β-Cell Replacement Strategies: The Increasing Need for a “β-Cell Dogma”

Type 1 diabetes is an auto-immune disease resulting in the loss of pancreatic β-cells and, consequently, in chronic hyperglycemia. Insulin supplementation allows diabetic patients to control their glycaemia quite efficiently, but treated patients still display an overall shortened life expectancy and an altered quality of life as compared to their healthy counterparts. In this context and due to the ever increasing number of diabetics, establishing alternative therapies has become a crucial research goal. Most current efforts therefore aim at generating fully functional insulin-secreting β-like cells using multiple approaches. In this review, we screened the literature published since 2011 and inventoried the selected markers used to characterize insulin-secreting cells generated by in vitro differentiation of stem/precursor cells or by means of in vivo transdifferentiation. By listing these features, we noted important discrepancies when comparing the different approaches for the initial characterization of insulin-producing cells as true β-cells. Considering the recent advances achieved in this field of research, the necessity to establish strict guidelines has become a subject of crucial importance, especially should one contemplate the next step, which is the transplantation of in vitro or ex vivo generated insulin-secreting cells in type 1 diabetic patients

[Reprogramming pancreatic cells to β cells].

International audienceType 1 diabetes (T1DM) is a common metabolic disorder affecting an ever-increasing number of patients worldwide. T1DM is caused by the selective destruction of pancreatic insulin-producing β-cells by the immune system. Such loss results in chronic hyperglycemia and could induce a number of cardio-vascular complications. Despite the classical insulin-based therapy, compared to healthy people, patients with T1DM display a shortened life expectancy due to the treatment's inability to strictly regulate glycemic levels. An alternative therapy involves pancreatic islet transplantation but the shortage of donors and the required immuno-suppressive treatments limit the widespread use of this approach. Therefore, the search of new approaches to generate functional β-cells is of growing interest. In this review, we describe several novel strategies aiming at the conversion of diverse pancreatic cells into β-cells, such as acinar, ductal, and endocrine cells. Clearly, such promising results could open new research avenues in the context of type 1 diabetes research

Implication of REDD1 in the activation of inflammatory pathways

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Induction of multiple cycles of pancreatic β-cell replacement.

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GABA signaling stimulates α-cell-mediated β-like cell neogenesis

Diabetes is a chronic and progressing disease, the number of patients increasing exponentially, especially in industrialized countries. Regenerating lost insulin-producing cells would represent a promising therapeutic alternative for most diabetic patients. To this end, using the mouse as a model, we reported that GABA, a food supplement, could induce insulin-producing beta-like cell neogenesis offering an attractive and innovative approach for diabetes therapeutics

<i>Neurog3</i> misexpression unravels mouse pancreatic ductal cell plasticity

<div><p>In the context of type 1 diabetes research and the development of insulin-producing β-cell replacement strategies, whether pancreatic ductal cells retain their developmental capability to adopt an endocrine cell identity remains debated, most likely due to the diversity of models employed to induce pancreatic regeneration. In this work, rather than injuring the pancreas, we developed a mouse model allowing the inducible misexpression of the proendocrine gene <i>Neurog3</i> in ductal cells <i>in vivo</i>. These animals developed a progressive islet hypertrophy attributed to a proportional increase in all endocrine cell populations. Lineage tracing experiments indicated a continuous neo-generation of endocrine cells exhibiting a ductal ontogeny. Interestingly, the resulting supplementary β-like cells were found to be functional. Based on these findings, we suggest that ductal cells could represent a renewable source of new β-like cells and that strategies aiming at controlling the expression of <i>Neurog3</i>, or of its molecular targets/co-factors, may pave new avenues for the improved treatments of diabetes.</p></div

<i>Neurog3</i> misexpression is maintained in newly-formed endocrine cells in adult Tam-treated HNFN3OE pancreata.

<p>The observation of islets in HNFN3OE animals treated with Tam for 10 months demonstrates that a clear majority of endocrine cells misexpress Neurog3 (<b>A-B</b>), this result being confirmed by qPCR analyses (<b>C</b>, n = 6 for each condition) Statistics were performed using the Mann-Whitney test.</p