Researchers have unlocked more about how Metformin works (
Zydrune Polianskyte-Prause, Tuomas A. Tolvanen, Sonja Lindfors, Vincent Dumont, Mervi Van, Hong Wang, Surjya N. Dash, Mika Berg, Jette-Britt Naams, Laura C. Hautala, Harry Nisen, Tuomas Mirtti, Per-Henrik Groop, Kristiina Wähälä, Jukka Tienari, and Sanna Lehtonen. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity. The FASEB Journal 0 0:0. 15 Oct 2018).
Metformin inhibits SHIP2 in cultured cells and in skeletal muscle and kidney of db/db mice. In SHIP2-overexpressing myotubes, metformin ameliorates reduced glucose uptake by slowing down glucose transporter 4 endocytosis. SHIP2 overexpression reduces Akt activity and enhances podocyte apoptosis, and both are restored to normal levels by metformin. SHIP2 activity is elevated in glomeruli of patients with T2D receiving nonmetformin medication, but not in patients receiving metformin, compared with people without diabetes. Furthermore, podocyte loss in kidneys of metformin-treated T2D patients is reduced compared with patients receiving nonmetformin medication.
So not only does Metformin reduce the glucose production of the liver by downregulating GNG (Joseph A. Baur and Morris J. Birnbaum, Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo.Nature Medicinevolume 24, pages1384–1394 (2018)), it also increases the uptake of glucose in skeletal muscle and the kidneys.
Another paper on the action of Metformin (Baur JA, Birnbaum MJ. Control of gluconeogenesis by metformin: does redox trump energy charge?. Cell Metab. 2014;20(2):197-9.).
Here’s yet another paper on an effect of Metformin (Cheryl A. Collier, Clinton R. Bruce, Angela C. Smith, Gary Lopaschuk, and David J. Dyck. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle).
Because increased muscle lipid storage and impaired FA oxidation have been associated with insulin resistance in this tissue, the ability of metformin to reverse these abnormalities in muscle FA metabolism may be a part of the mechanism by which metformin improves glucose clearance and insulin sensitivity.