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- Title
Association of the Kir6.2 E23K Variant with Reduced Acute Insulin Response in African Americans: The IRAS Family Study.
- Authors
Palmer, Nicholette D.; Campbell, Joel K.; Langefeld, Carl D.; Bryer-Ash, Michael; Haffner, Steven M.; Rotter, Jerome I.; Bowden, Donald W.
- Abstract
ATP-sensitive potassium (K[sub ATP]) channels are composed of pore-forming (Kir6.x) and regulatory sulfonylurea receptor (SURx) subunits. Population genetic studies and animal models have implicated the K[sub ATP] channel(s) in the maintenance of glucose homeostasis. While it is widely believed that Kir6.2 and SUR1 (encoded by KCNJ11 and ABCC8, respectively), directly effect pancreatic β-cell function, evidence is based primarily on experiments in model systems. Kir6.2 is expressed in a broad range of tissues, e.g. pancreatic islet cells and skeletal muscle, and no studies have addressed the physiological impact of variants in this gene in humans carefully phenotyped for different components of glucose homeostasis. The objective of this study was to evaluate the nonsynonymous E23K variant in Kir6.2 (expressed in both the pancreatic islet cell and skeletal muscle K[sub ATP] channels). The E23K variant was genotyped in 1411 Hispanic and 605 African American DNAs from participants in the Insulin Resistance and Atherosclerosis Family Study (IRASFS). Multiple measures of glucose homeostasis have been assessed in these subjects through minimal model analysis of the frequently sampled intravenous glucose tolerance test (FSIGT) and a fasting blood draw. In African Americans, the E23K variant of Kir6.2 was associated with a significant reduction in insulin secretion as measured by acute insulin response (AIR) in nondiabetic subjects P=0.020). The association followed a dominant (P=0.006) or additive (P=0.005) genetic model with E/E and E/K genotypes having a higher phenotypic mean (1059.48 ± 863.24 pmol/l and 809.03 ± 709.24 pmol/l, respectively) when compared with the K/K genotype (664.93 ± 627.57 pmol/l). Other measures of glucose homeostasis including insulin sensitivity (S[sub I]), and glucose effectiveness (S[sub G]) were not associated (P=745 and 0.608, respectively). These findings are consistent with in vitro studies which suggested E23K favors an open conformation of the protein complex thereby decreasing insulin secretion. Evidence of association with glucose homeostasis traits was not observed in Hispanic Americans. We conclude that the E23K mutation of the Kir6.2 gene is nominally associated with alterations in glucose-stimulated insulin secretion and is not strongly associated with other, measures of glucose homeostasis in an African American population.
- Subjects
INSULIN receptors; INSULIN resistance; HEALTH of African Americans; POTASSIUM channels; ADENOSINE triphosphate; BLOOD sugar; HOMEOSTASIS; PANCREATIC beta cells
- Publication
Diabetes, 2007, Vol 56, pA293
- ISSN
0012-1797
- Publication type
Article