Monogenic diabetes is caused by mutation in a single gene. Maturity- onset diabetes of the young (MODY) is the most common form of monogenic diabetes. According to the American Diabetes Association, MODY is defined as presentation before the age of 25 years with a strong family history suggestive of autosomal dominant inheritance. It is characterized by absence of β- cell autoimmunity and sustained pancreatic β- cell function. In the early 1990s, some of the MODY genes were first discovered in Asian family- based cohorts of young- onset diabetes in pursuit of the underlying cause due to the low prevalence of autoimmune type 1 diabetes in these young individuals. These early findings together with several large cohorts in Europe have provided the basis of the current knowledge in the field of MODY. The use of family- based linkage analysis and sequencing technology has discovered biological pathways implicated in the neogenesis, differentiation, and maturation of pancreatic β cells as well as intracellular signalling mechanisms underlying insulin sensing, synthesis, secretion, and processing as important causes of MODY.
Around 40 subtypes of monogenic diabetes have been identified, with variants in 14 genes being best described in the literature. These include six genes encoding proteins that, respectively, correspond to MODY subtypes 1–6: hepatocyte nuclear factor (HNF) 4α (HNF4α); glucokinase (GCK); HNF1α (HNF1α); pancreatic and duodenal homeobox 1 (PDX1); HNF1β (HNF1β); and neurogenic differentiation 1 (NEUROD1). Another eight genes have been identified as possibly causative in MODY subtypes 7–14, including Kruppel- like factor 11 (KLF11); carboxyl ester lipase (CEL); paired box–containing gene 4 (PAX4); insulin (INS); B- lymphocyte kinase (BLK); adenosine triphosphate (ATP)–binding cassette; sub- family C (CFTR/MRP) member 8 (ABCC8); potassium channel, inwardly rectifying subfamily J, member 11 (KCNJ11); and adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper containing 1 (APPL1). There is now a trend to replace the old nomenclature of MODY1 and MODY 2 with HNF4α- MODY or GCK- MODY for better clarity. Most of the monogenic diabetes genes are transcription factors implicated in pancreatic β- cell development, structure, and function, such as Pax6, Nkx2- 2, Nkx6- 1, and Pax- 4. Others are transmembrane channels implicated in insulin secretion, such as Kir6.2 (KCNJ11) and SUR1 (ABCC8). These rare variants in transcription factors typically cause significant insulin insufficiency and hyperglycaemia, with strong familial inheritance and full penetrance (Figure 1).
Fig1. (a) The cascade of transcription factors involved in pancreatic development as well as neogenesis, differentiation, and maturation of pancreatic β cells. Maturity- onset diabetes of the young (MODY) includes subtypes with mutations in transcription factors, namely MODY 1 with mutations of hepatic nuclear factor (HNF- 4α); MODY 3: HNF- 1α; MODY 4: insulin promotion factor (IDF- 1); MODY 5: HNF- 1β; MODY 6: neurogenic differentiation 1 (NeuroD1); and MODY 7: carboxyl ester lipase (CEL). Other genes include glucokinase, the glucose sensor (MODY 2), glucose transporter 2 (GLUT2), and additional transcription factors such as GATA, the family of PAX genes, Nkx 2.2 and Nkx 6.1, and neurogenin- 3 (Neurog3). These genes interact at different stages to control islet cell development and regulate glucose sensing and insulin secretion in order to maintain a normal range of blood glucose of 4–8 mmol/l at all times, irrespective of fasting and prandial states. (b) The multiple steps involved in regulation of insulin secretion, commencing with sensing of ambient blood glucose level by glucose transporter 2 (GLUT2), glycolysis by glucokinase (GK), and adenosine triphosphate (ATP) production by mitochondria. The generated ATP particles then close the potassium channels, leading to membrane depolarization and opening of calcium channels. The intracellular calcium influx is associated with translocation of insulin- and amylin- containing vesicles to the cellular surface for extracytosis. During these processes, transcription factors are also activated, resulting in insulin gene transcription and production to replenish the insulin- containing vesicles to ensure continuous insulin supply for rapid release on demand. MIDD, maternal- inherited diabetes and deafness.
Recently, more mutations associated with monogenic diabetes have been identified and the list is expected to grow with the increasing availability of DNA sequencing. Some mutations are extremely rare or associated with syndromic features (e.g. deafness, visual impairment, development abnormality). Rare variants aside, genome- wide association studies have revealed a high frequency of common variants of some MODY genes, especially in Asian populations, including HNF1α, HNF1β, GCK, and PAX4. These genetic variants might interact with other genetic, environmental, or life style factors to increase the risk of diabetes or related traits. These results are in keeping with epidemiological analysis indicating the important role of abnormal β- cell biology in the pathogenesis of type 2 diabetes in Asian populations undergoing rapid transition, with obesity as a major risk factor.
