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.

Ashleigh E Schaffer, Almira J Yang, Fabrizio Thorel, Pedro L Herrera, Maike Sander

Department of Cellular and Molecular Medicine, The University of California, San Diego, USA. masander@ucsd.edu

Molecular endocrinology (Baltimore, Md.) 2011 Nov

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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 overexpression 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 overexpression 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 bigenic inducible Cre-recombinase-based transgenic model, we analyzed the effects of Nkx6.1 overexpression on β-cell proliferation, β-cell mass, and glucose metabolism. We found that mice overexpressing Nkx6.1 in β-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 nondiabetic or diabetic conditions. Together these results demonstrate that sustained Nkx6.1 overexpression 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.

Citation

Ashleigh E Schaffer, Almira J Yang, Fabrizio Thorel, Pedro L Herrera, Maike Sander. 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. Molecular endocrinology (Baltimore, Md.). 2011 Nov;25(11):1904-14