Novel Insulin Sensitizer Modulates Nutrient Sensing Pathways and Maintains [beta]-Cell Phenotype in Human Islets

Major bottlenecks in the expansion of human [beta]-cell mass are limited proliferation, loss of [beta]-cell phenotype, and increased apoptosis. In our previous studies, activation of Wnt and mTOR signaling significantly enhanced human [beta]-cell proliferation. However, isolated human islets displayed insulin signaling pathway resistance, due in part to chronic activation of mTOR/S6K1 signaling that results in negative feedback of the insulin signaling pathway and a loss of Akt phosphorylation and insulin content. We evaluated the effects of a new generation insulin sensitizer, MSDC-0160, on restoring insulin/IGF-1 sensitivity and insulin content in human [beta]-cells. This novel TZD has low affinity for binding and activation of PPAR[gamma] and has insulin-sensitizing effects in mouse models of diabetes and ability to lower glucose in Phase 2 clinical trials. MSDC-0160 treatment of human islets increased AMPK activity and reduced mTOR activity. This was associated with the restoration of IGF-1-induced phosphorylation of Akt, GSK-3, and increased protein expression of Pdx1. Furthermore, MSDC-0160 in combination with IGF-1 and 8 mM glucose increased [beta]-cell specific gene expression of insulin, pdx1, nkx6.1, and nkx2.2, and maintained insulin content without altering glucose-stimulated insulin secretion. Human islets were unable to simultaneously promote DNA synthesis and maintain the [beta]-cell phenotype. Lithium-induced GSK-3 inhibition that promotes DNA synthesis blocked the ability of MSDC-0160 to maintain the [beta]-cell phenotype. Conversely, MSDC-0160 prevented an increase in DNA synthesis by blocking [beta]-catenin nuclear translocation. Due to the counteracting pathways involved in these processes, we employed a sequential ex vivo strategy to first induce human islet DNA synthesis, followed by MSDC-0160 to promote the [beta]-cell phenotype and insulin content. This new generation PPAR[gamma] sparing insulin sensitizer may provide an initial tool for relieving inherent human islet insulin signaling pathway resistance that is necessary to preserve the [beta]-cell phenotype during [beta]-cell expansion for the treatment of diabetes.