From gene to therapy in MODY: β-cell mechanisms and precision treatment Tongyu Wang [1,†] , Mengquan Tan [2,†] , Huixian Zhou [3,†] , Chujun Chen [4] , Meiling Zhong [5] , Yaling Dai [6,†] , Jiling Zeng* [7] , Siyuan Song* [8,9]

https://www.academia.edu/3064-9765/3/2/10.20935/AcadMolBioGen8301 Maturity-onset diabetes of the young (MODY) is a group of monogenic diabetes disorders marked by early-onset hyperglycemia and primary pancreatic β-cell dysfunction. MODY is often misclassified as type 1 or type 2 diabetes, which can lead to delayed genetic diagnosis and inappropriate therapy. This review summarizes established MODY mechanisms and organizes them in a clinically oriented way to link major MODY genes with β-cell stimulus–secretion defects and practical treatment choices. In GCK-MODY, reduced glucose phosphorylation shifts the glucose threshold needed to raise ATP, close ATP-sensitive potassium (KATP) channels, open voltage-dependent Ca2+ channels, and trigger insulin granule fusion, which explains stable mild hyperglycemia and limited benefit from routine glucose-lowering drugs outside pregnancy. In HNF1A- and HNF4A-MODY, impaired transcriptional programs weaken glucose-stimulated insulin secretion and often progress over time; sulfonylureas can bypass upstream defects by closing KATP through sulfonylurea receptor-1 (SUR1) binding and restoring depolarization and Ca2+-triggered exocytosis. In KCNJ11- and ABCC8-related diabetes, activating variants keep KATP more open, reduce depolarization, and suppress Ca2+ entry; many responsive variants allow a switch from insulin to sulfonylureas. In HNF1B-, PDX1-, and INS-related disease, reduced β-cell mass or chronic endoplasmic reticulum (ER) stress can limit secretory capacity and increase the need for insulin. The review also discusses advances in genetic testing, variant interpretation, and risk modifiers that shape penetrance and adult misclassification. Together, these established mechanisms provide a clinically useful summary that links molecular diagnosis with treatment selection, variant interpretation, and family counseling. https://www.academia.edu/journals/academia-molecular-biology-and-genomics/articles?source=journal-top-nav