Chlorogenic Acid and Synthetic Chlorogenic Acid Derivatives:  Novel Inhibitors of Hepatic Glucose-6-phosphate Translocase

Abstract

The enzyme system glucose-6-phosphatase (EC 3.1.3.9) plays a major role in the homeostatic regulation of blood glucose. It is responsible for the formation of endogenous glucose originating from gluconeogenesis and glycogenolysis. Recently, chlorogenic acid was identified as a specific inhibitor of the glucose-6-phosphate translocase component (Gl-6-P translocase) of this enzyme system in microsomes of rat liver. Glucose 6-phosphate hydrolysis was determined in the presence of chlorogenic acid or of new synthesized derivatives in intact rat liver microsomes in order to assess the inhibitory potency of the compounds on the translocase component. Variation in the 3-position of chlorogenic acid had only poor effects on inhibitory potency. Introduction of lipophilic side chain in the 1-position led to 100-fold more potent inhibitors. Functional assays on isolated perfused rat liver with compound 29i, a representative of the more potent derivatives, showed a dose-dependent inhibition of gluconeogenesis and glycogenolyosis, suggesting glucose-6-phosphatase as the locus of interference of the compound for inhibition of hepatic glucose production also in the isolated organ model. Gl-6-P translocase inhibitors may be useful for the reduction of inappropriately high rates of hepatic glucose output often found in non-insulin-dependent diabetes.

Normal kinetics of intestinal glucose absorption in the absence of GLUT2: Evidence for a transport pathway requiring glucose phosphorylation and transfer into the endoplasmic reticulum

“…Therefore, if a similar mechanism accounted for glucose release on the serosal side of the epithelial cells, transport should be inhibited by the chlorogenic acid derivative S4048, which blocks the glucose-6-phosphate translocase within the membrane of the endoplasmatic reticulum (24,25). In perfused intestine from wild-type mice, increasing concentrations of S4048 only slightly decreased glucose absorption (Fig.…”

A single HPLC‐PAD‐APCI/MS method for the quantitative comparison of phenolic compounds found in leaf, stem, root and fruit extracts of Vaccinium angustifolium

“…Considering that, in a separate pharmacological study, each extract (leaf, stem, root and fruit) elicited a range of in vitro anti-diabetic activities (Martineau et al, 2006), it is interesting that all the identified classes of phenolic compounds, chlorogenic acid, quercetin derivatives, procyanidins and anthocyanins, have demonstrated anti-diabetic potential in vitro and in vivo (Hemmerle et al, 1997;Rodriguez de Sotillo and Hadley, 2002;Kim et al, 2003;Tsuda et al, 2003;Pinent et al, 2004;Ajay et al, 2005;Coskun et al, 2005;Dias et al, 2005;Jayaprakasam et al, 2006 …”

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.…”

“…Photoaffinity probes S 0957 and S 1743 ( Figure 1) were synthesized in accordance with the procedures described [12,13].…”

“…These derivatives of chlorogenic acid are able to decrease hepatic glucose production and lower blood glucose levels in normal and diabetic animal models [12][13][14][15][16][17][18].…”