The <i>KCNJ11-E23K</i> Gene Variant Hastens Diabetes Progression by Impairing Glucose-Induced Insulin Secretion

The ATP-sensitive K+ (KATP) channel controls blood glucose levels by coupling metabolism to insulin secretion in pancreatic β-cells. E23K, a common polymorphism the pore-forming KATP subunit (KCNJ11) gene, has been linked increased risk of type 2 diabetes. Understanding risk-allele-specific pathogenesis potential improve personalized diabetes treatment, but underlying mechanism remained elusive. Using genetically engineered mouse model, we now show that K23 variant impairs glucose-induced and increases when combined with high-fat diet (HFD) obesity. KATP-channels β-cells two alleles (KK) showed decreased ATP inhibition, threshold for glucose-stimulated from KK islets was increased. Consequently, response glycemic control impaired mice fed standard diet. On an HFD, effects genotype were exacerbated, accelerating diet-induced progression causing β-cell failure. We conclude impairing at levels, thus loss function early stages progression.