Type I diabetes is an autoimmune disease in which the insulin-producing beta-cells are destroyed. Current treatment depends on the administration of insulin to replace the hormone that is no longer being produced by the pancreas. Researchers have been seeking ways to replenish the population of beta-cells, either through the use of stem cells or by transforming one of the other types of cells present in the islets of Langerhans. Of particular interest are alpha-cells, which normally secrete glucagon.
In the current study, investigators at Harvard University (Cambridge, MA, USA) used a mouse alpha-cell line to screen more than 30,000 small molecules for any compounds that could induce the alpha-cells to produce insulin. They reported in the August 9, 2010, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) that one compound, BRD7389, induced insulin expression after three days of treatment. Induction of insulin gene expression peaked after five days, and the cells adopted a beta-cell-like morphology. At the molecular level, induction of insulin expression was found to involve inhibition of multiple members of the RSK (ribosomal s6 kinase) family of protein kinases.
"Small molecules have critical roles in all levels of biology—including cell growth, proliferation, sensing, and signaling—so researchers in academia and at pharmaceutical companies alike have a great interest in them. Our approach is discovery-based rather than hypothesis-driven. We want to define the properties of a cell in a particular state so we can study how they change as the cell becomes diseased. To understand a bodily process, it helps to perturb it with bioprobes and determine the consequences. We believe this approach could lead us to choose more effective compounds as candidate probes, and as a result uncover more relevant therapeutic targets for drug discovery,” said senior author Dr. Stuart L. Schreiber, professor of chemistry and chemical biology at Harvard University.
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