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Significance Insulin resistance is a metabolic disorder in which target cells fail to respond to physiological levels of circulating insulin, leading to hyperinsulinemia and glucose intolerance. The molecular mechanism underlying insulin resistance is still largely unknown. Here, we found that intracellular Ca 2+ overloading in obesity attenuates insulin-stimulated phosphorylation of protein kinase B and its downstream signaling by preventing membrane localization of various pleckstrin homology (PH) domains. When at high intracellular levels, Ca 2+ binds tightly with phosphoinositides to yield Ca 2+ -phosphoinositides (PIPs), abrogating the membrane targeting of PH domains and disrupting insulin signaling. Thus, we identified a previously unknown physiological function of intracellular Ca 2+ as a critical negative regulator of insulin signaling, especially through the formation of Ca 2+ -PIPs.
Kang et al. (Wed,) studied this question.