Included findings of a fascinating study published in 2001, but previously overlooked, that provided detailed insight into Metformin's activation of AMP-kinase (AMPK) in rat tissue in ways that provide explanations for many of the anecdotally observed effects of Metformin that are not directly related to insulin resistance, most notably its ability to prevent weight regain in dieters and the way it appears to lower glycogen stores. Another study is cited that describes cardioprotective effects of the activation of AMPK that may explain metformin's observed cardioprotective effects.
Metformin's Activation of AMPK Blocks The Liver's Ability to Synthesize Triglycerides and Promotes Fat Burning.For an exhaustive look at how metformin's impact on AMP-kinase works in rat tissues (and probably human tissues), read this full text study:
Role of AMP-activated protein kinase in mechanism of metformin actionZhou et al. J. Clin. Invest. 108(8): 1167-1174 (2001). doi:10.1172/JCI13505.
This study found that
metformin activates AMPK in hepatocytes [liver cells]; as a result, acetyl-CoA carboxylase (ACC) activity is reduced [ACC promotes the creation of triglycerides], fatty acid oxidation is induced [i.e. fat is burned], and expression of lipogenic enzymes is suppressed [lipogenic enzymes are needed to create triglycerides].It also found that glucose uptake in muscles by metformin required the activation of AMPK. When it was blocked the uptake did not happen.
AMPK activation is also known to increase the breakdown of glycogen, which may be why some low carbers have observed that their glycogen stores appear already depleted when they embark on a low carb diet, so they don't lose the glycogen-associated water weight at the start of the diet that dieters lose who are not taking metformin. It may also be why when theu carb up they don't gain a lot of instant water weight either.
It is this impact of metformin on the liver, which is independent of its impact on glucose absorption that probably explains why metformin often causes modest weight loss, especially when it is first taken. It also explains why it makes weight loss maintenance much easier even in insulin sensitive dieters such as myself. Blocking the synthesis of fats and promoting the burning of fat at the liver (and possibly muscles) makes it much harder to gain weight.
Stimulation of AMPK May Be Why Metformin Appears CardioprotectiveAMPK has also been shown to have a protective effect on the heart. This review describes how AMPK may protect the body during heart attacks.
AMP-Activated Protein Kinase Conducts the Ischemic Stress Response Orchestra Lawrence H. Young. Circulation. 2008;117:832-840 doi: 10.1161/CIRCULATIONAHA.107.713115