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Metabolic Syndrome X, characterized by insulin resistance, dyslipidemia, obesity, and hypertension, affects over 70 million Americans. Imidazoline drugs, such as moxonidine, are emerging therapeutic agents for conditions associated with Syndrome X. Studies from our laboratory showed a reduction in blood pressure when moxonidine was injected into the rostral ventrolateral medulla (RVLM) of spontaneously hypertensive rats (SHR). Moxonidine also activated the insulin signaling cascade and increased glucose uptake in HEK 293T cells. Recently, we obtained a novel imidazoline compound, S43126. Interestingly, like moxonidine, S43126 reduced blood pressure in SHR rat model, whose effect was offset by I1‐imidazoline antagonist, efaroxan. However, S43126 showed no activity at the adrenoreceptors in rat tail artery. Immunoblotting analyses also showed that S43126 activated components of the insulin signaling pathway, such as protein kinase B (PKB/Akt) and insulin receptor substrates (IRS1/2), which were abolished by efaroxan. Furthermore, treatment of cells overexpressing cloned I1‐imidazoline receptor (IRAS) or siRNA‐silenced IRAS confirmed that the I1‐imidazoline receptor contributed to moxonidine and S43126 stimulation of the insulin signaling cascade. These results implicate S43126 and moxonidine as centrally acting antihypertensive agents that may regulate the insulin receptor signaling. This work is supported by NIH RO3DK067945‐01.