Association of the Kir6.2 E23K variant with reduced acute insulin response in African-Americans.

ABSTRACT

CONTEXT ATP-sensitive potassium channels are composed of pore-forming (Kir6.x) and regulatory sulfonylurea receptor (SURx) subunits and have been implicated in the maintenance of glucose homeostasis. Kir6.2 and SUR1 are expressed in a broad range of tissues, and no contemporary studies have addressed the physiological impact of variants in Hispanic-Americans and African-Americans carefully phenotyped for components of glucose homeostasis. OBJECTIVE: The objective of this study was to evaluate two nonsynonymous variants in Kir6.2 (E23K) and SUR1 (A1369S) and determine their role in vivo. DESIGN AND SETTING: The Insulin Resistance Atherosclerosis Family Study (IRAS-FS) is a community-based study of Hispanic-Americans (San Antonio, TX, and San Luis Valley, CO) and African-Americans (Los Angeles, CA). PARTICIPANTS: A total of 1,040 Hispanic-Americans and 500 African-American individuals formed the basis of this study. MAIN OUTCOME MEASURE(S) The primary glucose homeostasis phenotypes of interest in this study were derived from the frequently sampled iv glucose tolerance test and included insulin sensitivity (S(I)), acute insulin response, and disposition index. RESULTS: In African-Americans, both variants were associated with a significant reduction in insulin secretion in glucose-tolerant carriers of the minor alleles (additive P = 0.00053). S(I), a measure of insulin sensitivity, was not associated. In Hispanic-Americans, there was no association with measures of glucose homeostasis. CONCLUSIONS: We conclude that variation marked by the Kir6.2 E23K and SUR1 A1369S mutations is associated with alterations in glucose-stimulated insulin secretion but not with other measures of glucose homeostasis in an African-American population.