Revisiting the heterogeneity of maturity-onset diabetes of the young: A new classification scheme based on pathogenic mechanisms

To the Editor: Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders characterized by early onset (typically in adolescence or childhood), autosomal dominant inheritance, and impaired insulin secretion. To date, a total of 14 different MODY subtypes have been identified, each of which is caused by mutations in different genes [Supplementary Table 1, https://links.lww.com/CM9/C683]. However, the existing classification of MODY is difficult to apply in clinical practice. The greater the number of MODY gene mutation types, the more the existing MODY classification loses its rationality and clinical utility. In this article, we proposed a new classification for MODY. Based on its pathogenic mechanisms, we classified MODY into four types: insulin secretion disorders (Type A), endoplasmic reticulum stress (Type B), transcriptional regulation disorders (Type C), and signal transduction abnormalities (Type D). This new classification can reveal the similarities and differences between MODY subtypes and facilitate the selection of appropriate treatment strategies based on the pathophysiology and clinical presentation of each subtype. In pancreatic islet beta cells, insulin precursors encoded by the INS gene are cleaved, transported to the Golgi apparatus for processing into insulin and C-peptides, and stored in secretory vesicles. When blood glucose levels rise, glucose enters the cells and is metabolized to produce adenosine triphosphate (ATP). An increase in ATP closes ATP-sensitive potassium channels (KATP), leading to membrane depolarization, activates voltage-dependent Ca2+ channels (VDCCs), triggers Ca2+ influx, and promotes exocytosis and release of insulin vesicles [Figure 1]. The released insulin binds to receptors on target cells, triggering a series of signal transduction events that ultimately lower the blood sugar level. Based on the four processes of insulin secretion, insulin synthesis, gene transcriptional regulation, and signal transduction, we classified MODY into four types: A, B, C, and D [Supplementary Table 2, https://links.lww.com/CM9/C683].Figure 1: Molecular mechanism of MODY. In pancreatic islet beta cells, glucose is phosphorylated by glucokinase to G-6-P, which undergoes glycolysis and the TCA cycle to increase ATP. Rising ATP closes KATP channels, depolarizing the membrane and opening VDCC. Influxed Ca2+ elevates cytosolic Ca2+ concentration, triggering exocytosis of insulin-containing vesicles. Meanwhile, the INS gene produces preproinsulin, processed by the endoplasmic reticulum and Golgi into mature insulin stored in vesicles awaiting calcium ion-triggered release. ABCC8: ATP-binding cassette subfamily C member 8; AKT: Protein kinase B; APPL1: Adaptor protein, phosphotyrosine Interacting with PH domain and leucine zipper 1; ATP: Adenosine triphosphate; CEL: Carboxyl ester lipase; GCK: Glucokinase; GLUT2: Glucose transporter 2; HNF1A: Hepatocyte nuclear factor 1 alpha; HNF1B: Hepatocyte nuclear factor 1 beta; HNF4A: Hepatocyte nuclear factor 4 alpha; INS: Insulin; IR: Insulin receptor; IRS1: Insulin receptor substrate 1; IRS2: Insulin receptor substrate 2; KATP: ATP-Sensitive potassium channel; KCNJ11: Potassium inwardly rectifying channel subfamily J Member 11; KLF11: Kruppel-Like factor 11; NEUROD1: Neurogenic differentiation factor 1; PAX4: Paired box protein pax-4; PDX1: Pancreas/duodenum homeobox protein 1; PI3K: Phosphatidylinositol 3-kinase; PIP3: Phosphatidylinositol (3,4,5)-trisphosphate; SUR1: Sulfonylurea receptor 1; TRIB3: Tribbles homolog 3; VDCC: Voltage-dependent calcium channel.Type A. Insulin Secretion Disorders (MODY 2,12,13): Glucokinase (GCK), a key enzyme in glucose metabolism, is mainly expressed in pancreatic islet beta cells and hepatocytes. In β-cells, mutations in the GCK gene (MODY2) lead to glucose-6-phosphate production disorder, raise the insulin secretion threshold, and reduce insulin secretion. In hepatocytes, GCK mutations decrease glycogen synthesis and increase