Dipeptidyl Peptidase IV Inhibition Activates CREB and Improves Islet Vascularization through VEGF-A/VEGFR-2 Signaling Pathway

Abstract

Substitution of pancreatic islets is a potential therapy to treat diabetes and it depends on reconstitution of islet’s capillary network. In this study, we addressed the question whether stabilization of Glucagon-Like-Peptide-1 (GLP-1) by inhibiting Dipeptidyl Peptidase-IV (DPP-IV) increases β-cell mass by modulating vascularization. Mouse or porcine donor islets were implanted under kidney capsule of diabetic mice treated with DPP-IV inhibitor sitagliptin. Grafts were analyzed for insulin production, β-cell proliferation and vascularization. In addition, the effect of sitagliptin on sprouting and Vascular Endothelial Growth Factor (VEGF)-A expression was examined ex vivo. The cAMP response element-binding (CREB) and VEGF-A/ Vascular Endothelial Growth Factor Receptor (VEGFR)-2 signaling pathway leading to islet vascularization was explored. Sitagliptin increased mean insulin content of islet grafts and area of insulin-positive tissue as well as β-cell proliferation. Interestingly, sitagliptin treatment also markedly increased endothelial cell proliferation, microvessel density and blood flow. Finally, GLP-1 (7-36) stimulated sprouting and VEGF expression, which was significantly enhanced by sitagliptin- mediated inhibition of DPP-IV. Our in vivo data demonstrate that sitagliptin treatment phosphorylated CREB and induced islet vascularization through VEGF-A/VEGFR-2 signaling pathway. This study paves a new pathway for improvement of islet transplantation in treating diabetes mellitus.

Sitagliptin promotes mitochondrial biogenesis in human SH‐SY5Y cells by increasing the expression of PGC‐1α/NRF1/TFAM

“…In addition to reducing blood glucose concentration, sitagliptin has displayed diverse pharmacological effects. For example, a recent study demonstrated that treatment with sitagliptin increases β‐cell mass and islet vascularization through activating the transcriptional factor cAMP‐response element binding (CREB) protein . Notably, CREB has been reported to play a central role in regulating the expression of PGC‐1α .…”

Wound Healing Process, Diabetes and Implications of Dipeptidyl Peptidase IV (DPP IV/CD26)

“…Likewise, DPP IV/CD26 inhibition improved functional blood flow in grafts as a result of inhibitor acting. It is shown that sitagliptin improves VEGF secretion in transplanted porcine islets, which contributes to cell proliferation and angiogenesis by increasing VEGFR-2 expression [28]. DPP IV/CD26 inhibition with linagliptin also showed decreased blood glucose levels and accelerated skin re-epithelization in diabetic mice since levels of active GLP-1 in wound lysates increased.…”

“…However, its biological availability is controlled by dipeptidyl peptidase IV (DPP IV/CD26), a moonlighting protein with an enzymatic function which cleaves active GLP-1. One of the most important implications of DPP IV/CD26 inhibitors is indeed therapeutic support of DM, where it found its clinical importance, given its capability to contribute to the maintenance of glucose homeostasis [8].…”

The endocrine role between β cells and intra-islet endothelial cells [Review]

“…Other opinions demonstrate that it can activate signal transducer and activator of transcription 3 (STAT3) signaling, developing pancreatic microvasculature [75]. Sitagliptin, a Dipeptidyl Peptidase IV Inhibition, can activate cAMP response element-binding (CREB) in β cell, increase VEGF secretion, inducing neovascularization of islets [76].…”