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bioRxiv · 10.1101/2020.08.03.234070

Antidiabetic drug therapy alleviates type 1 diabetes in mice by promoting pancreatic alpha-cell transdifferentiation

Sarnobat, D.·Moffett, C. R.·Tanday, N.·Reimann, F.·Gribble, F. M.·Flatt, P. R.·Tarasov, A. I.
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Abstract

Gut incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance secretion of insulin in a glucose-dependent manner, predominantly by elevating cytosolic levels of cAMP in pancreatic {beta}-cells. Successful targeting of the incretin pathway by several drugs, however, suggests the antidiabetic mechanism is likely to span beyond the acute effect on hormone secretion and include, for instance, stimulation of {beta}-cell growth and/or proliferation. Likewise, the antidiabetic action of kidney sodium-glucose linked transporter-2 (SGLT-2) inhibitors exceeds simple increase glucose excretion. Potential reasons for these added benefits may lie in the long-term effects of these signals on developmental aspects of pancreatic islet cells. In this work, we explored if the incretin mimetics or SGLT-2 inhibitors can affect the size of the islet - or {beta}-cell compartments, under the condition of {beta}-cell stress. To that end, we utilised mice expressing YFP specifically in pancreatic -cells, in which we modelled type 1 diabetes by injecting streptozotocin, followed by a 10-day administration of liraglutide, sitagliptin or dapagliflozin. We observed an onset of diabetic phenotype, which was partially reversed by the administration of the antidiabetic drugs. The mechanism for the reversal included induction of {beta}-cell proliferation, due to a decrease in {beta}-cell apoptosis and, for the incretin mimetics, transdifferentiation of -cells into {beta}-cells. Our data therefore emphasize the role of chronic incretin signalling in induction of -/{beta}-cell transdifferentiation. We conclude that incretin peptides may act directly on islet cells, making use of the endogenous local sites of ectopic expression, whereas SGLT-2 inhibitors work via protecting {beta}-cells from chronic hyperglycaemia. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

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Sarnobat, D., Moffett, C. R., Tanday, N., Reimann, F., Gribble, F. M., Flatt, P. R., Tarasov, A. I.. 2020-08-04. Antidiabetic drug therapy alleviates type 1 diabetes in mice by promoting pancreatic alpha-cell transdifferentiation. https://doi.org/10.1101/2020.08.03.234070

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