gluconeogenesis, thereby causing hyperglycemia. Similarly, ABCC 8 (MODY 12) and KCNJ11 (MODY 13) encode the sulfonylurea receptor (SUR1) and KIR6.2, respectively, which are components of KATP (a complex composed of four KIR6.2 and four SUR1 subunits). Mutations in either of these genes can impair KATP channel functions, resulting in impaired glucose-dependent insulin secretion. Most patients present with mild fasting hyperglycemia or impaired glucose regulation and a low risk of diabetic vascular and neurological complications. However, they carry a significantly higher risk of gestational diabetes mellitus, necessitating monitoring of fetal and maternal risks during pregnancy. As the symptoms are usually mild in these patients, treatment typically involves dietary management or oral medication, particularly sulfonylureas [Supplementary Table 3, https://links.lww.com/CM9/C683]. Type B. Endoplasmic Reticulum Stress (Insulin Synthesis Disorders) (MODY8,10): Both CEL (MODY8) and INS (MODY10) mutations can cause endoplasmic reticulum stress in pancreatic islet β cells, leading to the inability or reduction of insulin secretion. Mutations in the CEL gene cause pancreatic acinar cells to secrete a mutant CEL protein, which is absorbed by pancreatic islets.[1] The protein accumulates as insoluble aggregates in the β-cell cytoplasm, inducing endoplasmic reticulum stress. Likewise, INS gene mutations can cause misfolding or aggregation of insulin, leading to endoplasmic reticulum stress and then inducing apoptosis of pancreatic β-cells [Supplementary Figure 1, https://links.lww.com/CM9/C683]. Patients with type B MODY typically present with moderate-to-severe hyperglycemia and may develop acute complications, such as diabetic ketoacidosis or hyperosmolar coma, early in the disease. Although CEL mutations can lead to pancreatic exocrine symptoms, the mechanism of hyperglycemia (absolute insulin deficiency) is similar to that of INS mutations. Thus, the cornerstone of the therapy is insulin, which can be combined with oral medications. Type C. Transcriptional Regulation Disorders (MODY 1,3,4–7,9,11): For disorders affecting the transcriptional regulation process of insulin production, we divided them into three subtypes (C1, C2, and C3) based on their mechanism of action and clinical characteristics. Subtype C1 (MODY1,3): Hepatocyte nuclear factor 4-alpha (HNF4A) (MODY1) and hepatocyte nuclear factor 1-alpha (HNF1A) (MODY3) are nuclear transcription factors that regulate genes, such as insulin (INS), glucose transporter 2 (GLUT2) and other proteins involved in glucose and mitochondrial metabolism. They cross-regulate each other: HNF1A binds the P2 promoter upstream of HNF4A to activate its transcription, while HNF4A binds to the DR1 direct repeat cis-element in the HNF1A promoter to activate its transcription. As a primary activator of HNF1A, HNF4A binds DNA as a homodimer, driving expression of many liver-specific genes involved in glucose, cholesterol, and fatty acid metabolism. This leads to reduced serum levels of triglycerides and apolipoproteins AI and CIII. Patients with this subtype C1 have a relatively high incidence, with onset typically occurring during adolescence. These patients typically presented with elevated postprandial blood glucose levels. The patient had a normal or low BMI, negative immunological markers, and a notably significant family history. Some patients may have elevated total cholesterol, putting them at greater risk of microvascular and macrovascular complications, particularly retinopathy and nephropathy. Oral hypoglycemic drugs, especially sulfonylureas, are the preferred treatment for this subtype, as these drugs can effectively lower blood glucose levels. It should be noted that the treatment goal of this subtype is to control blood glucose, which, in turn, prevents complications and comorbidities. Subtype C2 (MODY4,6,7,9,11): Pancreas/duodenum homeobox protein 1 (PDX1) (MODY4), Neurogenic differentiation factor 1 (NEUROD1) (MODY6), Kruppel-like factor 11 (KLF11) (MODY7), and Paired box protein Pax-4 (PAX4) (MODY9) are all transcription factors, among which PDX1 and NEUROD1 can regulate the differentiation, proliferation, and insulin secretion of pancreatic β cells. PDX1 binds to the A-box of the INS promoter, NEUROD1 binds to the E-box, and KLF11 binds to the GC-rich CCCCGCCCT sequence of the INS promoter, all of which promote INS transcription.