ERK5 plays an essential role in gestational beta-cell proliferation.

Restoring a functional beta-cell mass is a fundamental goal in treating diabetes. A complex signalling pathway network coordinates the regulation of beta-cell proliferation, although a role for ERK5 in this network has not been reported. This question was addressed in this study. We studied the activation of extracellular-signal-regulated kinase 5 (ERK5) in pregnant mice, a well-known mouse model of increased beta-cell proliferation. A specific inhibitor of ERK5 activation, BIX02189, was intraperitoneally injected into the pregnant mice to suppress ERK5 signalling. Beta-cell proliferation was determined by quantification of Ki-67+ beta cells. Beta-cell apoptosis was determined by TUNEL assay. The extent of beta-cell proliferation was determined by beta-cell mass. The alteration of ERK5 activation and CyclinD1 levels in purified mouse islets was examined by Western blotting. Extracellular-signal-regulated kinase 5 phosphorylation, which represents ERK5 activation, was significantly upregulated in islets from pregnant mice. Suppression of ERK5 activation by BIX02189 in pregnant mice significantly reduced beta-cell proliferation, without affecting beta-cell apoptosis, resulting in increases in random blood glucose levels and impairment of glucose response of the mice. ERK5 seemed to activate CyclinD1 to promote gestational beta-cell proliferation. Extracellular-signal-regulated kinase 5 plays an essential role in the gestational augmentation of beta-cell proliferation. ERK5 may be a promising target for increasing beta-cell mass in diabetes patients.