Actions of the novel oral antidiabetic agent HQL-975 in genetically obese diabetic db/db mice.
The hypoglycemic effect of the novel oral agent 3-[4-12-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl]-2S-propyla mino-propionic acid (HQL-975) was examined in db/db mice with genetically obese non-insulin dependent diabetes mellitus (NIDDM). The oral administration of HQL-975 at 3.5 and 35.3 mg/kg/d for 7 d decreased the plasma glucose level of these mice in a dose-dependent manner. HQL-975 also significantly decreased the plasma triglyceride, total cholesterol, non-esterified fatty acid and insulin levels. In the oral glucose tolerance test, HQL-975-treated mice showed improved glucose tolerance and decreased endogenous insulin secretion. HQL-975 increased glycemic response to exogenous insulin in the mice. In the HQL-975-treated db/db mice adipocytes, the glucose uptake, insulin binding, and GLUT4 expression were increased compared with those in untreated db/db mice adipocytes. These results indicate that HQL-975 improved insulin action in db/db mice through receptor and post-receptor effects. In conclusion, HQL-975 is a new oral antidiabetic agent with a hypoglycemic effect which is associated with an insulin-sensitizing effect. This agent may therefore be effective for the treatment of NIDDM.
Ishikawa
Y
Y
New Drug Research Department, Sumitomo Metal Industries, Kyoto, Japan.
Takagi
Y
Y
Takeno
H
H
Watanabe
K
K
Tani
T
T
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005947:Glucose / Q000493:pharmacokinetics; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008820:Mice, Obese; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis; D010080:Oxazoles / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D001786:Blood Glucose; C116088:HQL 975; D007004:Hypoglycemic Agents; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D010080:Oxazoles; D010649:Phenylalanine; D005947:Glucose