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Actions of the novel oral antidiabetic agent HQL-975 in insulin-resistant non-insulin-dependent diabetes mellitus model animals.

Abstract
The hypoglycemic effects of a novel oral antidiabetic agent HQL-975, were studied in normal rats, streptozotocin-induced diabetic (STZD) rats and genetically insulin-resistant non-insulin-dependent diabetes mellitus (NIDDM) model animals, KK-Ay mice and Zucker diabetic fatty (ZDF) rats. After the dietary administration of HQL-975 to KK-Ay mice, significant decreases in plasma glucose, insulin, triglyceride and non-esterified fatty acid levels were observed. The effective dosage of HQL-975 to decrease the plasma glucose level by 30% was 3.1 mg/kg per day. However, the plasma glucose level was not altered after the administration of HQL-975 in normal and STZD rats. The results suggest that HQL-975 is more effective against the abnormalities of glucose and lipid metabolism of insulin-resistant model animals than in that of normal and insulin-deficient diabetic animals. It is reported that ZDF rats indicate a severely diabetic state as a result of insulin resistance and further the presence of beta-cell insulin secretory defects. Here, HQL-975 (1-30 mg/kg per day for 7 days) was administered to ZDF rats; slight decreases in the plasma glucose (18%) and lipids (41%) levels were observed in the rats given 30 mg/kg. To clarify the action mechanism of HQL-975, we studied the effects of HQL-975 administration on the insulin action of target tissues in KK-Ay mice. After the dietary administration of HQL-975 (0.001, 0.003, 0.010% for 7 days) to KK-Ay mice, hepatic glycolytic and gluconeogenic key enzyme activities were measured. The glucose 6-phosphatase activity was decreased (20-40%) as compared with control. The results suggest that HQL-975 enhances the insulin action in hepatic enzyme regulation. To investigate the actions of HQL-975 in peripheral tissues such as muscle and adipose, an in vivo glucose uptake study using 3H-2-deoxyglucose was performed in KK-Ay mice treated with HQL-975 (0.010% for 7 days). The 2-deoxyglucose uptake of the basal state was not altered, but the insulin-stimulated 2-deoxyglucose uptake in muscle (41-191%) and adipose (46-88%) tissues was increased by the HQL-975 treatment as compared with control. These results suggest that HQL-975 also enhances the insulin action of peripheral tissues. Based on these findings, HQL-975 is expected to be useful for treatment of insulin-resistant patients with NIDDM.
AuthorsY Ishikawa, M N Saito, T Ikemoto, H Takeno, K Watanabe, T Tani
JournalDiabetes research and clinical practice (Diabetes Res Clin Pract) Vol. 41 Issue 2 Pg. 101-11 (Aug 1998) ISSN: 0168-8227 [Print] IRELAND
PMID9789716 (Publication Type: Journal Article)
Chemical References
  • HQL 975
  • Hypoglycemic Agents
  • Oxazoles
  • Phenylalanine
  • Deoxyglucose
Topics
  • Administration, Oral
  • Animals
  • Deoxyglucose (pharmacokinetics)
  • Diabetes Mellitus, Type 2 (drug therapy, metabolism, physiopathology)
  • Hypoglycemic Agents (therapeutic use)
  • Insulin Resistance
  • Liver (drug effects, enzymology)
  • Male
  • Mice
  • Mice, Inbred Strains
  • Oxazoles (therapeutic use)
  • Phenylalanine (analogs & derivatives, therapeutic use)
  • Rats
  • Rats, Inbred Strains
  • Rats, Wistar

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