Hepatic glucose uptake, gluconeogenesis and the regulation of glycogen synthesis

Abstract

Hepatic glycogen is replenished during the absorptive period postprandially. This repletion is prompted partly by an increased hepatic uptake of glucose by the liver, partly by metabolite and hormonal signals in the portal vein, and partly by an increased gluconeogenic flux to glycogen (glyconeogenesis). There is some evidence that the direct formation of glycogen from glucose and that formed by gluconeogenic pathways is linked. This includes: (i) the inhibition of all glycogen synthesis, in vivo, when gluconeogenic flux is blocked by inhibitors; (ii) a dual relationship between glucose concentrations, lactate uptake by the liver and glycogen synthesis (by both pathways) which indicates that glucose sets the maximal rates of glycogen synthesis while lactate uptake determines the actual flux rate to glycogen; (iii) the decrease of both gluconeogenesis and glycogen synthesis by the biguanide, metformin; and (iv) correlations between increased gluconeogenesis and liver glycogen in obese patients and animal models. The degree to which the liver extracts portal glucose is not entirely agreed upon although a preponderance of evidence points to about a 5% extraction rate, following meals, which is dependent on a stimulation of glucokinase. This enzyme may be linked to the expression of other enzymes in the gluconeogenic pathway. Perivenous cells in the liver may induce additional gluconeogenesis in the periportal cells by increasing glycolytically produced lactate. A number of potential mechanisms therefore exist which could link glycogen synthesis from glucose and gluconeogenic substrate.

Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

“…It maintains a balance between the uptake and storage of glucose by regulating glycogenesis and the production of glucose by glycogenolysis and gluconeogenesis (Radziuk & Pye 2001). Nonalcoholic fatty liver disease (NAFLD) is a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis.…”

N-(4-Substituted-benzoyl)-N′-(β-d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods

“…4,5 Hepatic glucose output is elevated in type 2 diabetic patients and current evidence indicates that glycogenolysis (release of an important contributor to the abnormally high production of glucose by the liver. 2,6,7 Glycogen phosphorylase (GP) is the enzyme responsible for glycogen breakdown to produce glucose and related metabolites for energy supply. 4,8,9 Due to its key role in modulation of glycogen metabolism, pharmacological inhibition of GP has been regarded as an effective therapeutic approach to treating type 2 diabetes.…”

SLC22A2 gene 808 G/T variant is related to plasma lactate concentration in Chinese type 2 diabetics treated with metformin

“…Non-metformin (n=200) [14] . Similarly, the present study indicates that the incidence of lactatemia in T2DM patients carrying the TT genotype in the metformin-treated group increased and their HbA1c decreased significantly compared to the nonmetformin-treated group.…”

“…Lactate, which is produced in the gut, liver, and peripheral tissues, such as erythrocytes and the skin, is utilized to form glucose in the liver [14] . The portion of lactate that is not metabolized is excreted almost completely in the urine by the kidney.…”