QRFP induces β-cell and human islet cell survival and insulin secretion and promotes glucose uptake in β-cells, adipocytes and muscle cells

RFamides are a family of peptides containing arginine-phenylalanine-amide at their C terminus. A novel 43-amino acid RFamide, named QRFP43, was discovered and identified as a ligand of the G protein-coupled receptor GPR103. There is a growing body of evidence that several RFamides, such as neuropeptide FF and most recently QRFP43, play a role in food intake, thermogenesis and energy homeostasis regulation. In two previous studies we have demonstrated that ghrelin and obestatin, both involved in the control of energy homeostasis, improve survival and proliferation of both pancreatic β-cells and human pancreatic islets. On these basis, we investigated the effects of QRFP43 on survival, proliferation, apoptosis, insulin secretion, activation of signaling pathways, cAMP levels in β-cell lines (hamster insulinoma HIT-T15 and rat insulinoma INS-1E) and human pancreatic islets. Obestatin action on glucose uptake in β-cells, human islets, mouse adipocytes (3T3-L1) and primary human vascular smooth muscle cells (hVSMC) was also investigated. Cell survival was assessed by MTT and proliferation by BrdU incorporation; apoptosis was evaluated by Hoechst 33258 nuclear staining and insulin secretion by RIA. Activation of survival signaling pathways was investigated by Western blot analysis and intracellular cAMP production by ELISA; glucose uptake was measured by [3H]2-deoxyglucose incorporation. QRFP43 promoted survival and proliferation and reduced apoptosis in β-cell lines and human pancreatic islets, either in serum free conditions or under treatment with the cytokines TNF-/IFN-γ/IL-1β, known to be involved in β-cell death occurring in both type 1 and type 2 diabetes. Moreover, QRFP43 stimulated both basal and glucose-induced insulin secretion in β-cells and human islets, activated ERK1/2 and PI3K/Akt phosphorylation and increased intracellular cAMP levels. Finally QRFP43 enhanced glucose uptake in β-cells, human pancreatic islets, 3T3-L1 adipocytes, hVSMC and skeletal muscle cells C2C12. In all, these findings suggest that QRFP43 exerts positive effects on β-cell survival and function and plays a novel role in the regulation of glucose metabolism.