Metformin Stimulates Intestinal Glycolysis and Lactate Release: A single‐Dose Study of Metformin in Patients With Intrahepatic Portosystemic Stent

Abstract

The pharmacodynamic and pharmacokinetic properties of metformin translate poorly from animal models to humans. In humans, metformin increases intestinal uptake of glucose tracers, but the fate of glucose is unknown.

Metformin maintains intrahepatic triglyceride content through increased hepatic de novo lipogenesis

“…The effects of an acute, single-dose of metformin on the plasma metabolome has been investigated. Rittig et al ( 46 ) reported that 90 min after patients with cirrhosis had taken 1000 mg of metformin, tricarboxylic acid (TCA) cycle intermediates were elevated suggesting increased tissue glycolysis, along with decreased microbiome-derived metabolites linked to benzoate and hippurate metabolism. Others have found significant changes in pathways linked with valine, leucine and isoleucine biosynthesis, phenylalanine metabolism, and FA metabolism after healthy males were given 500 mg of metformin ( 47 ).…”

Metformin improves glycemia independently of skeletal muscle AMPK via enhanced intestinal glucose clearance

“…Several lines of evidence indicate that the gastrointestinal tract is involved in the acute anti-hyperglycemic effect of metformin (Bailey et al, 2008; Koffert et al, 2017; Ma et al, 2022; Rittig et al, 2021). In accordance, we observed that metformin increased glucose clearance by ~75% in the proximal part (duodenum and jejunum) of the intestine (Figure 2G) that displayed ~10- and 70-fold higher metformin concentrations compared to the liver and muscle, respectively (Figure 2H).…”

“…In accordance, we observed that metformin increased glucose clearance by ~75% in the proximal part (duodenum and jejunum) of the intestine (Figure 2G) that displayed ~10- and 70-fold higher metformin concentrations compared to the liver and muscle, respectively (Figure 2H). Following uptake into the intestine, glucose is directed through glycolysis to form lactate since metformin increases anaerobic glucose metabolism in the intestine (Bailey et al, 2008; Rittig et al, 2021). This likely contributes to increased blood lactate levels that are associated with regular metformin use (Bailey and Turner, 1996).…”

“…Indeed, we found that the glucose clearance increased by ~75% in the intestine of acutely metformin-treated mice. This signifies that the intestine acts as a glucose sink following metformin treatment and thus plays a prominent role for the acute blood glucose-lowering effect of metformin (Bailey et al, 2008; Horakova et al, 2019; Rittig et al, 2021; Yang et al, 2021).…”

“…Several attempts have been made to elucidate the exact mechanism(s) by which metformin exerts its effect on blood glucose levels (Foretz et al, 2019; Rena et al, 2017). Some evidence points towards a role of metformin action to suppress hepatic glucose production (Foretz et al, 2010; Fullerton et al, 2013; Hunter et al, 2018; Madiraju et al, 2014, 2018; Miller et al, 2013; Shaw et al, 2005) but other sites of metformin action have also been proposed including the intestine (Bailey et al, 2008; Koffert et al, 2017; Ma et al, 2022; Rittig et al, 2021), gut microbiota (Wu et al, 2017), gut-brain-liver neuronal axis (Duca et al, 2015), and skeletal muscle (Musi et al, 2002; Zhou et al, 2001). This highlights that metformin likely exploits various tissue-specific mechanisms to regulate blood glucose levels.…”