Harnessing gut cells for functional insulin production: Strategies and challenges

Reprogrammed glucose-responsive, insulin + cells ("β-like") exhibit the potential to bypass the hurdles of exogenous insulin delivery in treating diabetes mellitus. Current cell-based therapies-transcription factor regulation, biomolecule-mediated enteric signaling, and transgenics - have demonstrated the promise of reprogramming either mature or progenitor gut cells into surrogate "β-like" cells. However, there are predominant challenges impeding the use of gut "β-like" cells as clinical replacements for insulin therapy. Reprogrammed "β-like" gut cells, even those of enteroendocrine origin, mostly do not exhibit glucose - potentiated insulin secretion. Despite the exceptionally low conversion rate of gut cells into surrogate "β-like" cells, the therapeutic quantity of gut "β-like" cells needed for normoglycemia has not even been established. There is also a lingering uncertainty regarding the functionality and bioavailability of gut derived insulin. Herein, we review the strategies, challenges, and opportunities in the generation of functional, reprogrammed "β-like" cells.