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- Title
The KCNJ11-E23K Gene Variant Hastens Diabetes Progression by Impairing Glucose-Induced Insulin Secretion.
- Authors
Sachse, Gregor; Haythorne, Elizabeth; Hill, Thomas; Proks, Peter; Joynson, Russell; Terrón-Expósito, Raul; Bentley, Liz; Tucker, Stephen J.; Cox, Roger D.; Ashcroft, Frances M.
- Abstract
The ATP-sensitive K+ (KATP) channel controls blood glucose levels by coupling glucose metabolism to insulin secretion in pancreatic b-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 glucoseinduced insulin secretion and increases diabetes risk when combined with a high-fat diet (HFD) and obesity. KATP-channels in b-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 b-cell failure. We conclude that the K23 variant increases diabetes risk by impairing insulin secretion at threshold glucose levels, thus accelerating loss of b-cell function in the early stages of diabetes progression.
- Publication
Diabetes, 2021, Vol 70, Issue 5, p1145
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db20-0691