macrosomia, and delivery could be induced at 38 weeks. However, well-designed studies have not proven that this approach leads to fewer complications, whereas insulin treatment may be associated with episodes of hypoglycemia, including severe hypoglycemia (33,34). If serial ultrasounds show normal fetal growth, the fetus has probably inherited the GCK mutation and will have an elevated glucose set point similar to that of the mother. In that setting, mild maternal hyperglycemia is desired (31,106), and treatment is not indicated and may be harmful by resulting in low birth weight (34).It is crucial to recognize HNF4A-MODY in pregnancy because fetuses that inherit the HNF4A mutation will be ∼800 g heavier than those that do not inherit the mutation. This tendency to gain weight, especially if combined with maternal hyperglycemia, can result in massive macrosomia (>5 kg), which can cause severe fetal and maternal complications (47). Thus, repeated ultrasound scans are needed, with early delivery if they reveal evidence of excessive fetal growth (47). It is also important to monitor the fetus carefully when the father has MODY, even though the mother is unaffected and has normal glucose levels, because, if the fetus is affected, the risk of macrosomia is as high as or higher than in conventional gestational diabetes mellitus (47).The excessive fetal insulin secretion caused by the HNF4A mutation that leads to macrosomia can also result in prolonged and severe neonatal hypoglycemia. For this reason, a pediatrician should be present at delivery, and urgent HNF4A testing for the specific mutation in the fetus should be performed rapidly. The emerging method of determining fetal mutation status using cell-free DNA from the mother allows for prediction of fetal outcome before delivery without relying on indirect evidence from maternal ultrasound scans (105).In HNF1A-MODY and HNF4A-MODY, as in all other forms of diabetes during pregnancy, maternal glycemic control is a major determinant of fetal outcomes. The challenges in both MODY subtypes are twofold: uncontrolled hyperglycemia during the first trimester (the time of organogenesis) and a risk of macrosomia and neonatal hypoglycemia accompanying sulfonylurea therapy in the third trimester (107). Therefore, different treatment strategies have been proposed: either stopping sulfonylurea therapy before pregnancy and switching to insulin, or continuing sulfonylurea in the preconception period and early pregnancy and then switching to insulin in the second trimester (108). The latter option has been suggested for patients with excellent glycemic control on sulfonylureas prior to pregnancy. Glyburide has been the most extensively studied sulfonylurea in pregnancy and is therefore recommended as the agent of choice (107).In general, however, studies of pregnancy affected by monogenic diabetes are scarce, and data from prospective studies are needed to better define the need for and timing of insulin treatment during pregnancy (31,106).Summary and A Way ForwardThe promise of precision medicine is based on the individual or groups of individuals. The approach incorporates aspects of family history (genetics), lifestyle, and environment, such that the health care provider can customize interventions, diagnostics, and therapeutics to permit a healthier life for the patient and reduce health care utilization and costs. In diabetes, there are numerous forms of the disease at presentation, ranging from monogenic (involving single gene mutations) to those with complex etiologies (such as autoimmune type 1 diabetes) that require exogenous insulin for survival, to the most common form (type 2 diabetes) that itself results from dysregulation of multiple, incompletely understood metabolic processes.Monogenic diabetes is currently the form of diabetes that is most relevant for the application of precision medicine in terms of diagnosis and treatment. However, the growing understanding of monogenic diabetes alone will not lead to much change in clinical practice. Practical application of this information requires several additions to diabetes management as it occurs in most places. It is also important to recognize that the distribution of various forms of monogenic diabetes relative to type 1 diabetes or type 2 diabetes may differ across global populations. As a preliminary proposal, this expert panel suggests that three programs are needed to accomplish and sustain population-based diagnosis and management of these disorders.1 1. A Regional InfrastructureThere should be basic agreement on definitions and guidelines developed by professional societies or governmental agencies. The American Diabetes Association’s Precision Medicine in Diabetes Initiative (6), including this Diabetes Care Editors’ Expert Forum, represents a step in this direction. Regional collection, storage, and management of data will be necessary. Such efforts are being undertaken in some countries in the form of disease-specific registries, but prospective management of data are insufficient in most locations. Depending on the size and geography of a given region, one or multiple specialized centers are needed. Ongoing financial support is necessary, and the case for providing it must be made based on the results of cost-effectiveness studies.2 2. Specialized ExpertiseRegional centers must be staffed by adequately trained professionals who are expert in the epidemiologic, genetic, and clinical aspects of diabetes. These specialty groups could manage the data, oversee laboratory methods, train personnel, and interact with clinical providers. Primary care providers need and will continue to need education and consultative support regarding individual cases, all of which can be provided by specialized diabetes centers.3 3. Research Toward Population-Based Management of Other Forms of DiabetesThe infrastructure and expert center networks might be expected, over time, to expand their activities to study of the genetic factors underlying other forms of diabetes. At present, combined clinical and genetic risk scores are in development to assess risks of developing type 1 diabetes and type 2 diabetes and to predict individuals’ need for and responses to various pharmacotherapies. In the future, clinical investigation of various kinds could be carried out efficiently through these centers of expertise. Ongoing screening for and treatment of individuals with monogenic disorders will naturally accrue data that bear on the population-based management of all forms of diabetes. It may be feasible to develop prospective trials of new methods of prevention or treatment of the more common types of diabetes using the same infrastructure and personnel.It should be recognized that all forms of diabetes evolve over time for every affected individual. The pathophysiology and appropriate treatments change over time and can be altered by the appearance of other comorbid conditions, complications, changes in lifestyle or environmental factors, and patients’ perceptions of their disease. Therefore, services provided by the systems just described are relevant not just at the time of screening and diagnosis but longitudinally throughout the life span of each individual.In summary, we suggest that a systematic approach to screening for and appropriately treating monogenic diabetes could establish a platform on which to base a broader initiative toward precision treatment of diabetes in general. For the present, it seems appropriate to go for the low-hanging fruit: the easily diagnosed cases of monogenic diabetes for which specific therapeutic approaches are already established, yet all too seldom correctly applied.

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