Objectives: 

Type 2 diabetes is characterized by the emergence of fasting hyperglycemia. This is associated with an inadequate insulin secretion from pancreatic b-cells to compensate for insulin-resistance in peripheral tissues. The ATP-potassium channel (KATP channel) is the key molecule involved in glucose-stimulated insulin secretion (GSIS). Physiological concentration of 17b-estradiol (E2) decreases KATP channel activity and enhances insulin secretion. E2 actions are essentially mediated by ERa and ERb. Here we evaluate the role of estrogen receptor beta (ERb) as an insulinotropic molecule and its potential antidiabetic properties.

Materials: 

C57BL/6, ERb-/- mice and db/db mice were used. Electrical activity and calcium records were analyzed in the whole islet of Langerhans. Plasma insulin, leptin, tryglicerides and glycerol levels were measured by ELISA.

Results: 

In vitro studies demonstrated that low doses of WAY 200070, an ERb specific agonist, decreased KATP channel activity and enhanced GSIS in sinergy with glucose in mouse and human islets. In a set of in vivo experiments we showed that a single-administration of WAY 200070 leaded to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Thus, we next studied the potential clinical use of ERb agonists by using streptozotocin-nicotinamide-induced mildly diabetic mice. These animals exhibit moderate hyperglycaemia and impaired glucose tolerance because of the lost of early-phase insulin secretion. One-week treatment with the ERb agonist caused a significant improvement in glucose tolerance and plasma insulin levels. Studies performed in db/db mice demonstrate that this compound restored first-phase insulin secretion, enhanced pancreatic b-cell mass and favored the control of body weight.

Conclusions: 

We conclude that ERb agonists should be considered as new antidiabetic drugs.

This work was supported by grants Ministerio de Ciencia e Innovacion grants BFU2008-01492, BFU2011-28358, Generalitat Valenciana grants PROMETEO/2011/080, Swedish Cancer Fund and Emerging Technology Fund of Texas.