Olfactory marker protein regulation of glucagon secretion in hyperglycemia

Abstract

Glucose metabolism: Smell receptor implicated in regulation of blood sugar The same signaling pathway that controls smell perception in the nose is involved in regulating the release of a pancreatic hormone needed when blood sugar levels are high. The olfactory marker protein (OMP) is a marker of chemical signaling mediated by olfactory receptors, which are located not only in the nose but throughout the body. A research team led by Eun Jig Lee and Yoon Hee Cho from Yonsei University College of Medicine, Seoul, South Korea, showed that human and mouse pancreatic alpha-cells, endocrine cells that secrete the peptide hormone glucagon to increase glucose levels in the bloodstream, express OMP. Blocking OMPactivity impairs glucagon response pathways. Therapeutics directed at olfactory receptor signaling in the pancreas could therefore help reduce excessive glucagon activity associated with diseases such as type 2 diabetes. The olfactory marker protein (OMP), which is also expressed in nonolfactory tissues, plays a role in regulating the kinetics and termination of olfactory transduction. Thus, we hypothesized that OMP may play a similar role in modulating the secretion of hormones involved in Ca2+ and cAMP signaling, such as glucagon. In the present study, we confirmed nonolfactory alpha-cell-specific OMP expression in human and mouse pancreatic islets as well as in the murine alpha-cell line alpha TC1.9. Glucagon and OMP expression increased under hyperglycemic conditions. Omp knockdown in hyperglycemic alpha TC1.9 cells using small-interfering RNA (siRNA) reduced the responses to glucagon release and the related signaling pathways compared with the si-negative control. The OMPlox/lox;GCG(cre/w) mice expressed basal glucagon levels similar to those in the wild-type OMPlox/lox mice but showed resistance against streptozotocin-induced hyperglycemia. The ectopic olfactory signaling events in pancreatic alpha-cells suggest that olfactory receptor pathways could be therapeutic targets for reducing excessive glucagon levels.