Transgenic overexpression of the transcription factor Nkx6.1 in β-cells of mice does not increase β-cell proliferation, β-cell mass, or improve glucose clearance

Abstract

The loss or dysfunction of the pancreatic endocrine β-cell results in diabetes. Recent innovative therapeutic approaches for diabetes aim to induce β-cell proliferation in vivo by pharmacological intervention. Based on the finding that over expression of the transcription factor Nkx6.1 in islets in vitro increases β-cell proliferation while maintaining β-cell function, Nkx6.1 has been proposed as a potential target for diabetes therapy. However, it is unknown whether elevated Nkx6.1 levels in β-cells in vivo have similar effects as observed in isolated islets. To this end, we sought to investigate whether over expression of Nkx6.1 in β-cells in vivo could increase β-cell mass and/or improve β-cell function in normal or β-cell-depleted mice. Using a biogenic inducible Cre-recom-binase-based transgenic model, we analyzed the effects of Nkx6.1 over expression on β-cell proliferation, j3-cell mass, and glucose metabolism. We found that mice over expressing Nkx6.1 in (3-cells displayed similar β-cell proliferation rates and β- cell mass as control mice. Furthermore, after partial β-cell ablation, Nkx6.1 overexpression was not sufficient to induce β-cell regeneration under either no diabetic or diabetic conditions. Together these results demonstrate that sustained Nkx6.1 over expression in vivo does not stimulate β-cell proliferation, expand β-cell mass, or improve glucose metabolism in either normal or β-cell-depleted pancreata. Thus, raising cellular Nkx6.1 levels in β-cells in vivo is unlikely to have a positive impact on type 2 diabetes. © 2011 by The Endocrine Society.