Given the mixed phenotypes, it can be challenging to distinguish individuals with MODY from the large number of individuals with type 1 diabetes or young- onset type 2 diabetes. It is estimated that more than 80% of cases of MODY are not diagnosed or are misclassified in clinical practice, not least because the costs of genetic analysis can be prohibitive for widespread screening for mutations in individuals with diabetes. In 2008, a consensus group recommended clinical criteria for MODY testing that included onset of diabetes below 25 years, parental history of diabetes, non- insulin dependence (for HNF1α- and HNF4α- MODY), and fasting plasma glucose of 5.5–8.0 mmol/l and HbA1c <8% (64 mmol/mol) for GCK- MODY. These criteria have high specificity but low sensitivity, with other forms of familial monogenic diabetes yet to be discovered. By extending the screening criteria to individuals diagnosed under the age of 30 years or with C- peptide positivity after three years of diagnosis (random or glucagon- stimulated C- peptide ≥0.2 nmol/l), more positive cases have been diagnosed. Common variants near the HNF1α gene influence the levels of high- sensitivity C- reactive protein (hsCRP) in healthy populations and low levels of hsCRP may distinguish HNF1α- MODY from type 1 diabetes and type 2 diabetes with increased sensitivity up to 90% when combined with clinical criteria.
In cohorts with clinical features of MODY and depending on additional selection criteria, such as C- peptide or autoimmune markers to prioritize diagnostic testing, the proportions of young individuals with monogenic diabetes might range from less than 10% to more than 50%. In most cohorts, over 70% of confirmed individuals with MODY had mutations in HNF1α, GCK, and HNF1β. In a consecutive cohort of unrelated Chinese individuals with type 2 diabetes diagnosed before the age of 40 years, 5–10% had GCK or HNF1α mutations. There are relatively few MODY cohorts in African, Arabic, or Latin American populations. Given the known differences in genetic, ecological, and cultural factors, different patterns of MODY might be expected. Recently, a work group has reported good discriminatory performance of MODY risk calculators, although their applicability in non- Europid populations remains uncertain.
There are few cohort studies on monogenic diabetes in the USA and an estimated 95% of cases might be misdiagnosed as type 1 diabetes or type 2 diabetes. In the latest analysis of a multiethnic cohort of young people under the age of 20 years with a clinical diagnosis of type 2 diabetes, whole- exome sequencing was performed to discover genetic variants associated with MODY genes classified as likely pathogenic (LP) or pathogenic (P) according to current guide lines. Among 3333 participants, 93 (2.8%) carried an LP/P variant in HNF4α (n = 16), GCK (n = 23), HNF1α (n = 44), PDX1 (n = 5), INS (n = 4), or CEL (n = 1). Compared with those with no LP/P variants, young people with MODY had a younger age at diagnosis and lower fasting C- peptide levels. They were also less likely to have hypertension and had higher high- density lipoprotein (HDL) cholesterol levels. Among these 2.8% of young people with clinically diagnosed type 2 diabetes, the diagnosis of MODY through sequencing would have changed clinical management in 89% of them. However, there were no clinical criteria that could reliably separate MODY from other forms of diabetes, which calls for new tools and algorithms to select individuals for genetic testing.
Accurate diagnosis of MODY has implications for choices of treatment. Typically, GCK- MODY is characterized by mild fasting hyperglycaemia and might not necessitate treatment. Individuals with MODY due to HNF4α and HNF1α mutations are sensitive to sulfonylureas. These individuals also respond well to incretin- based therapy with dipeptidyl peptidase 4 inhibitors and glucagon- like peptide 1 receptor agonists. Many individuals with transcription factor MODY eventually require insulin due to progressive β- cell failure, often due to factors such as delayed diagnosis, long disease duration, and suboptimal glycaemic levels with ongoing glucolipotoxicity and inflammation.
Timely recognition of MODY also influences antenatal care, as maternal–offspring genotype concordance or discordance affects the pregnancy outcome. Using GCK- MODY as an example, intensive insulin treatment in an affected mother during pregnancy might result in low birth weight of affected offspring, who require a higher fasting plasma glucose to trigger insulin secretion. By contrast, high fasting hyperglycaemia in an affected mother might lead to high birth weight in an unaffected offspring due to fetal hyperin sulinaemia. Although individuals with some MODY sub types (e.g. GCK- MODY) run a mild clinical course and rarely develop complications, depending on the coexistence of other risk factors and genotypes, individuals with MODY might exhibit marked heterogeneity in terms of insulin insufficiency, complications, and treatment requirements, even among family members carrying the same variant.
Precise diagnosis, classification, and treatment are particularly important in young individuals with type 2 diabetes presentation. In Chinese people, young- onset diabetes is associated with a 1.5–6- fold increased risk of hospitalization with acute or chronic complications, cardiovascular–renal complications, and premature death, in part due to long disease duration and poor risk factor management. The insidious nature of these symptoms might lead to delayed presentation with complications, while early diagnosis through screening of family members on identification of an index individual might prevent these adverse outcomes. With the rising prevalence of young- onset diabetes especially in low- and middle- income countries, healthcare professionals need to appreciate the multiple aetiologies that might coexist in an individual with an atypical presentation of diabetes. In these individuals, precision diagnosis can have important implications for treatment selection, with some benefiting from early insulin treatment (e.g. LADA) and others from oral glucose- lowering drugs (e.g. MODY) (Table 1 and Figure 2).
Table1. Clinical features, pathophysiology, and treatment implications of the 14 subtypes of maturity- onset diabetes of the young (MODY) due to rare mutations that often follow a Mendelian mode of inheritance with full penetrance.
Fig2. A proposed algorithm for identifying individuals with monogenic diabetes and targeted treatment. BMI, body mass index; HbA1c, glycated haemoglobin; MODY, maturity- onset diabetes of the young, maturity- onset diabetes of the young. Source: Adapted from Hattersley and Patel 2017.
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