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 AMPKThr172 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 AMPKSer485. This inhibitory Ser485 site can inhibit activation of AMPKThr172, possibly contributing to the impaired growth inhibitory effect by metformin at high glucose conditions.