| First Author | Sachse G | Year | 2021 |
| Journal | Diabetes | Volume | 70 |
| Issue | 5 | Pages | 1145-1156 |
| PubMed ID | 33568422 | Mgi Jnum | J:306958 |
| Mgi Id | MGI:6712906 | Doi | 10.2337/db20-0691 |
| Citation | Sachse G, et al. (2021) The KCNJ11-E23K Gene Variant Hastens Diabetes Progression by Impairing Glucose-Induced Insulin Secretion. Diabetes 70(5):1145-1156 |
| abstractText | The ATP-sensitive K(+) (KATP) channel controls blood glucose levels by coupling glucose metabolism to insulin secretion in pancreatic beta-cells. E23K, a common polymorphism in the pore-forming KATP channel subunit (KCNJ11) gene, has been linked to increased risk of type 2 diabetes. Understanding the risk-allele-specific pathogenesis has the potential to improve personalized diabetes treatment, but the underlying mechanism has remained elusive. Using a genetically engineered mouse model, we now show that the K23 variant impairs glucose-induced insulin secretion and increases diabetes risk when combined with a high-fat diet (HFD) and obesity. KATP-channels in beta-cells with two K23 risk alleles (KK) showed decreased ATP inhibition, and the threshold for glucose-stimulated insulin secretion from KK islets was increased. Consequently, the insulin response to glucose and glycemic control was impaired in KK mice fed a standard diet. On an HFD, the effects of the KK genotype were exacerbated, accelerating diet-induced diabetes progression and causing beta-cell failure. We conclude that the K23 variant increases diabetes risk by impairing insulin secretion at threshold glucose levels, thus accelerating loss of beta-cell function in the early stages of diabetes progression. |
