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

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 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, due to a 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.

Taurine rescues pancreatic β‐cell stress by stimulating α‐cell transdifferentiation

“…45 For cluster analysis (Figure 7F), we used the mean values for 25 phenotypic characteristics presented in this study (Figures 1-4), inclusive of global animal physiological indexes as well as proliferative, apoptotic and differentiation parameters from current study and our earlier works. [46][47][48][49] The analysis was performed using the kmeans function of the R core and visualized using the factoextra library. The optimal number of clusters was calculated using the elbow method.…”

Effects of long‐acting analogues of lamprey GLP‐1 and paddlefish glucagon on alpha‐ to beta‐cell transdifferentiation in an insulin‐deficient transgenic mouse model

“…21 Consistent with previous studies, multiple low-dose STZ resulted in loss of islet numbers and diminished islet area due to specific destruction of β-cells despite some compensatory transdifferentiation of Glu + YFP + alpha cells to Ins + YFP + β-cells. 15,16 In addition to transdifferentiation of non-β-cells to functional β-cells, other potentially important pathways to overcome β-cell loss include β-cell proliferation, protection of β-cells against apoptosis and β-cell neogenesis.…”

“…This antibody reacts with all variants of green fluorescent protein from the jellyfish Aequorea victoria, including YFP, and is therefore suitable for fluorescent protein detection in the transgenic mice employed. 15,16 The slides were incubated overnight at 4 C, washed with phosphate-buffered saline (PBS) and treated with secondary antibodies as follows: (i) Alexa Fluor 488 goat anti-mouse:…”

“…10 GLP-1 and its long-acting analogues have been shown to stimulate β-cell proliferation, decrease apoptosis and restore the impaired autophagic flux evident in animal models of T2DM. [11][12][13] In addition, the established GLP-1R agonists exendin-4 14 and liraglutide 15 and a long-acting analogue of the GLP-1R/GCGR dual agonist, oxyntomodulin, 16 promote transdifferentiation of α-cells to generate new β-cells.…”

Increased NKX6.1 expression and decreased ARX expression in alpha cells accompany reduced beta-cell volume in human subjects

“…The reason that we used these transcription factors was that NKX6.1-positive progenitors are used for marking pancreatic beta cells during human beta-cell development 17 , and ARX is one of the most important transcription factors that participates in the differentiation of alpha cells 18 , among human alpha cells and their correlations with clinical and histological parameters. The included patients had not been administered antidiabetic agents because insulin therapy 19 , GLP-1 (glucagon-like peptide-1) receptor agonist 20 , 21 and DPP-4 (dipeptidyl peptidase-4) inhibitor 22 are thought to affect islet-cell transdifferentiation.…”