Effects of Metformin on Lactate Uptake and Gluconeogenesis in the Perfused Rat Liver

Abstract

To directly assess the effects of the biguanide, metformin, on hepatic gluconeogenesis, it was added at high therapeutic levels (90 microg/ml) to the medium perfusing an isolated rat liver. Lactate (1 mg/min) was infused simultaneously along with [14C]lactate with or without [3H]lactate. [6-(3)H]glucose was added at the beginning of the perfusion in studies where [3H]lactate was not infused. Glucose levels decreased relative to control studies (metformin dose = 0) and lactate concentrations increased in this closed system. Quantitative analysis of the relationship between labeled glucose and lactate indicated that the flux of carbon from lactate to glucose and CO2 was halved, whereas reflux from glucose to lactate increased by approximately 80%. This was corroborated by measurement of labeled lactate extraction as well as glucose, CO2, and lactate production across the liver. Glycogen content of the liver fell by 60% relative to control and was greater for the gluconeogenic pathway. These data are consistent with an inhibitory action of metformin on gluconeogenesis, which is due to a primary inhibition of hepatic lactate uptake.

Intrahepatic Mechanisms Underlying the Effect of Metformin in Decreasing Basal Glucose Production in Rats Fed a High-Fat Diet

“…This strongly suggests that, in addition to its downstream inhibitory action on glucose production at the level of Glc6Pase, Met has an upstream suppressive effect on the lactate uptake by the liver. This corroborates recent data obtained from perfused rat livers (30).…”

“…The decreasing effect of Met on HGP has been previously ascribed to the inhibition of either gluconeogenesis (2,3,30) or glycogenolysis (5). We emphasize that the major effect of Met on Glc6Pase activity reported herein strongly suggests that both pathways may be affected as well, because Glc6Pase is a common step for both gluconeogenesis and glycogenolysis.…”

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

“…Lactate, a substrate for HGP, was significantly increased in the high-dose Met group relative to both the lower Met dose and Veh. In isolated mitochondria or hepatocytes, Met has been shown to impair mitochondrial respiration by complex 1 inhibition, resulting in increased glycolysis and glucose uptake, decreased liver lactate uptake and decreased use of lactate as a substrate for glucose production (Radziuk et al 1997, Owen et al 2000, Otto et al 2003. However, Met is also known to activate lactate production in the intestine and muscle (Borst & Snellen 2001), which may hypothetically, in an in vivo system, lead to an excessive gluconeogenic substrate loading, overriding Met-related reductions in lactate usage.…”

Metformin, cancer and glucose metabolism

“…The multiplicity of effects of metformin also includes the reduction in gluconeogenesis in liver cells due to the decreased uptake of gluconeogenic substrates such as L-alanine (Komori et al 1993) and lactate (Radziuk et al 1997) and the direct inhibition of the redox shuttle enzyme glycerophosphate dehydrogenase (Madiraju et al 2014). Metformin also reduces glucose output through the decrease in cAMP, protein kinase A activity and phosphorylation of protein kinase A substrates induced by glucagon .…”