LAUSR

To the Editor: It is currently accepted that metformin inhibits complex I of the respiratory chain, altering the ratio of AMP or ADP to ATP and subsequently inhibiting gluconeogenesis [1, 2]. The original insulin clamp studies of the 1990s investigating the effect of metformin on glucose metabolism in obese and lean individuals with type 2 diabetes support this mechanism of action [3], demonstrating a reduction in endogenous glucose production (EGP) following metformin treatment. However, an increasing number of alternative pathways of metformin action have been proposed, including 5′AMP-activated protein kinase (AMPK)-dependent and -independent effects, as well as gastrointestinal mechanisms of action [4, 5]. It is, therefore, with great interest that we read the article recently published in Diabetologia entitled ‘Metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes’ [6]. In the article, using studies of whole-body glucose metabolism, including non-steady state glucose tracer kinetics and hyperinsulinaemic–euglycaemic clamping, Gormsen et al report that metformin treatment is associated with an increase in the glucose rate of disappearance (Rd), glucagon levels and EGP both in healthy control individuals and in individuals with recent-onset type 2 diabetes with good glycaemic control. These changes were absent in a placebo-treated group. In this letter we present data from our recent study of nondiabetic individuals, which aimed to investigate the effect of metformin on glucose kinetics. Our findings corroborate the findings of Gormsen et al, adding to the pool of evidence indicating that the mechanism of action of metformin may be extra-hepatic. Our study was conducted in the Clinical Research Centre at Ninewells Hospital, Dundee, between September 2016 and August 2017. It was co-sponsored by the University of Dundee and NHS Tayside, and ethical approval was granted by the East of Scotland Research Ethics Committee. The study was conducted in accordance with the Good Clinical Practice guidelines and the Declaration of Helsinki. The study was registered on the public database clinicaltrials.gov (identifier NCT02733679). Formal written informed consent was obtained from each individual prior to inclusion. Here we report the data from the non-diabetic controls. In this non-randomised, non-blinded, open-label crossover study we treated non-diabetic individuals with two commonly used diabetes drugs, namely, metformin and pioglitazone. The time in study was 17 weeks, consisting of two 8 week treatment periods separated by 1 week washout. During treatment period one, participants were treated with metformin, titrated to a maximum of 1000 mg twice daily. During treatment period two, participants were treated with pioglitazone, titrated to 30 mg once daily. Each participant had three study visits: baseline, post-metformin and post-pioglitazone. Each visit included a dual-tracer mixed-meal test (MMT), to assess glucose kinetics in the fasted and non-steady state. In brief, participants received a standardised meal the evening before the MMT. They were fasted from midnight * Ewan R. Pearson [email protected]