Figure 7

Overview of selected AMPK and IGF-IR signalling pathways relevant to this study in normal (A) and hyperglycaemic (B) conditions. In normal conditions, metformin activates AMPK^Thr172 through the LKB1 signalling pathway. Activated AMPK inhibits cell growth by repressing mTOR activity through activation of TSC2 and phosphorylation of inhibitory serine residues on IRS-1. In addition, as demonstrated in the present study, metformin suppresses IGF-IR activation and reduces IRS-1 levels, which disable further signalling through the PI3K/Akt pathway. During hyperglycaemia, signalling through the IGF-IR pathway appears more robust, leading to phosphorylation of Akt and AMPK^Ser485. This inhibitory Ser485 site can inhibit activation of AMPK^Thr172, possibly contributing to the impaired growth inhibitory effect by metformin at high glucose conditions.