Metformin has been used as a first-line drug for the treatment of individuals with type 2 diabetes for over 60 years. The mechanism by which metformin lowers glucose levels in the blood has been controversial. It has been generally accepted that it is likely the that metformin’s effects are mediated through inhibition of mitochondrial respiratory complex I, which leads to the elevation of 5′ -adenosine monophosphate (AMP) levels. Studies undertaken by Gaochao Zhou and David Moller in 2001 and then Reuben Shaw and Lew Cantley in 2005 suggested that AMP lowers glucose levels by activating AMPK in the liver that lowers glucose levels by inhibiting hepatic glucose production. This conclusion was latter challenged by Benoit Viollet and Marc Foretz in 2010, as metformin still lowered blood glucose in mice lacking AMPK in the liver.

In a compelling study undertaken by ex-Alessi lab postdoc and MRC-PPU PI Kei Sakamoto and ex-MRC postdoc (with Kei) Roger Hunter, now working in Nestlé Research, provides strong evidence that the ability of metformin to reduce glucose production from the liver is mediated by AMP binding to and inhibiting fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis. Kei Sakamoto working with Elton Zeqiraj, another ex-Alessi postdoc now a PI at Leeds University were able to design a mutant of FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P2). Kei then generated a knock-in mouse of this mutant and showed that this mutation markedly blunted their response to metformin treatment. Kei also showed that the antihyperglycemic effect of metformin in high-fat diet–fed diabetic FBP1-KI mice was also significantly reduced. These results also indicate that targeting FBP1 could lead to the development of more effective glucose lowering drugs for the treatment of diabetes. To read a copy of Kei’s paper click here (https://www.nature.com/articles/s41591-018-0159-7).

Congratulations as well to Kei who has also been promoted to “Nestlé Fellow”. This is the highest recognition level of expertise in R&D and is granted to individuals who are internationally recognized leaders in science and technology.