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

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 anti diabetic 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 alpha or beta cell compartments, under the condition of beta-cell stress. To that end, we utilised mice expressing YFP specifically in pancreatic alpha-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, decrease in beta-cell apoptosis and, for the incretin mimetics, transdifferentiation of alpha-cells into beta-cells. Our data therefore emphasize the role of chronic incretin signalling in induction of alpha-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.