Effect of a novel hypoglycemic agent, KAD-1229 on glucose metabolism and fructose-2,6-bisphosphate content in isolated hepatocytes of normal rats.
The effects of a novel hypoglycemic agent, calcium(2s)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate dihydrate (KAD-1229), which is a benzyl succinate derivative, on liver metabolism were investigated using isolated hepatocytes from normal rats. In the presence of 10 mM glucose, KAD-1229 increased the L-lactate production (41.1 +/- 0.9 versus 60.9 +/- 2.6 mumol of lactate/g of cells/30 min; P < 0.05) and inhibited gluconeogenesis in hepatocytes (0.94 +/- 0.02 versus 0.70 +/- 0.03 mumol of [2-14C]-pyruvate converted to glucose/g of cells/20 min; P < 0.05). These effects by KAD-1229 were accompanied by an increase in the cellular content of fructose-2,6-bisphosphate (F-2,6-P2), which is one of the important regulators of hepatic glucose metabolism, in a dose-dependent manner (0.05-2.5 mM). KAD-1229 also stimulated the oxidation of [2-14C]-pyruvate and [6-14C]-glucose in the tricarboxylic acid cycle (+18 and +31%, respectively), indicating that stimulation of tricarboxylic acid cycle activity and/or enhancement of the glycolytic flux rate had occurred. Moreover, KAD-1229 did not modify the activities of 6-phosphofructo 2-kinase or fructose-2,6-bisphosphatase, but increased significantly the accumulation of fructose 6-phosphate in hepatocytes. These results suggest that KAD-1229 has extrapancreatic effects on hepatic glucose metabolism, that its actions are mediated through the inhibition of fructose-1,6-bisphosphatase and stimulation of both the 6-phosphofructo 1-kinase reaction and tricarboxylic acid cycle activity by increasing the F-2,6-P2 content in hepatocytes, and that these multiple effects may account in part for the ability of KAD-1229 to reduce blood glucose levels in vivo.
Nakashima
E
E
Third Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Nakamura
J
J
Koh
N
N
Sakakibara
F
F
Hamada
Y
Y
Hotta
N
N
D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D005635:Fructosediphosphates / Q000378:metabolism*; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014044:Tolbutamide / Q000494:pharmacology
D005635:Fructosediphosphates; D007004:Hypoglycemic Agents; D007211:Indoles; D054833:Isoindoles; D007773:Lactates; D011773:Pyruvates; C027652:fructose 2,6-diphosphate; D014044:Tolbutamide; C087255:mitiglinide; D005947:Glucose