TY - JOUR

T1 - Metformin stimulates intestinal glycolysis and lactate release

T2 - A single-dose study of metformin in patients with intrahepatic portosystemic stent

AU - Rittig, Nikolaj

AU - Aagaard, Niels K

AU - Sundelin, Elias

AU - Villadsen, Gerda E

AU - Sandahl, Thomas D

AU - Holst, Jens J

AU - Hartmann, Bolette

AU - Brøsen, Kim

AU - Grønbaek, Henning

AU - Jessen, Niels

PY - 2021

Y1 - 2021

N2 - The pharmacodynamic effects of metformin remain elusive, but several lines of evidence suggest a critical role of direct effects in the gastrointestinal (GI) tract. We investigated if metformin stimulates intestinal glucose metabolism and lactate release in the prehepatic circulation. We included eight patients with transjugular intrahepatic portosytemic stent (TIPS) in an open label study. Portal and arterialized peripheral blood was obtained before and 90 minutes after ingestion of 1000 mg metformin. Metformin increased lactate concentrations by 23% (CI95%:6-40) after 90 minutes in the portal vein. The plasma concentration of glucose, insulin, and C-peptide was higher in the portal vein compared with arterialized blood (p<0.05, all) and was lowered at both sampling sites following metformin ingestion (p<0.01, all). Plasma concentration of GLP-1 was 20% (CI95%:2-38) higher in the portal vein at baseline and metformin increased the concentration with 11% (1.5 pmol/l, p=0.05). The median concentration of growth differentiation factor 15 was 10% (CI95%:1-19) higher in the portal vein compared with arterialized blood. Ninety minutes after metformin administration, the median portal vein concentration increased to around 3000 ng/ml with a mean portal/arterial ratio of 1.5 (95%CI: 1.2 to 1.8). Non-targeted metabolomics showed that metformin acutely affected benzoate-hippurate metabolism. A single-dose of metformin directly affects substrate metabolism in the upper GI tract in humans with direct stimulation of non-oxidative glucose metabolism. These data suggest glucose lowering effects of metformin can be intrinsically linked with the GI tract without hepatic uptake of the drug.

AB - The pharmacodynamic effects of metformin remain elusive, but several lines of evidence suggest a critical role of direct effects in the gastrointestinal (GI) tract. We investigated if metformin stimulates intestinal glucose metabolism and lactate release in the prehepatic circulation. We included eight patients with transjugular intrahepatic portosytemic stent (TIPS) in an open label study. Portal and arterialized peripheral blood was obtained before and 90 minutes after ingestion of 1000 mg metformin. Metformin increased lactate concentrations by 23% (CI95%:6-40) after 90 minutes in the portal vein. The plasma concentration of glucose, insulin, and C-peptide was higher in the portal vein compared with arterialized blood (p<0.05, all) and was lowered at both sampling sites following metformin ingestion (p<0.01, all). Plasma concentration of GLP-1 was 20% (CI95%:2-38) higher in the portal vein at baseline and metformin increased the concentration with 11% (1.5 pmol/l, p=0.05). The median concentration of growth differentiation factor 15 was 10% (CI95%:1-19) higher in the portal vein compared with arterialized blood. Ninety minutes after metformin administration, the median portal vein concentration increased to around 3000 ng/ml with a mean portal/arterial ratio of 1.5 (95%CI: 1.2 to 1.8). Non-targeted metabolomics showed that metformin acutely affected benzoate-hippurate metabolism. A single-dose of metformin directly affects substrate metabolism in the upper GI tract in humans with direct stimulation of non-oxidative glucose metabolism. These data suggest glucose lowering effects of metformin can be intrinsically linked with the GI tract without hepatic uptake of the drug.

U2 - 10.1002/cpt.2382

DO - 10.1002/cpt.2382

M3 - Journal article

C2 - 34331316

VL - 110

SP - 1329

EP - 1336

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 5

ER -