Reframing metformin as a gut-targeted glucose-lowering therapy: Mechanistic insights and translational relevance

1. Introduction

The development and use of metformin – a longstanding cornerstone of type 2 diabetes mellitus (T2DM) therapy and a World Health Organisation essential medication – attest to the unpredictability of both scientific advancement and clinical translation. The quote from the legendary American baseball player and coach, Yogi Berra, well known for his malapropisms, is therefore apt. Originally derived from a plant (Galega officinalis) and used traditionally as a folk remedy, metformin’s substantial glucose-lowering capacity, without the induction of hypoglycaemia, was first appreciated in 1929. Despite this early recognition, metformin was not introduced for the management of T2DM until 1957 (in France) and only gained approval from the US Food and Drug Administration in 1995. It is now appreciated that metformin also has pleotropic properties beyond glucose lowering, which are being explored in diverse contexts, including ageing, cancer, and both cardiovascular and neurological disorders. Given its erratic development, it is perhaps not surprising that recent advances have redefined both the sites and mechanisms underlying the glucose-lowering action of metformin – a paradigm shift from the liver to the intestine [1]. This commentary summarises these insights and their substantial implications for refining the clinical application of metformin, particularly in settings where use of conventional formulations is constrained or contraindicated, such as gestational diabetes mellitus (GDM) and T2DM associated with renal impairment.