Novel cell therapy for type 1 diabetes mellitus

Abstract

Pancreas transplants are an established therapy for type 1 diabetes mellitus (T1DM). However, they are beset with various clinical problems and cannot solve the increasing burden accrued by T1DM patients [1]. Transplantation of pancreatic islet cells into the portal vein can virtually normalize blood glucose levels, while circumventing a number of problems associated with pancreas transplantation [1]. However, this approach, including the problems associated with cadaveric organ and cell harvesting, makes these options practicable for only a few T1DM patients. Generating surrogate insulin-producing cells is feasible and rodent studies suggest that such cells may be adequate to treat T1DM [2]. However, such cells do not have the sophisticated machinery to detect glucose levels that is possessed by native islet cells. Thus, their ability to steer insulin release in response to glucose levels is not given. The report by Unniappan and colleagues in this issue presents another option [3]. They considered the possibility of using a drug-operated system that could induce target cells to release insulin each and every time the drug stimulus is given. The drug inducing the “gene-switch” and subsequent insulin production in the cells is mifepristone. Mifepristone is notorious in other circles as a progesterone antagonist that can function as an abortifacient in the first trimester; however, the drug also has numerous other possible clinical applications. A C-terminal deletion mutant of the human progesterone receptor fails to bind to progesterone but can bind mifepristone. This mutant receptor construct can activate transcription of reporter genes containing the progesterone response element when mifepristone is present. Wang et al. [4,5] developed this gene-switch system based on this technology that permits a regulatory system applicable for gene-transfer studies (Fig. 1). A regulator is constructed. The transactivator gene encodes a chimeric regulator (GLVP) that consists of a VP16 activation domain, a Gal4 DNA binding domain, and a truncated progesterone binding domain that responds to mifepristone. Any promoter can be used to target the expression of the regulator to any particular cell or tissue of interest. Next, a target must be constructed. The target can be any gene with an SV40 polyadenylation signal placed under the control of a minimal promoter. Upon activation, the regulator then binds to the Gal4 sites and induces target gene expression. The regulator is inactive without mifepristone. When mifepristone is added, the activated regulator dimerizes and binds to the Gal4 DNA binding site that induces the target gene expression. Unniappan et al. used exactly this drug-dependent regulatory system [3]. The next tool the investigators needed was a suitable cell line. They reasoned that the gut might be a source of potentially therapeutic cells. For their purpose, they selected gut K cells that have been shown to express glucokinase, the glucose sensor of pancreatic beta cells. Transgenic mice expressing human insulin under the control of a K cell-specific promoter were shown to be resistant to T1DM development induced by the beta cell toxin streptozotocin in an earlier study [6]. K cells release glucose-dependent insulinotropic polypeptide (GIP), a gastrointestinal hormone that is secreted in response to food intake and that modulates beta cell function. GIP acts on various tissues, including pancreatic beta cells, via interaction with its G protein-coupled receptor. The most important effect of GIP is its potentiation of insulin secretion. In an earlier study, the authors took advantage J Mol Med (2009) 87:659–661 DOI 10.1007/s00109-009-0476-x