Differential hypoglycemic effect of 2,5-anhydro-D-mannitol, a putative gluconeogenesis inhibitor, in genetically diabetic (db/db) and streptozotocin-induced diabetic mice.
2,5-Anhydro-D-mannitol (AM), a putative gluconeogenesis inhibitor, completely reversed the hyperglycemia in genetically diabetic (db/db) mice that exhibited hyperinsulinemia and enhanced hepatic gluconeogenic enzyme (glucose-6-phosphatase (G-6-Pase) and fructose-1,6-diphosphatase (F-1,6-DPase)) activities compared with the control +/+ mice. In contrast, AM only partially reversed the hyperglycemia of streptozotocin (STZ)-treated +/+ mice in which the hepatic gluconeogenic enzyme activities were enhanced to the same degree as in the db/db mice, whereas the blood insulin level was depressed. In the db/db mice, the STZ-treatment attenuated the hyperinsulinemia and exaggerated the hyperglycemia as well as the hepatic gluconeogenic enzyme activities, and it greatly reduced the hypoglycemic action of AM. Not only the dose-response curve of AM but also the time-course of the blood glucose level (expressed as % of pre-treatment value) following 320 mg/kg of AM were almost identical between +/+, STZ-treated +/+ and STZ-treated db/db mice. In the STZ-treated +/+ mice, a combination treatment of insulin (320 micrograms/kg) with AM (320 mg/kg) caused hypoglycemia that was greater than that induced by AM or insulin alone. On the other hand, in vitro studies with purified F-1,6-DPase revealed that phosphorylated AM (AM-1,6-diphosphate) but not AM itself inhibited the gluconeogenic enzyme activities. These results suggest that inhibition of gluconeogenesis is responsible, at least in part, for the hypoglycemic activity of AM. AM appears to inhibit hepatic gluconeogenic enzyme activities after being phosphorylated by an insulin-dependent mechanism.
Kodama
H
H
Basic Research Group, Tsukuba Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
Fujita
M
M
Yamaguchi
I
I
D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D003921:Diabetes Mellitus, Experimental / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005943:Gluconeogenesis / Q000187:drug effects*; D007003:Hypoglycemia / Q000145:classification*; D007328:Insulin / Q000494:pharmacology; D008353:Mannitol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL
D001786:Blood Glucose; D007328:Insulin; D008353:Mannitol; C031765:2,5-anhydromannitol