Lars Christian Gormsen, march 2016
Metformin has been used for decades and is now the preferred first-line glucose-lowering drug in patients with type 2 diabetes. In some patients, metformin also has a favorable effect on circulating lipids, presumably due to enhanced hepatic oxidation of fatty acids. However, metformin pharmacokinetics and drug effects vary considerably between patients. These variations are likely to be caused by the complex trans-cellular transport of metformin through diverse organs, ranging from the liver to the intestines, skeletal muscles and the kidney. Most of these organs are inaccessible in experimental setups and consequently, surprisingly little is known about the uptake and elimination of metformin in target tissues.
We are therefore using 11C-labelled metformin PET in preclinical and clinical studies to non-invasive imaging of metformin bio-distribution and tissue kinetics.
We have validated a novel method to synthesize the radiotracer and are currently exploring the effect of mutations in the human gene encoding the major metformin transporter in the liver, OCT1.
In a parallel setup, the effects of oral metformin on hepatic fatty acid uptake, oxidation and re-secretion from the liver is studied in a group of patients with type 2 diabetes of short duration. In these studies, we use 11C-labelled metformin PET and 14C-labelled triglycerides to explore the intra-hepatic fate of fatty acids before and after metformin treatment. Combined, these studies should enable us to optimally identify the patients who will benefit the most from metformin treatment. In addition, our estimates of tissue uptake and elimination may shed light on some of the other beneficial effects of metformin, particularly in patients with e.g. breast and prostate cancer.