The insulinotrophic effect of insulin-like peptide 5 in vitro and in vivo

Abstract

Insulin-like peptide 5 (INSL5), a member of the insulin/relaxin superfamily, can activate the G-protein-coupled receptor relaxin/insulin-like family peptide receptor 4 (RXFP4), but its precise biological functions are largely unknown. Recent studies suggest that INSL5/RXFP4 is involved in the control of food intake and glucose homoeostasis. We report in the present study that RXFP4 is present in the mouse insulinoma cell line MIN6 and INSL5 augments glucose-stimulated insulin secretion (GSIS) both in vitro and in vivo. RXFP4 is also expressed in the mouse intestinal L-cell line GLUTag and INSL5 is capable of potentiating glucose-dependent glucagon-like peptide-1 (GLP-1) secretion in GLUTag cells. We propose that the insulinotrophic effect of INSL5 is probably mediated through stimulation of insulin/GLP-1 secretion and the INSL5/RXFP4 system may be a potential therapeutic target for Type 2 diabetes.

Signal transduction pathways activated by insulin‐like peptide 5 at the relaxin family peptide RXFP4 receptor

“…This would suggest that INSL5, released from L‐cells in the gastrointestinal tract, may activate RXFP4 receptors in an autocrine/paracrine manner. Indeed, our cAMP result in the NCI‐H716 enteroendocrine cells and the ERK1/2 result in GLUTag cells (Luo et al , ) support this notion.…”

“…A previous study showed that INSL5 potentiated glucose‐stimulated insulin secretion in MIN6 insulinoma cells and primary murine islets, suggesting that INSL5–RXFP4 receptors may constitute a novel incretin axis, similar to GLP‐1–GLP‐1 receptor (Luo et al , ). We first confirmed that rxfp4 mRNA is expressed in MIN6 cells using real‐time quantitative PCR, though at a markedly lower level than glp1r ( n = 6; Figure A).…”

“…INSL5 activated ERK1/2 phosphorylation in a heterologous system expressing RXFP4 receptors (Belgi et al , ) and in pancreatic MIN6 and enteroendocrine GLUTag cells that endogenously express the receptor (Luo et al , ). Here, we confirm the activation of ERK1/2 but in addition demonstrate that RXFP4 receptors activate Akt, p38MAPK and S6RP, which are signalling proteins involved in a wide variety of cellular functions including growth, survival, proliferation and/or metabolism.…”

“…Relatively little is known of the signal transduction pathways activated by RXFP4 receptors, but these receptors are known to couple to Pertussis toxin (PTX)‐sensitive Gα i/o proteins to inhibit forskolin‐stimulated cAMP accumulation (Liu et al , ; Belgi et al , ). RXFP4 receptors also activate ERKs 1 and 2 (ERK1/2) in a heterologous system overexpressing these receptors (Belgi et al , ) and in MIN6 and GLUTag cells endogenously expressing RXFP4 receptors (Luo et al , ). RXFP4 receptors do not appear to couple to Gα q proteins since INSL5 evokes an intracellular Ca 2 + response only in systems co‐transfected with the promiscuous Gα 16 (Liu et al , ).…”

Liquid chromatography/mass spectrometry based detection and semi‐quantitative analysis of INSL5 in human and murine tissues

“…Liu and collaborators showed that INSL5 stimulates the G‐protein coupled receptor RXFP4 (GPR100 or GPCR142) but no precise physiological function of the peptide was initially identified . Since then INSL5 has been implicated in the regulation of metabolism, either by affecting glucose tolerance through an impact on insulin production, insulin secretion or the regulation of hepatic glucose production or through the stimulation of food‐intake . Consistent with an orexigenic function, Grosse et al reported a fall in INSL5 plasma levels after refeeding of starved mice; however, they observed poor reproducibility and batch dependence of several commercially available immunoassays.…”