2‐Methoxyestradiol ameliorates glucose tolerance with the increase in β‐cell mass in db/db mice

Aims/Introduction: 2‐Methoxyestradiol (2ME) is an estradiol metabolite with little estrogenic activity. Previous data identified its anti‐carcinogenic properties and possible cardiovascular benefits. However, its effect on diabetes mellitus has not been fully elucidated. The aim of the present study was to determine the effects of 2ME on glucose metabolism in the diabetic state. Materials and Methods: To evaluate the effects of 2ME, pellets of two different doses of the drug were implanted into female db/db mice at the age of 5 weeks. Intraperitoneal glucose tolerance test and insulin tolerance test were carried out at the age of 8 weeks. The pancreas was harvested for morphological analysis and β‐cell function at the age of 9 weeks. Results: 2ME improved random blood glucose levels and glucose tolerance with increases in insulin levels during an intraperitoneal glucose tolerance test. Insulin sensitivity judged by an insulin tolerance test was comparable in the low‐ and high‐dose 2ME groups and the control group. Although glucose‐stimulated insulin secretion in isolated islets was comparable among the three groups, β‐cell mass in 2ME‐treated groups was higher than the control group. In the 2ME‐treated groups, the number of Ki67‐positive cells in islets was higher, whereas the number of cleaved caspase‐3‐positive cells was comparable with the control. Conclusions: 2ME ameliorates glucose tolerance by promoting the proliferation of β‐cell mass in db/db mice. Our data suggests its potential clinical usefulness as a disease‐modifying drug for type 2 diabetes mellitus. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00087.x, 2011)