The effects of E23K polymorphism in Kir6.2 subunit on insulin sensitivity in skeletal muscle cells by long-chain fatty acyl CoA.
ATP-sensitive K(+) (K(ATP)) channels couple intermediary metabolism to cellular activity. Genetic disruption of these channels impairs glucose homeostasis. Similar effects occur from a single-nucleotide polymorphism of the Kir6.2 subunit seen in greater than 50% of the human population, which causes a point mutation of Glu23 to lysine. This E23K variant shows higher susceptibility to diabetes due to mechanisms that are not fully understood. This study was designed to examine the dysregulation of E23K on insulin sensitivity in the presence of long-chain fatty acyl CoA (LC-CoA), a major active form of free fatty acids. Physiological concentrations of LC-CoA decreased insulin sensitivity in E23K-transfected L6 muscle cells by increasing the activation of negative regulators in the insulin signaling pathway. LC-CoA also reduced IRS-1 and Akt phosphorylation and glucose transport. This effect was not due to the expression of the E23K mutant on cell membrane. Our results indicate that E23K could impair insulin sensitivity, thus predisposing E23K carriers to insulin resistance.
Wan
Jun
J
Institute of Cardiovascular Research, Renmin Hospital of Wuhan University, China. wanjun@whu.edu.cn
Jiang
Xuejun
X
Bai
Jing
J
Shen
Difei
D
Wang
Teng
T
D000214:Acyl Coenzyme A / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D011110:Polymorphism, Genetic; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D051381:Rats; D000099161:Kcnj11 Channel
D000214:Acyl Coenzyme A; D018698:Glutamic Acid; D007328:Insulin; D008239:Lysine; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel