Exposure of aortae from db+/? non-diabetic control mice to high glucose (HG, 40 mM) containing Krebs for 3-h significantly (P < 0.05) reduced acetylcholine (ACh)-induced EDV compared to ACh-induced EDV in aortae maintained in normal glucose (NG, 11 mM) Krebs. The reduction of EDV was partially reversed following a 3-h exposure to 50 μM metformin; metformin also improved ACh-induced EDV in aortae from diabetic db/db mice. Immunoblot analysis of MMECs cultured in HG versus NG revealed a significant reduction of the ratio of phosphorylated (p-eNOS)/eNOS and p-Akt/Akt, but not the expression of total eNOS or Akt. The 3-h exposure of MMECs to metformin significantly (P < 0.05) reversed the HG-induced reduction in phosphorylation of both eNOS and Akt; however, no changes were detected for phosphorylation of AMPK or the expression of SIRT1.
Our data indicate that a 3-h exposure to metformin can reverse/reduce the impact of HG on endothelial function, via mechanisms linked to increased phosphorylation of eNOS and Akt.