Lipogenic action of the novel oral antidiabetic agent HQL-975 in genetically obese diabetic KK-Ay mice.
HQL-975 (3-{4-12-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxyl-phenyl}-2S- propylamino-propionic acid) is a new oral antidiabetic agent which has been shown to be effective in insulin-resistant diabetic animals. In the present study, we examined the effects of HQL-975 on glucose utilization and insulin action in KK-Ay mice with genetically obese non-insulin diabetes. (1) Dietary administration of HQL-975 (19 mg/kg/d for 7 d) improved hyperglycemia, hyperlipidemia and hyperinsulinemia in the mice. (2) The HQL-975-treated mice showed enhanced net glucose utilization, that is, glucose was significantly incorporated into total lipids in the white adipose tissue (WAT) and liver, and into glycogen in the diaphragm for the last 24 h of the drug administration period. (3) Treatment improved the decreased stimulative action of insulin in the epididymal WAT and the agent increased insulin-stimulated lipogenesis from both glucose and acetate. (4) Treatment also increased the activity of lipogenic enzymes such as glycerol-3-phosphate dehydrogenase and fatty acid synthetase. (5) In vitro exposure of WAT to HQL-975 enhanced lipogenesis in the presence of insulin. From these findings, we conclude that HQL-975 improves glucose utilization of KK-Ay mice through the enhancement of insulin action, which is associated with its lipogenic effects.
New Drug Research Department, High Quality-Life Research Laboratories, Bio-Medical Division, Sumitomo Metal Industries, Kyoto, Japan.
Y
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Ishikawa
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H
Takeno
K
K
Watanabe
T
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Tani
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008820:Mice, Obese; D010080:Oxazoles / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D005230:Fatty Acids, Nonesterified; C116088:HQL 975; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D010080:Oxazoles; D010649:Phenylalanine; D005947:Glucose