G6PC2 encodes a glucose-6-phosphatase catalytic subunit primarily expressed in pancreatic islet β-cells that plays a critical role in glucose homeostasis by modulating insulin secretion sensitivity to glucose 1. The enzyme opposes glucokinase action in pancreatic islets, thereby regulating fasting blood glucose (FBG) levels 2. G6PC2 localizes to the endoplasmic reticulum membrane and contains essential structural motifs including a PAP2 motif critical for enzyme activity and a disulfide bond required for protein expression 1. Multiple non-synonymous single nucleotide polymorphisms (SNPs) in G6PC2 significantly affect protein expression and enzyme activity, with 16 of 22 analyzed SNPs causing >50% reduction in protein expression through proteasomal degradation 3. The most clinically significant variant is rs560887, which is an important determinant of human FBG variability 3. Meta-analyses demonstrate that G6PC2 variants are associated with FBG levels and type 2 diabetes risk, particularly in Caucasian populations 4. DNA methylation at CpG sites near G6PC2 mediates the effects of genetic variants on fasting glucose, suggesting epigenetic regulation of this pathway 5. These findings establish G6PC2 as a key regulator of glucose sensing in pancreatic β-cells with significant clinical implications for diabetes risk.