Monogenic diabetes: Classification, diagnosis, and precision management

Monogenic diabetes (MGD) comprises a heterogeneous group of diabetes disorders caused by pathogenic variants in a single gene affecting pancreatic β-cell development or function, insulin action, or immune regulation. Although individually rare, MGD is clinically important because many patients are misdiagnosed as having type 1 or type 2 diabetes, despite major differences in mechanism, treatment, prognosis, and inheritance. PubMed/MEDLINE, Embase, and Google Scholar were used to select high-quality evidence to provide a practical overview of the epidemiology, clinical recognition, diagnosis, and precision-based management of MGD. A mechanism-based classification is proposed comprising β-cell dysfunction causing insulin deficiency, defects in insulin action causing severe insulin resistance, and monogenic immune dysregulation causing autoimmune β-cell destruction. The author integrates experience with four cases illustrating different forms of MGD where the concept of precision medicine is applied. MGD should be considered in patients diagnosed within the first 6 months of life, those with a strong multigenerational family history, absent islet autoantibodies, preserved endogenous insulin secretion, mild stable fasting hyperglycemia, or extra-pancreatic manifestations. Genetic confirmation is essential because treatment varies substantially between subtypes. HNF1A-MODY and KCNJ11- or ABCC8-related neonatal diabetes may respond remarkably well to sulfonylureas, while GCK-MODY generally requires no pharmacological treatment. Oral thiamine can improve diabetes and correct anemia in patients with thiamine-responsive megaloblastic anemia due to homozygous SLC19A2 variants. Accurate molecular diagnosis also enables appropriate surveillance, cascade testing, genetic counseling, and reproductive planning. Greater awareness and wider access to genetic testing are essential to reduce misdiagnosis and enable personalized treatment.