Antidiabetic effect of a nitrosamine-free dephostatin analogue, methoxime-3,4-dephostatin, in db/db mice.
Et-3,4-dephostatin, a protein-tyrosine phosphatase (PTPase) inhibitor, potentiates insulin-dependent signal transduction and shows an antidiabetic effect in mice. However, it contains a nitrosamine moiety that is often mutagenic and carcinogenic. Therefore, we previously designed and synthesized methoxime-3,4-dephostatin as a nitrosamine-free analogue of dephostatin. In the present paper, we studied in situ and in vivo antidiabetic effects of this PTPase inhibitor. Methoxime-3,4-dephostatin induced 2-deoxyglucose transport by mouse 3T3-L1 adipocytes and rat L6 myocytes without insulin. It also inhibited glucagon-induced glucose release from primary culture rat hepatocytes. When hepatocytes were prepared from starved rats, methoxime-3,4-dephostatin did not inhibit the release of glucose, indicating that the chemical may act on glycogenolysis. Oral administration of methoxime-3,4-dephostatin for 3-7 days inhibited the increase in the blood glucose level in type-2 diabetes model db/db mice. It also decreased food and water intakes of mice, but showed no liver or blood toxicity.
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan.
A
A
Hiroki
H
H
Hatakeyama
M
M
Kawakami
T
T
Watanabe
I
I
Takei
K
K
Umezawa
D016475:3T3 Cells; D000818:Animals; D002395:Catecholamines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006873:Hydroquinones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009603:Nitroso Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats
C432919:4-(ethyl)(nitroso)amino-3,4-benzenediol; D002395:Catecholamines; D006873:Hydroquinones; D007004:Hypoglycemic Agents; D009603:Nitroso Compounds; D010091:Oximes; C084037:dephostatin; C005514:N,N'-monomethylenebis(pyridiniumaldoxime); D005947:Glucose