Bruno Doiron and Ralph A DeFronzo,
Dept of Medicine – Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA
Syner-III offers a new treatment paradigm for the treatment of type I diabetes and type 2 diabetes mellitus compared to current approaches to treat diabetes. The intellectual property encompasses approaches to preferentially increase the number of beta (insulin-producing) cells in the adult pancreas without increasing the number of non-insulin-producing cells.
The technology provides for in vivo exposure of pancreatic cells to three compounds that work synergistically at the cellular level in the pancreas to stimulate formation of insulin-producing beta cells. The method acts on postdevelopmental mechanisms to induce beta cell formation without stem cells and without activating the embryonic pathway; thus, undesired cells are not induced. Prior attempts at beta cell regeneration have relied upon pancreatic injury to induce beta cell proliferation, dedifferentiation and activation of the embryonic pathway, or stem cell replacement. We report on an alternative method to transform adult non-stem (somatic) cells into pancreatic beta cells. The Syner-III approach targets cellular mechanisms involved in pancreatic function in the organ’s adult state and utilize a synergistic approach that integrates three important levels of cellular regulation to induce beta cell formation: (i) glucose metabolism, (ii) membrane receptor function, and (iii) gene transcription. Prior methods with cocktails of transcriptional factors and stem cells produce hybrid cells which coexpress glucagon and/or somatostatin. We demonstrate in this paper that Syner-III induces beta cell formation directly from adult pancreatic somatic cells. This approach to increase the number of insulin secreting pancreatic beta cells in adult subjects can be used as prevention, treatment, or cure of diabetes. We also compared Syner-III to a three-pronged cocktail comprised only of transcriptional factors and demonstrate that integration of multiple levels of cellular physiology is essential to produce a synergistic effect to induce beta cell formation that cannot be achieved simply by employing a cocktail of transcriptional factors that only target nuclear reprogramming in vivo. Further, we demonstrated that Syner-III restores normoglycemia and beta cell function (insulin secretion) for in excess of one year in a wild type mice mouse model.
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