Development of a novel antidiabetic zinc complex with an organoselenium ligand at the lowest dosage in KK-A(y) mice

J Inorg Biochem. 2013 Apr;121:10-5. doi: 10.1016/j.jinorgbio.2012.12.008. Epub 2012 Dec 23.

Abstract

Diabetes mellitus (DM) is a considerably diagnosed metabolic disease and a serious problem worldwide. We prepared various zinc complexes and studied their potential for use as new antidiabetic agents. In this study, we synthesized a seleniferous zinc complex, di(2-selenopyridine-N-oxidato)zinc(II) ([ZPS]) that has a Zn(Se2O2) coordination mode. Analyses of structure-activity relationships between its insulin-like activity and the coordination mode of [ZPS]-related complexes showed that it had high insulin-like activity. Hypoglycemic effects of [ZPS] on type 2 diabetic KK-A(y) mice were exerted at the lowest dose administered (1.25-2.5 mg Zn/kg body weight), unlike previously synthesized zinc complexes. Furthermore, [ZPS] afforded us a new advantage; we were able to investigate the tissue distribution of the ligand by measuring the amount of selenium in the organs of [ZPS]-treated mice. Gastrointestinal absorption and tissue penetration of zinc derived from [ZPS] in ddY mice, which was monitored using an isotope tracer technique, was significantly increased compared to that of ZnCl2. These results suggest that [ZPS] has superior antidiabetic effects compared to previously reported zinc complexes, and is thus a potential novel antidiabetic agent that facilitates the possibility of organoselenium ligands as new metal delivery systems for treating DM.

MeSH terms

  • Animals
  • Area Under Curve
  • Biological Availability
  • Blood Glucose / metabolism
  • Coordination Complexes / chemical synthesis*
  • Coordination Complexes / pharmacokinetics*
  • Coordination Complexes / pharmacology
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / drug therapy*
  • Glycated Hemoglobin A / metabolism
  • Half-Life
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / pharmacology
  • Insulin / pharmacology
  • Ligands
  • Male
  • Mice
  • Organoselenium Compounds / chemical synthesis
  • Organoselenium Compounds / chemistry*
  • Organoselenium Compounds / pharmacokinetics
  • Organoselenium Compounds / pharmacology
  • Zinc / chemistry*

Substances

  • Blood Glucose
  • Coordination Complexes
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin
  • Ligands
  • Organoselenium Compounds
  • di(2-selenopyridine-N-oxidato)zinc(II)
  • Zinc