Metformin
Metformin chronically activates amp-activated kinase (AMPK). AMPK slows liver glucose output by down-regulating expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase; in skeletal muscle, it boosts the efficiency of insulin-stimulated glucose uptake by increasing expression of GLUT-4. These effects mandate a down-regulation of insulin secretion.
The resulting reduction of liver insulin activity will suppress liver production of IGF-I while boosting that of IGFBP-1, thereby decreasing plasma free IGF-I.
Stimulation of AMPK with Metformin also interferes with the Ras–Raf–MEK–ERK pathway of IGF-I signaling by inhibiting the ability of IGF-I to activate ras and its downstream targets.
Stimulation of AMPK with Metformin also blocks the ability of the PI3K-Akt pathway to activate mTOR.
Since the Ras–Raf–MEK–ERK cascade, as well as mTOR and its downstream targets, are key mediators of IGF-I’s ability to increase hypertrophy a systemic increase in AMPK activity as brought about by Metformin will hinder the potential for hypertrophy not only by diminishing plasma levels of insulin and free IGF-I, but also by intervening in the post-receptor intracellular pathways mediated events which bring about these bodybuilding effects.