Metformin: Blood sugar control is also a matter of the mind

The long-established active ingredient metformin is the drug of choice for the treatment of type 2 diabetes in overweight, non-insulin-dependent diabetics. Despite its long availability , the exact mechanism of metformin's action remains unclear . It is believed that metformin primarily exerts a beneficial effect on blood sugar levels by reducing glucose production in the liver. This effect appears to be mediated by the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK).

However, this is probably not the only mechanism of action. Inhibition of mitochondrial respiratory chain complexes, influence on cAMP signaling, and inhibition of mitochondrial glycerophosphate dehydrogenase and fructose-1,6-bisphosphatase are also under discussion. Furthermore, metformin also appears to mediate a therapeutic effect by altering microbiome dynamics, increasing intestinal glucose uptake, and enhancing the hormonal secretion of growth and differentiation factor 15 and glucagon-like peptide 1 (GLP-1).

As if that weren't enough, researchers led by Dr. Hsiao-Yun Lin from Baylor College of Medicine in Houston have now discovered that the brain also mediates clinically relevant effects of metformin. The results of their study have been published in the journal "Science Advances."

Crucial to the results of this study were mice with a specific knockout of Ras-related protein 1 (Rap1) in the forebrain (Rap1ΔCNS mice). Rap1 is a small guanosine triphosphatase (GTPase), similar to the better-known proto-oncogene Ras. In their GDP-bound form, these proteins are inactive and become active when they bind GTP. In this form, they regulate countless cellular processes, with Rap1 being predominantly involved in cell adhesion and the formation of cell junctions.

The Rap1ΔCNS mice used by the researchers as a model system showed unexpected resistance to the antidiabetic effects of metformin at clinically relevant low doses (50 to 150 mg/kg), which pointed in the right direction. Other antidiabetic agents, including rosiglitazone, exendin-4, glibenclamide, dapagliflozin, and insulin, continued to lead to normal blood sugar reduction. With metformin, in contrast, blood sugar reduction was only achieved in the model mice at extremely high doses of ≥ 200 mg/kg.