Various strategies to induce beta cell neogenesis: a comprehensive review for unravelling the potential future therapy for curing diabetes

Abstract

Pancreatic endocrine cells are categorized in to 5 types (alpha, beta, delta, pancreatic polypeptide cells and epsilon), which expresses glucagon, insulin, somatostatin, pancreatic polypeptide, and ghrelin, respectively. Several studies including lineage tracing in Ins2^Akita diabetic mice have been done to investigate the identities of pancreatic endocrine cells which concludes, alpha cells have enormous plasticity, which enables them to be reprogrammed by specific transcription factors into insulin secreting beta like cells. Gene therapy has provided the beneficial outcome. Pdx1, MaFA and PAX4 (the transcription factors) in alpha cells can be over expressed which results in reprogramming the targeted alpha cells into beta cells. This trans-differentiation may be induced by infusing an adeno-associated virus (AAV) loaded with distinct transcription factors in the duct of pancreas. Several researches have demonstrated the successful restoration of enhanced insulin secretion in diabetes induced mice. Additionally ductal neurogenin3 (Ngn3), Sglt2 inhibitors, Igfbp1, GLP1 and several clinical and non-clinical agents has been postulated as a basis of beta cell neogenesis. Alpha cell owing to its high plasticity, on prolonged exposure to GABA reprogrammed into beta-like cell due to downregulation of Arx expression by GABA. The various approaches for beta cell neogenesis open a new window towards the establishment of novel gene therapy accession to treat diabetes. However, broad studies are still needed to improve and optimize this treatment methodology. The potentiality of endogenous pancreatic alpha cell to beta cell conversion methods and its outcomes are invigorating. This accomplishment is presently being under trial in non-human primates.

Keywords: AAV (adeno associated virus); GABA (gamma aminobutyric acid); Ngn3 (neurogenin 3); PAX4 (paired; Pdx1 (pancreatic and duodenal homeobox1); Transdifferentiation; alpha cells; beta cells; box4); diabetes; gene therapy; reprogramming; transcription factors.