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Association of the Kir6.2 E23K Variant with Reduced Acute Insulin Response in African-Americans

Departments of Biochemistry (N.D.P., D.W.B.), Internal Medicine (D.W.B), and Biostatistical Sciences (C.D.L.), and Center for Human Genomics (N.D.P., D.W.B.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157; Gonda (Foldschmied) Diabetes Center (M.B.-A.), Division of Endocrinology, Diabetes and Hypertension (M.B.-A.), David Geffen School of Medicine at UCLA, Los Angeles, California 90095; and Medical Genetics Institute (J.I.R., K.D.T.), Cedars-Sinai Medical Center, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Donald W. Bowden, Ph.D., Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157. E-mail: dbowden{at}wfubmc.edu.

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 1040 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.

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