The recent discovery that genetically modified α cells can regenerate and convert into β-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-β-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into β-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated β-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of α cells and a concomitant increase in β-like cell counts, suggestive of α-to-β-like cell conversion processes also in humans. This newly discovered GABA-induced α cell-mediated β-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes.

Recently, it was demonstrated that pancreatic new-born glucagon-producing cells can regenerate and convert into insulin-producing β-like cells through the ectopic expression of a single gene, Pax4. Here, combining conditional loss-of-function and lineage tracing approaches, we show that the selective inhibition of the Arx gene in α-cells is sufficient to promote the conversion of adult α-cells into β-like cells at any age. Interestingly, this conversion induces the continuous mobilization of duct-lining precursor cells to adopt an endocrine cell fate, the glucagon+ cells thereby generated being subsequently converted into β-like cells upon Arx inhibition. Of interest, through the generation and analysis of Arx and Pax4 conditional double-mutants, we provide evidence that Pax4 is dispensable for these regeneration processes, indicating that Arx represents the main trigger of α-cell-mediated β-like cell neogenesis. Importantly, the loss of Arx in α-cells is sufficient to regenerate a functional β-cell mass and thereby reverse diabetes following toxin-induced β-cell depletion. Our data therefore suggest that strategies aiming at inhibiting the expression of Arx, or its molecular targets/co-factors, may pave new avenues for the treatment of diabetes.

It was recently demonstrated that embryonic glucagon-producing cells in the pancreas can regenerate and convert into insulin-producing β-like cells through the constitutive/ectopic expression of the Pax4 gene. However, whether α cells in adult mice display the same plasticity is unknown. Similarly, the mechanisms underlying such reprogramming remain unclear. We now demonstrate that the misexpression of Pax4 in glucagon(+) cells age-independently induces their conversion into β-like cells and their glucagon shortage-mediated replacement, resulting in islet hypertrophy and in an unexpected islet neogenesis. Combining several lineage-tracing approaches, we show that, upon Pax4-mediated α-to-β-like cell conversion, pancreatic duct-lining precursor cells are continuously mobilized, re-express the developmental gene Ngn3, and successively adopt a glucagon(+) and a β-like cell identity through a mechanism involving the reawakening of the epithelial-to-mesenchymal transition. Importantly, these processes can repeatedly regenerate the whole β cell mass and thereby reverse several rounds of toxin-induced diabetes, providing perspectives to design therapeutic regenerative strategies.

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Type 1 diabetes is caused by the loss of insulin-producing β-cells as a result of an autoimmune condition. Despite current therapeutic approaches aimed at restoring the insulin supply, complications caused by variations in glycaemia may still arise with age. There is therefore mounting interest in the establishment of alternative therapies. Most current approaches consist in designing rational protocols for in vitro or in vivo cell differentiation/reprogramming from a number of cell sources, including stem, progenitor or differentiated cells. Towards this ultimate goal, it is clear that we need to gain further insight into the interplay between signalling events and transcriptional networks that act in concert throughout pancreatic morphogenesis. This short review will therefore focus on the main events underlying pancreatic development with particular emphasis on the genetic determinants implicated, as well as on the relatively new concept of endocrine cell reprogramming, that is the conversion of pancreatic α-cells into cells displaying a β-cell phenotype. Keywords: β-cells, diabetes, mouse models, pancreas, reprogramming IntroductionDiabetes mellitus is one of the most common endocrine diseases in all populations and all age groups, affecting approximately 300 million people worldwide. Diabetes represents a group of metabolic diseases of which there are two main types: type 1 diabetes, which is caused by a cell-mediated autoimmune loss of insulin-producing β-cells in the pancreas, and type 2 diabetes, which involves either a failure in insulin production or endorgan insulin resistance. In type 1 diabetes, the administration of exogenous insulin is the mainstay of treatment. However, although insulin-based therapy allows a measure of control of blood glucose levels in patients with type 1 diabetes, appropriate glucose targets can be difficult to reach due to environmental variations, such as exercise, diet, pregnancy or age. These variations may lead to long-term complications, including retinopathy, which could result in loss of vision, nephropathy leading to renal failure, and neuropathy with the risk of foot ulcers, amputation or even cardiovascular symptoms [1]. Recent clinical trials have shown that the transplantation of human islets of Langerhans, isolated from the pancreases of organ donors, can alleviate insulin dependence in type 1 diabetic patients. However, the scarcity of organ donors has been driving research into alternative sources of functionally competent, insulin-secreting β-cells as substitutes for donor . Interestingly, recent evidence of an inherent plasticity of mature pancreatic cells has fuelled interest into in vivo (re-)generation of β-cells, whether it is through β-cell self-replication, differentiation from putative precursor cells or by reprogramming from endogenous cell types. Hence, gaining further insight into the molecular and genetic determinants of normal β-cell development and/or renewal is crucial for the design of protocols, whether it be for in vitro or in vivo β-cell g...

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).To efficiently treat type 1 diabetes, exogenous insulin injections currently represent the main approach to counter chronic hyperglycaemia. Unfortunately, such a therapeutic approach does not allow for perfectly maintained glucose homeostasis and, in time, cardiovascular complications may arise. Therefore, seeking alternative/improved treatments has become a major health concern as an increasing proportion of type 2 diabetes patients also require insulin supplementation. Towards this goal, numerous laboratories have focused their research on β-cell replacement therapies. Herein, we will review the current state of this research area and describe the cell sources that could potentially be used to replenish the depleted β-cell mass in diabetic patients.

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