Effects Of Olfactory Receptor Olfr109 Sensing Insulin Peptide And Denatured Insulin On Islet Homeostasis And The Underlying Molecular Mechanism

Pancreatic islets are the only tissues in the body that produce insulin,and insulin accounts for about 10%of the total protein content of islet beta cells.Recent studies have shown that not only functionally intact insulin,but also short insulin peptides produced by cleavage of misfolded insulin are also released into the blood from vesicles in islet beta cells upon glucose stimulation.These insulin peptides of different lengths,as well as denatured insulin,can act as antigens to trigger islet autoimmunity,which is functionally related to the pathogenesis of type 1 diabetes(T1D);meanwhile,type 2 diabetes(T2D)increases insulin demand due to insulin resistance,and insulin Peptide levels also increased accordingly.Notably,the binding ability of these insulin peptide fragments to MHC II molecules is poor,with an affinity around micromolar(μM)level,but the physiological concentration of these insulin peptides in plasma is only even less than nanomolar(nM)level.Whether pancreatic beta cells have an underlying mechanism to sense these insulin fragments and initiate signaling cascades to regulate islet homeostasis is unclear.Furthermore,recent evidence suggests that local proliferation of islet-resident macrophages also plays a key role in islet inflammation and diabetes development.However,the mediation of this process by islets is largely unknown.Linking pancreatic islet secretions to their potential high-affinity receptors such as GPCRs and studying their corresponding functions,such as their role in insulin secretion and signaling between islet beta cells and islet-resident macrophages,will provide Help to elucidate the mechanism that regulates islet homeostasis and provide new ideas for the development of new anti-diabetic strategies.Mammals perceive odor information through olfactory receptors(ORs).Olfactory receptors are a subfamily of G protein-coupled receptors(GPCRs)and are one of the largest mammalian gene families.About 400 of the 826 GPCRs expressed in the human body are olfactory receptors,mainly expressed in the epithelium of the nasal mucosa,responsible for converting the chemical signals of odor molecules into electrical signals to form olfactory perception.American scientists Linda Buck and Richard Axel won the 2004 Nobel Prize in Physiology or Medicine for their discovery of olfactory receptors and how the olfactory system is organized.In addition to playing a leading role in odor perception,recent studies have found that olfactory receptors are distributed in a variety of organs and tissues,and play different physiological functions in these organs,such as mediating sperm chemotaxis,muscle production,Cancer cell growth inhibition,hair growth,liver steatosis and adipose tissue lipolysis,etc.However,the gene expression profile and function of olfactory receptors in pancreatic islets,as well as their effects on glucose-induced insulin and glucagon secretion,remaining unknown.Both diabetes-related insulin-cleaving peptides and insulin can be secreted by pancreatic beta cells.By screening the expression and localization of olfactory receptors(ORs)in pancreatic islets,we identified Olfr109(corresponds to human olfactory receptor OR12D3)as a receptor for insulin peptides and denatured insulin.The insulin peptide insB:9-23 reduces insulin secretion by activating the Olfr109 Gi signaling pathway,and promotes the proliferation of islet-resident macrophages through the β-cell-macrophage circuit and the β-arrestinl-mediated CCL2 pathway.The β-arrestin-1-/-mouse model demonstrates this.Islet-specific knockout of Olfr109 induced by Pdxl-Cre+/-Olfr109fl/fl and knockout of Olfr109 in Akita mice improved glucose metabolism and islet homeostasis in high-fat-fed mice as well as in Akita mice.In addition,we further determined the interaction mode between insB:9-23 and Olfr109,and further developed a specific pepducin antagonist targeting Olfr109,which can significantly improve glucose metabolism in obese mice and diabetic model mice.Overall,we found that the olfactory receptor Olfr109 on pancreatic β cells can act as a quality-checking protein to recognize insulin peptides early and inactivate insulin,thereby reducing insulin secretion.However,in long-term Akita or high-fat model mice,the compensatory effect of islets could not be maintained,and excessive insB:9-23 continued to activate Olfr109 to reduce insulin secretion and promote the proliferation of islet-resident macrophages to damage islets homeostasis and glucose homeostasis.