The KCNJ11-E23K Gene Variant Hastens Diabetes Progression by Impairing Glucose-Induced Insulin Secretion
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posted on 2021-02-10, 22:40 authored by Gregor Sachse, Elizabeth Haythorne, Thomas Hill, Peter Proks, Russell Joynson, Raul Terrón-Expósito, Liz Bentley, Stephen J. Tucker, Roger D. Cox, Frances M. AshcroftThe ATP-sensitive potassium (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 glycaemic control were impaired in KK mice on a
standard diet. On a 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.