Research Abstract:
The focus of our laboratory is to define metabolic signaling pathways that mediate cell growth and proliferation in adult human and rodent islets. Stimulating islet beta-cells to proliferate is a clinical goal that could have a beneficial impact on both type 1 diabetes for ex vivo transplantation protocols and in type 2 diabetes for approaches that generate beta-cell replication in vivo. Mammalian Target of Rapamycin (mTOR) is a unique protein kinase that integrates signals derived from growth factors and nutrients to regulate cell growth and proliferation. Our previous studies have demonstrated that nutrients stimulate mTOR-mediated DNA synthesis and cell cycle progression, prerequisite events required for mitosis, in rodent islets but are rarely effective in human islets.
Our recent findings have identified glycogen synthase kinase-3 (GSK-3) as a key component in the regulation of mTOR-dependent regenerative processes. Remarkably, a highly specific GSK-3 inhibitor or lithium possess the unique ability to stimulate mTOR-dependent DNA synthesis and promotion of cells to enter the cell cycle in human islets. Our ongoing studies will utilize molecular and genetic approaches to understand the transcriptional and translational signals that facilitate GSK-3/mTOR-mediated regenerative processes necessary to expand human beta-cells ex vivo.
Selected Publications:
Kwon G, Marshall CA, Liu H, Pappan KL, Remedi MS, McDaniel ML: Glucose-stimuated DNA synthesis through mammalian target of rapamycin (mTOR) is regulated by KATP channels: Effects on cell cycle progression in rodent islets. J Biol Chem 2006 281:3261-3267.
Remedi MS, Rocheleau JV, Tong A, Patton BL, McDaniel ML, Piston DW, Koster JC, Nichols CG. Hyperinsulinism in mice with heterozygous loss of KATP channels. Diabetologia 2006 49:2368-2378.
Pappan KL, Zhijun P, Kwon G, Marshall CA, Coleman T, Goldberg IJ, McDaniel ML, Semenkovich CF. Pancreatic beta-cell lipoprotein lipase independently regulates islet glucose metabolism and normal insulin secretion. J Biol Chem 2005 280:9023-9029.
Kwon G, Marshall CA, Pappan KL, Remedi MS, McDaniel ML. Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins and growth factors. Diabetes 2004 53:3159-3167.
Kwon G, Pappan KL, Marshall CA, Schaffer JE, McDaniel ML. Cyclic AMP dose-dependently prevents palmitate-induced apoptosis by both PKA- and cAMP-GEF-dependent pathways in beta-cells. J Biol Chem 2004 279:8938-8945.
Last Updated: 09/07/2007 |