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

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.

Keywords: HMG20A; LRH-1/NR52A; PAX4; diabetes; redifferentiation; regeneration; single-cell transcriptomics; transdifferentiation; β-cell heterogeneity.

Figure 1

Diabetes progression stages. Diabetes is a continuum that is not clinically symptomatic until the levels of functional β-cell mass are below a threshold (dash line) that disables the capacity of the islets to compensate for the insulin demand. However, the alterations in the functional β-cell mass appear at earlier stages, before the onset of hyperglycemia.

Figure 2

Heterogeneity of islet β-cells. (A) Differences in insulin and other β-cell marker genes give rise to the apparition of different β-cell subpopulations with different functionalities. (B) The maintenance of the proportions of these subpopulations ensures the adequate function of the islets. Aging and stress conditions can alter these subpopulations with detrimental consequences for islet functionality and adaptation that can eventually lead to the development of diabetes under stress conditions.

Figure 3

⍺- to β-cell transdifferentiation. The common origin of ⍺- and β-cells resulted in permissive epigenetic marks in ⍺-cells that under specific circumstances can activate their transdifferentiation into β-cells. This reprogramming of ⍺-cells into β-cells that is activated in islets under stress conditions is not able to regenerate an adequate β-cell mass to recover the endogenous control of glycemia. However, this process that involves a close crosstalk between islet cells as well as with the immune system cells can be stimulated by different treatments, such as GLP-1 and likely GABA, as well as the novel small molecule BL001.

Figure 4

Redifferentiation of islet β-cells. The metabolic stress-induced overload of β-cells triggers their dedifferentiation in an attempt to avoid cell death. This process is due to the reactivation of gene set characteristics of the immature β-cells. Nevertheless, this process can be reversed since the dedifferentiated β-cells retain the potential to be redifferentiated.