Ascochlorin誘導体, AS-6, の血糖低下作用ならびに脂肪組織におけるinsulin効果増強作用

抄録

Ascochlorin had been isolated by the present authors from a fungus, Ascochyta visiae. This is a hydrophobic sesquiterpenoid and therefore a more polar 4-0-hydroxycarbonyl methylascochlorin (AS-6) was developed for convenience in pharmacological studies.
The hypoglycemic effect of AS-6 was studied in normoinsulinemic, hypoinsulinemic and hyperinsulinemic animal models. AS-6 was given mixed with the commercial diet (CE-2, Nihon CLEA CO., ) for one or 10 weeks to ddY mice, genetically obese Zucker fatty rats and genetically obese diabetic mice C₅₇BL/ksj dbm (dbm-mice). AS-6 was orally given to streptozotocin diabetic rats (STZ-rats) for 14 days by gastric intubation. Serum glucose and triglyceride were determined and compared with each control. AS-6 treatment significantly reduced serum glucose and triglyceride in all experimental animals. In particular, serum glucose in dbm-mice was decreased after one week of AS-6 treatment by 23.2% compared to the dbm control and after 10 weeks by 44.0%. AS-6 showed a lowering of serum immunoreactive insulin (IRI) in normal and dbm-mice. This fact suggests that AS-6 accerelates glucose utilization without stimulating pancreatic insulin release.
The mechanism of AS-6 was studied using epididymal fat pads from STZ rats. The tissue slices derived from AS-6 treated STZ rats significantly increased conversion of ¹⁴C-glucose to CO₂ and total lipids compared to the STZ control which deteriolated to remarkably below normal.
Adippocytes from AS-6 treated rats bound significantly more insulin at 1, 10, 100μU/ml insulin concentration than those of the controls and significantly increased 2-deoxyglucose uptake.
There is attenuated insulin sensitivity of glucose metabolism in adipocytes from STZ control, however, AS-6 treatment improved insulin sensitivity of glucose metabolism.