Selective Kinase Response Modulators (SKRMS) from Humulus lupulus and Acacia nilotica Modulate Multiple Kinases and Improve Insulin Sensitivity in vitro and in vivo

Abstract

Metabolic syndrome afflicts an estimated 65 million people in the US and is correlated with obesity, insulin resistance, dyslipidemia, atherosclerosis, coronary heart disease, and type 2 diabetes. We screened 203 phytoextracts for lipogenic activity in the murine 3T3-L1 adipocyte under conditions of insulin resistance. A modified hop extract, Rho-isoalpha acids (RIAA) and an Acacia nilotica extract (ANE) increased lipid accumulation 225% and 170%, respectively, compared to 140% for troglitazone and 125% for rosiglitazone. RIAA and ANE demonstrated synergy at several ratios. Additional 3T3-L1 studies showed that RIAA and certain RIAA + ANE combinations improved insulin signaling through the PI3K/Akt pathway, decreased IRS-1pS307 and increased glucose uptake. Screening RIAA and ANE against select protein kinases in cell free assays indicated selective inhibition of multiple kinases including PKC, PI3K, and GSK3. Oral dosing RIAA and ANE in combination and at various ratios dramatically lowered serum glucose and insulin within seven days in the diabetic db/db mouse model, similar to metformin and rosiglitazone. RIAA + ANE appear to cooperatively modulate multiple protein kinases, improving insulin signaling in the adipocyte, in vitro, and in the whole body (db/db mouse). We have coined the term Selective Kinase Response Modulators (SKRM) to describe molecules that cooperatively modulate multiple kinases of a given pathway (Supported by MetaProteomics, LLC).