Proposed pathways involved in regenerative processes and preservation of the β-cell phenotype in human islets in vitro.

<p>mTOR is pivotal in regulating a balance between proliferation and differentiation. Human islets (left panel), display a high level of insulin signaling pathway resistance due to chronic mTOR activation. This results in negative feedback, IRS-1/2 degradation and the inability of Akt to inhibit GSK-3 and engage the Wnt/β-catenin pathway. To enhance human β-cell proliferation, pharmacologic inhibition of GSK-3, in combination with mTOR-mediated β-catenin nuclear translocation is required. To shift this balance in favor of maintaining β-cell differentiation (right panel), GSK-3 inhibitors are removed and islets are treated with the PPARγ sparing TZD, MSDC-0160 that enhances AMPK activity, downregulates mTOR/S6K1-dependent negative feedback and restores the insulin-signaling pathway. Activation of Akt by insulin/IGF-1 results in increases in differentiation markers, <i>insulin</i>, <i>pdx-1</i>, <i>nkx6.1</i> and <i>nkx2.2,</i> promotes β-cell survival and restores insulin content. Downregulation of mTOR also prevents β-catenin translocation to the nucleus, blocking DNA synthesis. Thus, DNA synthesis and differentiation do not occur simultaneously. MSDC-0160 may produce a unique modulation of nutrient sensors that give rise to signals that cause β-cells to leave the cell cycle and differentiate (right panel). The cycling of proliferation, followed by treatment with MSDC-0160 to allow restoration of insulin content, may maintain a balance between regenerative processes and preservation of the β-cell phenotype. Dotted line indicates reduced signaling levels.