Insulin Signaling, Glucose Metabolism, and the Angiotensin II Signaling System

Taniyama et al. (1) have recently reported that angiotensin II (Ang II) in vitro decreases insulin receptor substrate-1 protein levels via Src, phosphoinositide-dependent kinase-1, and reactive oxygen species–mediated phosphorylation of Ser307. This leads to the targeting of insulin receptor substrate-1 for proteasome-dependent degradation, which then impairs insulin signaling. These findings provide a rationale for understanding the molecular basis of the positive effect of Ang II type 1 receptor antagonists on insulin resistance. The relationship between Ang II and insulin signaling shown in vitro leads us to assess whether this is operative also in vivo in humans. We analyzed a cohort of patients with Bartter’s/Gitelman’s syndrome (BS/GS), which attract much attention for persistent normo-/hypotension despite biochemical and hormonal abnormalities typical of hypertension. BS/GS, caused by gene defects in specific kidney transporters and ion channels, presents hypokalemia, sodium depletion, activation of the renin-angiotensin-aldosterone system, and increased …