Role of olfactory marker protein in modulating glucagon secretion in α cells of pancreatic islets

Abstract

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia. In type 2 diabetes, defective insulin release and insulin resistance is often accompanied by increased glucagon levels which aggravate hyperglycemia. Although defective glucagon secretory response causes various problems in diabetic patients, compared with β cell physiology, the mechanisms involved in pancreatic α cell physiology remain elusive. Olfactory marker protein (OMP) is a cytoplasmic protein expressed primarily in mature chemosensory neurons in the main olfactory epithelium. Recently, OMP has been shown to be expressed in non-olfactory tissue including the endocrine system. As OMP plays a role in regulating the kinetics and termination of olfactory transduction, we hypothesized that OMP may have a similar function in modulating hormone secretion involving Ca2+ and 3’,5’-cyclic adenosine monophosphate (cAMP) signaling. In this study, non-olfactory α cell-specific OMP expression in human and mouse pancreatic islets, as well as in mouse α cell line αTC1.9 was confirmed. To investigate the role of Omp in αTC1.9 cells, Omp was knocked down using siRNA. This resulted in elevated glucagon release and related signaling pathways, including increased phosphorylation of cAMP response elements binding protein (CREB) and prolonged cAMP responses. In Omp-/- mice, basal glucagon levels were higher compared to those in Omp+/+ wild-type mice but showed resistance against streptozotocin (STZ)-induced hyperglycaemia. Furthermore, glucagon secretion from isolated mouse pancreatic islets was analyzed. The results correlated with our in vitro and in vivo experiments. Together, these results suggest that OMP contributes to regulating the kinetics of intracellular cAMP production in pancreatic α cells, which changes in the levels of secreted glucagon. Non-olfactory expression of OMP is an indicator of potential olfactory receptor (OR)-associated events in non-olfactory systems. Future studies that focus on regulating glucagon secretion by targeting ORs expressed on α cells using odorants are required for the development of novel treatments for diabetes.