Excessive gluconeogenesis causes the hepatic insulin resistance paradox and its sequelae

The effect of metformin on urate metabolism: Findings from observational and Mendelian randomization analyses

“…3 This inhibition of gluconeogenesis leads to reduced fatty acid and urate synthesis, thereby decreasing serum urate levels. 34 Our analysis, while showing a lack of discernible effects on urate for the remaining four selected targets, does not definitively negate their potential influence. It is important to recognize that the intricate interplay of complex biological pathways, genetic instrument strength affected by genetic variability, sample size and statistical power, biological target functionality, and the potential for residual confounding collectively contribute to the variable effects observed across different metformin targets.…”

“…Metformin's inhibitory action on the MCI of the respiratory chain prevents mitochondrial ATP production and activates AMPK, ultimately inhibiting gluconeogenesis 3 . This inhibition of gluconeogenesis leads to reduced fatty acid and urate synthesis, thereby decreasing serum urate levels 34 …”

Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective

“…Mice with inhibition of intestinal gluconeogenesis exhibited increased hepatic lipid uptake and de novo lipogenesis, thereby increasing the risk of MAFLD [118]. Notably, over-enhanced gluconeogenesis further contributes to hepatic insulin resistance and promotes de novo lipogenesis, which is involved in MAFLD progression from steatosis to NASH and fibrosis, and ultimately increases the risk of cirrhosis and hepatocellular carcinoma [119]. Recent studies have revealed the important role and mechanism of inhibiting hepatic gluconeogenesis in ameliorating steatosis and alleviating MAFLD [120,121].…”

Effect of short-term moderate intake of ice wine on hepatic glycolipid metabolism in C57BL/6J mice

“…In vivo, fructose is phosphorylated by the high-activity keto-hexokinase C (KHK-C) to produce fructose 1-phosphate, which continues to be broken down to dihydroxyacetone phosphate and glyceraldehyde by aldolase B, and then enters into the process of glycolysis or participates in gluconeogenesis. 7 Gluconeogenesis is a process of net synthesis of glucose from non-glucose substances (including fructose, lactate, pyruvate, glycerol, and some amino acids) as raw materials in living organisms, 8 in which non-glucose substances are converted to oxaloacetate, which is catalyzed by phosphoenolpyruvate carboxykinase (PEPCK) to form phosphoenolpyruvic acid (PEP), and then undergoes a complicated reaction to finally become glucose. 9 Fatty acid synthesis occurs in the cytoplasmic matrix, where acetyl coenzyme A (acetyl-CoA), the raw material, is catalyzed by acetyl coenzyme A carboxylase (ACC), a catalytic process that is the rate-limiting and irreversible step in fatty acid synthesis.…”