Effects of islet neogenesis associated protein depend on vascular endothelial growth factor gene expression modulated by hypoxia-inducible factor 1-alpha

MENCUCCI, MV; DEL ZOTTO, H; ROMÁN, CL; AHRTZ, L; GAGLIARDINO, JJ; MAIZTEGUI, B; ALGAÑARÁS, M; FLORES, LE

PEPTIDES

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2019 vol. 117

0196-9781

Background: Pharmacology has provided efficient tools to improve insulineffect/secretion but the decrease in β-cell mass remains elusive. INGAP-PP couldprovide a therapeutic alternative to meet that challenge.Aim: To further understand the mechanism that links INGAP-PP effects upon β-cellmass and function with islet angiogenesis.Methodology: Normal male Wistar rats were divided into 2 groups and injected with asingle dose of 100 mg/Kg suramin or saline. Both groups were divided into 2 subgroupsthat received daily doses of 2mg/kg INGAP-PP or saline for ten days. Plasma glucose,triacylglycerol, TBARS, and insulin levels were measured. Pancreasimmunomorphometric analyses were also performed. Pancreatic islets were isolated tomeasure glucose-stimulated insulin secretion (GSIS). Specific islet mRNA levels werestudied by qRT-PCR. Statistical analysis was done using ANOVA.Results: No differences were recorded in body weight, food intake, or any other plasmaparameter measured in all groups. Islets from INGAP-PP-treated rats significantlyincreased GSIS, β-cell mass, and mRNA levels of Bcl-2, Ngn-3, VEGF-A, VEGF-R2,CD31, Ang1 and Ang2, Laminin β-1, and Integrin β-1, and decreased mRNA levels ofCaspase-8, Bad, and Bax. Islets from suramin-treated rats showed significant oppositeeffects, but INGAPP-PP administration rescued most of the suramin effects in animalstreated with both compounds.ACCEPTED MANUSCRIPTConclusion: Our results reinforce the concept that INGAP-PP enhances insulinsecretion and β-cell mass, acting through PI3K/Akt/mTOR pathways andsimultaneously activating angiogenesis through HIF-1α-mediated VEGF-A secretion.Therefore, INGAP-PP might be a suitable antidiabetic agent able to overcome twomajor alterations present in T2D.