Proposed model involving GSK-3 inhibition and the mTOR pathway to stimulate human Beta-cell growth and proliferation

Proposed model involving GSK-3 inhibition and the mTOR pathway to stimulate human β-cell growth and proliferation. Increased nutrient metabolism inhibits AMPK activity, and LiCl or 1-Akp directly inhibits GSK-3. This blocks TSC1/2, resulting in mTOR activation and signaling to 4EBP1 and S6K1. An increased glucose concentration and/or GSK-3 inhibition results in increases in β-catenin steady-state levels. Direct inhibition of GSK-3 with LiCl or 1-Akp mediates β-catenin nuclear translocation that is rapamycin sensitive. Overactivation of mTOR/S6K1 results in feedback inhibition of IRS1/2 and Akt signaling. Overactivation of mTOR/S6K1 may also provide a feedforward mechanism that inhibits GSK-3 and increases in β-catenin steady-state levels but does not result in nuclear translocation (dashed line indicates a proposed pathway). AMPK, AMP-activated protein kinase; Rheb, Ras homolog enriched in brain; TSC, tuberous sclerosis complexes 1 and 2.

Publication

Glycogen Synthase Kinase-3 and Mammalian Target of Rapamycin Pathways Contribute to DNA Synthesis, Cell Cycle Progression, and Proliferation in Human Islets. (2009) Hui Liu, et al. Diabetes. 2009 Mar;58(3):663-672. Figure: F8. All organisms Mus musculus Capra hircus Bos taurus Homo sapiens Rattus norvegicus Oryctolagus cuniculus Xenopus laevis

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