Vascular endothelial growth factor B regulates insulin secretion in β cells of type 2 diabetes mellitus mice via PLCγ and the IP3R‑evoked Ca2⁺/CaMK2 signaling pathway

Abstract

Vascular endothelial growth factor B (VEGFB) plays a crucial role in glucolipid metabolism and is highly associated with type 2 diabetes mellitus (T2DM). The role of VEGFB in the insulin secretion of β cells remains unverified. Thus, the present study aimed to discuss the effect of VEGFB on regulating insulin secretion in T2DM development, and its underlying mechanism. A high-fat diet and streptozocin (STZ) were used for inducing T2DM in mice model, and VEGFB gene in islet cells of T2DM mice was knocked out by CRISPR Cas9 and overexpressed by adeno-Associated Virus (AAV) injection. The effect of VEGFB and its underlying mechanism was assessed by light microscopy, electron microscopy and fluorescence confocal microscopy, enzyme-linked immunosorbent assay, mass spectrometer and western blot analysis. The decrement of insulin secretion in islet β cell of T2DM mice were aggravated and blood glucose remained at a high level after VEGFB knockout (KO). However, glucose tolerance and insulin sensitivity of T2DM mice were improved after the AAV–VEGFB 186 injection. VEGFB KO or overexpression can inhibit or activate PLCγ/IP3R in a VEGFR1-dependent manner. Then, the change of PLCγ/IP3R caused by VEGFB/VEGFR1 will alter the expression of key factors on the Ca 2+ /CaMK2 signaling pathway such as PPP3CA. Moreover, VEGFB can cause altered insulin secretion by changing the calcium concentration in β cells of T2DM mice. These findings indicated that VEGFB activated the Ca 2+ /CaMK2 pathway via VEGFR1-PLCγ and IP3R pathway to regulate insulin secretion, which provides new insight into the regulatory mechanism of abnormal insulin secretion in T2DM.

Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats

“…It should be noted that in all groups treated with LH/hCG receptor agonists, the expression of another VEGF isoform, VEGF-B, was significantly suppressed. According to recent studies, VEGF-B is involved in the control of lipid homeostasis and insulin production [64] and acts as an activator of antioxidant cascades [65]. Besides this, VEGF-B acts as an antagonist of VEGF-A in the regulation of angiogenesis, making it an important target for the development of anticancer drugs [66][67][68].…”