Abstract
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.
Highlights
Diabetes, a metabolic disease characterized by chronic hyperglycemia due to insufficient production of insulin to meet the insulin demand, is nowadays the most prevalent chronic disease affecting approximately 463 million adults worldwide, and its incidence is expected to rise up to 700 million people by 2045 (IDF, www.idf.org)
Independent studies performed in both mouse and human islets, tracing the activity of the Pdx1 and the insulin promoters using a dual reporter lentiviral system, disclosed the existence of two phenotypically different β-cell subpopulations based on their insulin expression levels: a predominant INSHIGH population with increased expression in mature β-cell markers, such as MafA, Nkx6.1, Slc2a2 (Glut2), and Gck, and an INSLOW population that accounts for 15–20% of β-cells, with increased proliferation rate and increased expression of Pax4, MafB, and Nkx2.2, among other genes [18]
This increase in PAX4 expression could be indicative of both a possible α- to β-cell transdifferentiation, since PAX4 determines the commitment to the β-cell lineage, and an expansion of the β-cell subpopulation primed to proliferation that we described in the previous section
Summary
A metabolic disease characterized by chronic hyperglycemia due to insufficient production of insulin to meet the insulin demand, is nowadays the most prevalent chronic disease affecting approximately 463 million adults worldwide, and its incidence is expected to rise up to 700 million people by 2045 (IDF, www.idf.org (accessed on 18 April 2021)). Independent studies performed in both mouse and human islets, tracing the activity of the Pdx and the insulin promoters using a dual reporter lentiviral system (expressing RFP under the control of the Pdx promoter and GFP under an insulin promoter), disclosed the existence of two phenotypically different β-cell subpopulations based on their insulin expression levels: a predominant INSHIGH population with increased expression in mature β-cell markers, such as MafA, Nkx6.1, Slc2a2 (Glut2), and Gck, and an INSLOW population that accounts for 15–20% of β-cells, with increased proliferation rate and increased expression of Pax, MafB, and Nkx2.2, among other genes [18]. This will require a better characterization of these subpopulations of β-cells, their physiological role, and the regulatory mechanisms that control their proportions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
