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- Title
CS-917, a Fructose 1,6-Bisphosphatase Inhibitor, Suppresses Gluconeogenesis in Human Hepatocytes, whereas Metformin Stimulates Glycolysis in Caco-2 Cells.
- Authors
Okuno, Akira; Takahashi, Kanako; Tanaka, Jun; Yoshida, Taishi
- Abstract
CS-917 (MB06322) is a novel inhibitor of fructose 1,6-bisphosphatase, a rate-limiting enzyme in gluconeogenesis (GNG). Although metformin (MET) has been reported to improve hyperglycemia by inhibiting GNG in diabetic patients, we have previously demonstrated in mode of action between CS-917 and MET. CS-917 reduced plasma glucose concentration in Goto-Kakizaki rats by reducing glucose production, while MET reduced plasma glucose levels by accelerating glucose consumption. In this study, we evaluated the effect of both agents on GNG in primary human hepatocytes isolated from 3 donors and on glycolysis in a human enterocyte-derived cell line, colon carcinoma (Caco-2) cells. GNG was determined by measuring glucose concentration in the hepatocyte culture medium including lactate and pyruvate as a substrate. Glycolysis was determined by measuring glucose utilization, lactate concentration and the appearance of anionic metabolites of [sup 14]C-glucose in the Caco-2 cell-culture medium. CS-917 (0.003-1µM) inhibited GNG in a dose-dependent manner (IC[sub 50]s = 0.041, 0.043 and 0.061µM). In contrast, MET did not inhibit GNG at concentrations of 0.3-100µM. MET (100-1000µM) stimulated glycolysis in a dose-dependent manner, as indicated by increased glucose utilization, lactate production, and the increased anionic metabolites, CS-917 (10-100µM) did not alter glucose utilization or the appearance anionic metabolites but caused a very small, though statistically significant, increase in lactate concentration. These results suggest that CS-917 directly inhibits GNG in hepatocytes while MET activates glyculysis in enterocytes leading to increased lactate production and glucose utilization. CS-917, but not metformin, inhibits GNG directly and offers a novel antihyperglycemic mode of action that warrants further investigation for the treatment of hyperglycemia in type 2 diabetes.
- Publication
Diabetes, 2007, Vol 56, pA130
- ISSN
0012-1797
- Publication type
Academic Journal