Regenerating β cells of the pancreas – potential developments in diabetes treatment

Abstract

The etiology of diabetes is mainly attributed to insulin deficiency due to the lack of β cells (type 1), or to insulin resistance that eventually results in β cell dysfunction (type 2). Therefore, an ultimate cure for diabetes requires the ability to replace the lost insulin-secreting β cells. Strategies for regenerating β cells are under extensive investigation. Areas covered: Herein, the authors first summarize the mechanisms underlying embryonic β cell development and spontaneous adult β cell regeneration, which forms the basis for developing β cell regeneration strategies. Then the rationale and progress of each β cell regeneration strategy is reviewed. Current β cell regeneration strategies can be classified into two main categories: in vitro β cell regeneration using pluripotent stem cells and in vivo reprogramming of non-β cells into β cells. Each has its own advantages and disadvantages. Expert opinion: Regenerating β cells has shown its potential as a cure for the treatment of insulin-deficient diabetes. Much progress has been made, and β cell regeneration therapy is getting closer to a clinical reality. Nevertheless, more hurdles need to be overcome before any of the strategies suggested can be fully translated from bench to bedside.

Pax4 in Health and Diabetes

“…As Pax4 is a principal transcription factor for β cell specification during embryonic development, and can promote β cell survival, proliferation, and transdifferentiation from non-β islet cells in adult islets, targeting Pax4 holds promise to restore β cell mass and function [68,69]. Indeed, transgenic mice over-expressing Pax4 in various cells, including islet progenitors, β, α, and δ cells, have shown increased β cell mass and are resistant to STZ-induced T1D [44,45,48,49,51].…”

Staprexanthones, Xanthone-Type Stimulators of Pancreatic β-Cell Proliferation from a Mangrove Endophytic Fungus

“…Diabetes affects 1 in 11 adults (20–79 years old) of the global population and causes 10% of global health expenditures . Although type 1 and type 2 diabetes are fundamentally different diseases, they are both associated with deficiency of the functional insulin-producing β-cells. − To overcome the β-cell deficiency in diabetes, several β-cell replacement strategies, including pancreas transplantation, islet transplantation, stem-cell-derived insulin-producing cell transplantation, and β-cell regeneration, have been explored as potential treatments . However, while pancreas transplantation and islet transplantation are severely limited by the availability of organ donors, the stem-cell-derived insulin-producing cell approach is encumbered by several challenges, such as the functional immaturity of induced β-like cells and the inherent risks of placing allogeneic tissue in the body .…”

“…3−6 To overcome the β-cell deficiency in diabetes, several β-cell replacement strategies, including pancreas transplantation, islet transplantation, stem-cell-derived insulin-producing cell transplantation, and β-cell regeneration, have been explored as potential treatments. 7 However, while pancreas transplantation and islet transplantation are severely limited by the availability of organ donors, 8 the stem-cell-derived insulin-producing cell approach is encumbered by several challenges, such as the functional immaturity of induced β-like cells and the inherent risks of placing allogeneic tissue in the body. 9 Alternatively, induction of endogenous β-cell regeneration, which circumvents the issue of immune rejection and donor limitation, is an alluring strategy that could provide new avenues for therapeutic development.…”

“…To date, three mechanisms of β-cell regeneration in vivo have been identified, including replication of pre-existing βcells, neogenesis from β-cell progenitors, and trans-differentiation from other endocrine cells. 7 Among them, induction of pre-existing β-cell proliferation is more attractive, and several stimulators, such as WS6, 10 5-iodotubercidin, ABT-702, 11 and N-ethylcarboxamidoadenosine, 12 have been identified from commercial compound libraries. However, the structural diversity of commercial compounds is limited and the rates of β-cell replication stimulated by these compounds remain low (in the range of 1−3%/day).…”