The treatment of diabetes by islet transplantation is presently hampered by the shortage of organ donors. The generation of insulin-producing cells is therefore a major objective in the long-term goal of curing diabetes. Alternative sources of pancreatic b-cells include existing pancreatic cells, embryonic stem cells, and cells from other tissues such as liver. This commentary considers evidence for two new sources of b-cells: intrahepatic biliary epithelial cells and gall bladder epithelium. These observations raise the possibility that a patient's own cells may be used as a source of insulinproducing cells for cell replacement in diabetes.

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Unbiased machine learning workflow ranks miRNAs associated with insulin transcriptionForced expression of topranked miRNAs drives pro-endocrine program in progenitor cells Knockdown of top-ranked miRNAs retards insulin gene transcription in human isletsInsulin transcriptassociated miRNAs are reduced in islets of donors with type 2 diabetes

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Objective: Pancreatic islet β-cells are factories for insulin production; however ectopic expression of insulin is also well recognized. The gallbladder is a next-door neighbour to the developing pancreas. Here, we wanted to understand if gallbladders contain functional insulin-producing cells. Design: We compared developing and adult mouse as well as human gallbladder epithelial cells and islets using immunohistochemistry, flow cytometry, ELISAs, RNA-sequencing, real time PCR, chromatin immunoprecipitation and functional studies. Results: We demonstrate that the epithelial lining of developing, as well as adult mouse and human gallbladders naturally contain interspersed cells that retain the capacity to actively transcribe, translate, package, and release insulin. We show for the first time that human gallbladders also contain functional insulin-secreting cells with the potential to naturally respond to glucose in vitro and in situ. Notably, in a NOD mouse model of type 1 diabetes, we observed that insulin-producing cells in the gallbladder are not targeted by autoimmune cells. Conclusion: In summary, our biochemical, transcriptomic, and functional data in human gallbladder epithelial cells collectively demonstrate their potential for insulin-production under pathophysiological conditions, opening newer areas for diabetes research and therapy.