1-OR: The Improvement Effects of Glucokinase Loss-of-Function Mutation on Lipid Metabolism

Glucokinase-maturity onset diabetes of the young (GCK-MODY), resulting from GCK loss-of-function mutation, is a unique form of diabetes characterized by mild hyperglycemia, favorable lipid profiles, and a low incidence of microvascular and macrovascular complications despite prolonged hyperglycemia. While GCK plays a crucial role in glucose and lipid metabolism, the impact of GCK mutation on lipid metabolism remains elusive. In this study, we aimed to investigate the mechanism underlying the improved lipid metabolism, particularly in liver and adipose tissue, using a mouse model. CRISPR/Cas9 methods was used to generate a heterozygous loss-of-function mutant model by knocking out the GCK gene in C57BL6/J mice. The GCK^+/- mice exhibited elevated fasting blood glucose, HDL-c, and ApoA, resembling the phenotype observed in GCK-MODY patients. Metabolic cage analysis revealed a reduced respiratory exchange ratio and increased heat production in GCK^+/- mice, suggesting a preference for fat burning over carbohydrate burning compared to WT mice. Additionally, GCK^+/- mice showed higher liver and kidney weight (%), but a reduced fat mass (%). Transmission electron microscopy analysis of hepatic tissue showed increased sizes and decreased total volume of lipid droplets (LDs) in GCK^+/- mice. Meanwhile, lipidomics analysis of liver revealed significantly reduced levels of TG and DG in the GCK^+/- mice. Proteomic data found that several key regulators for LDs lipolysis were reduced in the liver of GCK^+/- mice. Immunohistochemistry studies indicated reduced F4/80-positive cells in the liver of GCK^+/- mice, suggesting improved hepatic inflammation under normal diet conditions. These findings suggest that partial inactivation of GCK enhances lipid consumption and utilization in the liver and adipose tissue probably through altering LDs formation and lipolysis, providing new insights into the treatment of diabetes and its cardiovascular complications by targeting GCK as a therapeutic target.