Use of metformin is associated with a decreased risk of HCC in diabetic patients in a dose-dependent manner, via inhibition of hepatoma cells proliferation and induction of cell cycle arrest at G0/G1 phase.

A fine control of the blood glucose level is essential to avoid hyper-or hypo-glycemic shocks associated with many metabolic disorders, including diabetes mellitus and type I glycogen storage disease. Between meals, the primary source of blood glucose is gluconeogenesis and glycogenolysis. In the final step of both pathways, glucose-6-phosphate (G6P) is hydrolyzed to glucose by the glucose-6-phosphatase (G6Pase) complex. Because G6Pase (renamed G6Pase-␣) is primarily expressed only in the liver, kidney, and intestine, it has implied that most other tissues cannot contribute to interprandial blood glucose homeostasis. We demonstrate that a novel, widely expressed G6Pase-related protein, PAP2.8/ UGRP, renamed here G6Pase-␤, is an acid-labile, vanadate-sensitive, endoplasmic reticulum-associated phosphohydrolase, like G6Pase-␣. Both enzymes have the same active site structure, exhibit a similar K m toward G6P, but the V max of G6Pase-␣ is ϳ6-fold greater than that of G6Pase-␤. Most importantly, G6Pase-␤ couples with the G6P transporter to form an active G6Pase complex that can hydrolyze G6P to glucose. Our findings challenge the current dogma that only liver, kidney, and intestine can contribute to blood glucose homeostasis and explain why type Ia glycogen storage disease patients, lacking a functional liver/kidney/intestine G6Pase complex, are still capable of endogenous glucose production.

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT). In addition to disrupted glucose homeostasis, GSD-Ib patients have unexplained and unexpected defects in neutrophil respiratory burst, chemotaxis and calcium flux, in response to the bacterial peptide f-Met-Leu-Phe, as well as intermittent neutropenia. We generated a G6PT knockout (G6PT-/-) mouse that mimics all known defects of the human disorder and used the model to further our understanding of the pathogenesis of GSD-Ib. We demonstrate that the neutropenia is caused directly by the loss of G6PT activity; that chemotaxis and calcium flux, induced by the chemokines KC and macrophage inflammatory protein-2, are defective in G6PT-/- neutrophils; and that local production of these chemokines and the resultant neutrophil trafficking in vivo are depressed in G6PT-/- ascites during an inflammatory response. The bone and spleen of G6PT-/- mice are developmentally delayed and accompanied by marked hypocellularity of the bone marrow, elevation of myeloid progenitor cell frequencies in both organs and a corresponding dramatic increase in granulocyte colony stimulating factor levels in both GSD-Ib mice and humans. So, in addition to transient neutropenia, a sustained defect in neutrophil trafficking due to both the resistance of neutrophils to chemotactic factors, and reduced local production of neutrophil-specific chemokines at sites of inflammation, may underlie the myeloid deficiency in GSD-Ib. These findings demonstrate that G6PT is not just a G6P transport protein but also an important immunomodulatory protein whose activities need to be addressed in treating the myeloid complications in GSD-Ib patients.

Objectives The intestinal microbiota has been known to involve in obesity and host immune response. We aimed to investigate the intestinal microbiota and potential genetic function in relation to clinical presentation in psoriasis patients. Methods Faecal microbiota and predicted genetic function inferred from high‐throughput 16S ribosomal RNA sequencing were analysed between psoriasis (n = 32) and age‐, gender‐ and body mass index (BMI)‐matched non‐psoriasis subjects (n = 64), from a referral medical centre. The correlation between altered microbiota and disease activity, arthritis and systemic anti‐psoriatic drugs was also investigated. Results We observed a distinct faecal microbial community structure in psoriasis patients, with an increased abundance of phylum Firmicutes and decreased abundance of phylum Bacteroidetes, across different subgroup of subjects. Ruminococcus and Megasphaera, of the phylum Firmicutes, were the top‐two genera of discriminant abundance in psoriasis. A number of functional genes and metabolic pathways involving bacterial chemotaxis and carbohydrate transport were predicted over‐represented, whereas genes related to cobalamin and iron transport were predicted under‐represented in faecal microbiota of psoriasis patients. Conclusions The distinct faecal microbial composition in psoriasis might be associated with altered transport of carbohydrate, cobalamin and iron, as well as chemotaxis.