[2]KLF11 and PAX4 directly or indirectly regulated the expression of the INS gene, thereby affecting insulin secretion. PAX4 gene mutations can also affect the expression of glucokinase and GLUT2, reducing β-cell sensitivity and uptake capacity for glucose. BLK (MODY11) stands out as a tyrosine kinase that is expressed in both B cells and pancreatic β cells, but mutated BLK can also cause reduced insulin synthesis by modulating the transcriptional regulation process of insulin.[3] Patients with this subtype may exhibit excessive adiposity and ketoacidosis at onset. They are also susceptible to complications, such as diabetic microangiopathy and nephropathy. As the pathophysiology entails modulation of INS, treatment generally involves insulin and dietary management at onset. Later, the patient may be transitioned to oral antidiabetic agents after achieving blood glucose control. Subtype C3 (MODY5): Hepatocyte nuclear factor 1 beta (HNF1B) (MODY5) is a transcription factor that plays an important role in the development and function of multiple organs, such as the pancreas, kidney, genitalia, and liver. Mutations of HNF1B gene can cause loss or reduction of HNF1B function, which affects the differentiation, proliferation, and insulin secretion of pancreatic β-cells. In addition, HNF1B gene can also regulate the reabsorption of magnesium in the distal convoluted tubule by regulating the FXYD domain-containing ion transport regulator 2 (FXYD2) gene (FXYD2 encodes the basolateral Na-K-ATPase subunit); therefore, patients may have hypomagnesemia, hyperuricemia, and hypokalemia.[4] Patients with this subtype typically present with progressive hyperglycemia. Moreover, the patients are prone to complications, such as malformations of the kidney, digestive system, and reproductive system. Due to poor islet function, insulin treatment is required in the early stages of the disorder. Type D. Signal Transduction Abnormality (MODY14):APPL1 (MODY14) encodes a protein involved in insulin signal transduction. As an adaptor protein, APPL1 can promote the recruitment of insulin receptor (IR) substrate 1 and IR substrate 2 to the plasma membrane, thereby facilitating their binding to the IR. APPL1 is also a downstream effector molecule in insulin signal transduction, which enhances insulin-stimulated Akt phosphorylation by directly interacting with Akt and primarily competitively inhibiting tribbles homolog 3 (TRB3).[5] When this gene undergoes a missense mutation, it affects the action of insulin on the liver, muscle, and adipose tissue, leading to insulin resistance and pancreatic β-cell dysfunction, which causes diabetes. In the early stage of onset, patients may have diabetic ketoacidosis. Insulin therapy is administered when ketoacidosis occurs. When the disorder is under control, drug and diet control may be considered. In summary, reclassifying MODY according to the mechanism is a more scientific and reasonable method, which addresses the confusion and inconvenience caused by the increasing number of gene mutations in the traditional MODY classification, and clarifies the pathogenesis and process of various types of MODY. Notably, the new classification represents a significant refinement of the previous version. However, genetic testing remains the gold standard for the diagnosis of MODY. To fully leverage the strengths of both, we recommend combining the traditional MODY classification with the new classification in clinical practice, thereby providing patients with more comprehensive treatment guidance. Acknowledgments The authors thank all the participants in this study. Funding This study was supported by the National Key Research and Development Program of China (No. 2023YFC2506000, and 2023YFC2506006). Conflicts of interest None.