Harnessing the Endogenous Plasticity of Pancreatic Islets: A Feasible Regenerative Medicine Therapy for Diabetes?

Diabetes is a chronic metabolic disease caused by an absolute or relative deficiency in functional pancreatic β‐cells that leads to defective control of blood glucose. Current treatments for diabetes, despite their great beneficial effects on clinical symptoms, are not curative treatments, leading to a chronic dependence on insulin throughout life that does not prevent the secondary complications associated with diabetes. The overwhelming increase in DM incidence has led to a search for novel antidiabetic therapies aiming at the regeneration of the lost functional β‐cells to allow the re‐establishment of the endogenous glucose homeostasis. Here we review several aspects that must be considered for the development of novel and successful regenerative therapies for diabetes: first, the need to maintain the heterogeneity of islet β‐cells with several subpopulations of β‐cells characterized by different transcriptomic profiles correlating with differences in functionality and in resistance/behavior under stress conditions; second, the existence of an intrinsic islet plasticity that allows stimulus‐mediated transcriptome alterations that trigger the transdifferentiation of islet non‐β‐cells into β‐cells; and finally, the possibility of using agents that promote a fully functional/mature β‐cell phenotype to reduce and reverse the process of dedifferentiation of β‐cells during diabetes.
Authors were/are funded by grants from Consejería de Salud, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía (PI-0727-2010, December 2010 to B.R.G., PI-0085-2013, December 2013 to P.I.L., and PI-0001-2020, December 2020 to B.R.G. and P.I.L.); Consejería de Economía, Innovación y Ciencia, Junta de Andalucía (P10-CTS-6359 to B.R.G.); Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, cofunded by Fondos FEDER (PI10/00871, January 2011 and PI13/00593, January 2014 to B.R.G.); Ministerio de Economía y Competitividad, Plan Nacional (BFU2017-83588-P, January 2018 to B.R.G. and PRE2018-084907, January 2018 to E.M.-V.); Juvenile Diabetes Research Foundation JDRF (17-2013-372, August 2013 and 2-SRA-2019-837-S-B, August 2019 to B.R.G:); and Fundacion Vencer el Cancer (to B.R.G.). Special thanks to ALUSVI (Asociación Lucha y Sonríe por la Vida, Pilas), a local Andalusian association, and the Fundacion DiabetesCero for their unconditional financial support.