Pharmacologic treatment of type 2 diabetes includes sulfonylurea drugs which are associated with an increased risk of oral cancer, and metformin which is associated with lactic acidosis. Novel agents with less risks are needed. Basic and clinical research show that imidazoline compounds such as moxonidine, act centrally to lower blood pressure, and are insulin sensitizing agents.
Objectives: To provide insight into the mechanism(s) by which moxonidine acts as an insulin sensitizing agent
Methods: HEK293 kidney and HepG2 liver cells which possess both insulin and imidazoline receptors were subjected to dose-response and time-course studies with moxonidine. In some experiments, efaroxan, an inhibitor to the I1-subtype of imidazoline receptors was used. Some cells had the I1-imidazoline receptor anti-sera selected (IRAS) protein overexpressed before treatment. Treated cells were lysed, and Western blot was performed on cell extracts using phospho-specific antibodies. Glucose uptake studies were carried out using 3H-2-deoxyglucose.
Results: Moxonidine caused an increased phosphorylation of protein kinase B (PKB) by up to 3.5 fold in both HepG2 and HEK293 cells in a time and dose-dependent manner. The increased PKB phosphorylation could be blocked by efaroxan (10:M). Moxonidine caused a dose-dependent phosphorylation of protein dependent kinase (PDK) of up to 3 fold in HEK293 and 2 fold in HepG2 cells. Cells overexpressing the imidazoline receptor protein IRAS, showed greater phosphorylation of PKB compared to control, following moxonidine treatment. Moxonidine caused a time dependent increase in glucose uptake in HepG2 cells of up to 2.5 fold, and this could be blocked by efaroxan and by phosphatidyl inositol-3-kinase inhibitor LY294002.
Conclusions: Moxonidine activated key molecules in the insulin signaling pathway and may cause insulin sensitization by crosstalk between imidazoline and insulin receptors. Expanded use of insulin sensitizers to treat type 2 diabetes, may reduce the risk of oral cancer associated with agents that cause insulin release.