Duration-dependent alterations of lipid profiles and microvascular complications in GCK-MODY

Heterozygous inactivating mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young type 2 (GCK-MODY), a monogenic diabetes subtype characterized by stable hyperglycemia and low complication risk. However, the long-term effects of distinct dietary patterns on lipid metabolism and chronic complications in GCK-MODY remain poorly understood. In this study, we employed a knock-in mouse model carrying a novel MODY-associated mutation, GCK-Q26L (hereafter called GCK^Mut), to systematically investigate age- and diet-dependent changes in lipid homeostasis and microvascular pathology. When fed a normal diet, GCK^Mut mice developed progressive renal injury by 60 weeks, characterized by NF-κB pathway activation and upregulation of pro-inflammatory and fibrotic mediators. In contrast, GCK^Mut mice fed a high-fat diet at 28 weeks showed improved lipid profiles and reduced renal injury, accompanied by PPAR-driven fatty acid oxidation. However, these benefits declined by 40 weeks and reversed to dyslipidemia and nephropathy by 60 weeks. Together, these findings demonstrate that GCK inactivation exerts strong age- and diet-dependent effects on renal metabolism and microvascular integrity. The study highlights previously underestimated long-term risks in GCK-MODY and establishes a useful model for mechanistic insight and therapeutic exploration.