Kir6.2 Variant E23K Increases ATP-Sensitive K+ Channel Activity and Is Associated With Impaired Insulin Release and Enhanced Insulin Sensitivity in Adults With Normal Glucose Tolerance
Year: 2009
Type: article
Study design: Observational Study
Abstract: OBJECTIVE: The E23K variant in the Kir6.2 subunit of the ATP-sensitive K(+) channel (K(ATP) channel) is associated with increased risk of type 2 diabetes. The present study was undertaken to increase our understanding of the mechanisms responsible. To avoid confounding effects of hyperglycemia, insulin secretion and action were studied in subjects with the variant who had normal glucose tolerance. RESEARCH DESIGN AND METHODS: Nine subjects with the E23K genotype K/K and nine matched subjects with the E/E genotype underwent 5-h oral glucose tolerance tests (OGTTs), graded glucose infusion, and hyperinsulinemic-euglycemic clamp with stable-isotope-labeled tracer infusions to assess insulin secretion, action, and clearance. A total of 461 volunteers consecutively genotyped for the E23K variant also underwent OGTTs. Functional studies of the wild-type and E23K variant potassium channels were conducted. RESULTS: Insulin secretory responses to oral and intravenous glucose were reduced by approximately 40% in glucose-tolerant subjects homozygous for E23K. Normal glucose tolerance with reduced insulin secretion suggests a change in insulin sensitivity. The hyperinsulinemic-euglycemic clamp revealed that hepatic insulin sensitivity is approximately 40% greater in subjects with the E23K variant, and these subjects demonstrate increased insulin sensitivity after oral glucose. The reconstituted E23K channels confirm reduced sensitivity to inhibitory ATP and increase in open probability, a direct molecular explanation for reduced insulin secretion. CONCLUSIONS: The E23K variant leads to overactivity of the K(ATP) channel, resulting in reduced insulin secretion. Initially, insulin sensitivity is enhanced, thereby maintaining normal glucose tolerance. Presumably, over time, as insulin secretion falls further or insulin resistance develops, glucose levels rise resulting in type 2 diabetes.
Source: Diabetes
DOI: 10.2337/db09-0025
Authors: Dennis T. Villareal, Joseph C. Koster, Heather Robertson, Alejandro Akrouh, Kazuaki Miyake, Graeme I. Bell, Bruce W. Patterson, Colin G. Nichols, Kenneth S. Polonsky
Institutions: Washington University in St. Louis, University of Chicago
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: University of Chicago, University of Washington, Institute of Clinical and Translational Sciences, Kovler Family Foundation, National Institutes of Health, Diabetes Research and Training Center, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: G1515766535, Diabetes Research & Training Center, REGULATION OF HEPATIC INSULIN EXTRACTION, G2807054497, G303945890, G552340580, Regulation of Hepatic Insulin Extraction, Diabetes Research and Training Center, ELECTRICAL CONTROL OF INSULIN SECRETION, G87705910, Washington University Nutrition Obesity Research Center, Diabetes Research Center, Diabetes Research and Training Center
OpenAlex ID: W2105169225