Plasma glucose levels are reduced in rats and mice treated with an inhibitor of glucose-6-phosphate translocase.

Abstract

The activity of glucose-6-phosphatase (G-6-Pase) in isolated rat microsomes was inhibited by a new selective inhibitor of the multi-subunit G-6-Pase system, 1-[2-(4-chloro-phenyl)-cyclopropylmethoxy]-3,4-dihydroxy-5-(3-imid azo[4,5-b]pyridin-1-yl-3-phenyl-acryloyloxy)-cyclohexanecarboxylic acid (compound A) with a 50% inhibitory concentration (IC50) of approximately 10 nmol/l. Compound A (500 nmol/l) inhibited the uptake of [14C]glucose-6-phosphate (G-6-P) into intact isolated rat microsomes, confirming that this agent blocks G-6-P translocation, as suggested by previous studies using intact and permeabilized microsomes. The inhibition of microsomal G-6-P transport by compound A was associated with inhibition of the rate of glucose output from rat hepatocytes incubated in the presence of 25 nmol/l glucagon (IC50 approximately 320 nmol/l.) Compound A (1 micromol/l) also inhibited the basal rate of glucose production by rat hepatocytes by 47%. Intraperitoneal administration of compound A to fasted mice lowered circulating plasma glucose concentrations dose-dependently at doses as low as 1 mg/kg. This effect was comparatively short-lived; glucose lowering was maximal at 30 min after dosing with 100 mg/kg compound A (-71%) and declined thereafter, being reversed within 3 h. A similar time course of glycemic response was observed in fasted rats; glucose lowering was maximal 30 min after dosing with 100 mg/kg compound A (-36%) and declined until the effect was fully reversed by 3 h postdose. In rats subjected to compound A treatment, liver glycogen content was increased. G-6-P and lactate levels were maximally elevated 30 min after dosing and declined thereafter. Cumulatively, these results suggest that the mechanism of glucose lowering by compound A was via inhibition of G-6-Pase activity, mediated through inhibition of the T1 subunit of the microsomal G-6-Pase enzyme system. Drug levels measured over the same time course as that used to assess in vivo efficacy peaked within 30 min of administration, then declined, which is consistent with the transient changes in plasma glucose and liver metabolites.

Global gene expression analysis in liver of obese diabetic db/db mice treated with metformin

“…It could be objected that the down-regulation of G6pc mRNA and reduction of blood glucose level occurred too quickly, since the drug was orally administered. However, it has been reported that the blood concentration of metformin reached almost maximal level within 1 h following oral administration in the rat [34], and intraperitoneal administration of an inhibitor of G6PC translocase reduced blood glucose levels significantly 30 min after administration [35]. Furthermore, it has recently been reported that mice injected with short hairpin RNA exhibited a significant reduction in postprandial glucose levels accompanied by a decrease in G6pc expression [36].…”

Identification of protein components of the microsomal glucose 6-phosphate transporter by photoaffinity labelling

“…A major advance was derived from the cloning of murine and human glucose-6-phosphatase by Chou and co-workers [20,42] and the finding that the glucose-6-phosphatase gene is normal in patients suffering from glycogen storage disease types 1b and 1c [43]. Progress on a parallel path came with the development of a new class of highly specific high-affinity inhibitors of the glucose-6-phosphatase system that act exclusively on microsomal glucose 6-phosphate transport while leaving the enzymic phosphohydrolase activity unchanged [12][13][14][15][16][17][18]. Thus there now is convincing molecular evidence in favour of the substrate transport model of glucose-6-phosphatase.…”

Yerba Maté (Ilex paraguariensis) Aqueous Extract Decreases Intestinal SGLT1 Gene Expression but Does Not Affect Other Biochemical Parameters in Alloxan-Diabetic Wistar Rats

“…Studies with CGA (5-caffeyolquinic acid) (25,41,42) and its synthetic derivatives (21,43) have demonstrated their ability to inhibit hepatic G-6-Pase activity in Vitro. The synthetic derivatives also reduce the glucose release in ViVo in animal models, by both gluconeogenesis and glycogenolysis, leading to a decrease in blood glucose (21,22,42).…”

“…Mounting evidence suggests that dietary polyphenols may modulate glucose absorption and metabolism (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Cohort studies have reported that high coffee consumption might be associated with a lower risk of type 2 diabetes, and this effect may be attributed to CGAs (20).…”

“…Cohort studies have reported that high coffee consumption might be associated with a lower risk of type 2 diabetes, and this effect may be attributed to CGAs (20). Indeed, pure 5-caffeoylquinic acid (5-CQA) and some synthetic derivatives were able to reduce blood glucose in animals (21)(22)(23)(24)(25).…”