The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis

Abstract

Aims/hypothesis Chemokine (C-C motif) ligand 5 (CCL5) acts at C-C chemokine receptors (CCRs) to promote immune cell recruitment to sites of inflammation, but is also an agonist at G-protein-coupled receptor 75 (GPR75), which has very limited homology with CCRs. GPR75 is coupled to Gq to elevate intracellular calcium, so we investigated whether islets express this receptor and whether its activation by CCL5 increases beta cell calcium levels and insulin secretion. Methods Islet CCL5 receptor mRNA expression was measured by quantitative RT-PCR and GPR75 was detected in islets by western blotting and immunohistochemistry. In some experiments GPR75 was downregulated by transient transfection with small interfering RNA. Real-time changes in intracellular calcium were determined by single-cell microfluorimetry. Dynamic insulin secretion from perifused islets was quantified by radioimmunoassay. Glucose homeostasis in lean and obese mice was determined by measuring glucose and insulin tolerance, and insulin secretion in vivo. Results Mouse and human islets express GPR75 and its ligand CCL5. Exogenous CCL5 reversibly increased intracellular calcium in beta cells via GPR75, this phenomenon being dependent on phospholipase C activation and calcium influx. CCL5 also stimulated insulin secretion from mouse and human islets in vitro, and improved glucose tolerance in lean mice and in a mouse model of hyperglycaemia and insulin resistance (ob/ob ). The improvement in glucose tolerance was associated with enhanced insulin secretion in vivo, without changes in insulin sensitivity. Conclusions/interpretation Although CCL5 is implicated in the pathogenesis of diabetes through activation of CCRs, it has beneficial effects on beta cells through GPR75 activation.

20-HETE in the regulation of vascular and cardiac function

“…Liu et al, 2013) reported that isolated human and mouse islets express GPR75 and the chemokine CCL5 increases intracellular calcium levels via activation of GPR75 and suggested CCL5-mediated stimulation of insulin secretion is also a function of GPR75 activation. Binding of CCL5 to GPR75 was not confirmed in these studies (Ignatov, Robert, Gregory-Evans, & Schaller, 2006; B. Liu et al, 2013), however, it is possible that 20-HETE pairing with GPR75 interferes with CCL5-GPR75 binding and modulates CCL5 effect on insulin secretion.…”

Defining G protein-coupled receptor peptide ligand expressomes and signalomes in human and mouse islets

“…Islets were isolated from 10 to 12 weeks old male mice of the inbred C57BL/6 (C57; Charles River) and outbred Crl:CD1 (ICR) mice (Charles River) strains by collagenase digestion of the exocrine pancreas [16]. All animal procedures were carried out in accordance with the UK Home Office Animals (Scientific Procedures) Act 1986.…”

Animal models for diabetes: Understanding the pathogenesis and finding new treatments

“…An example of this is the administration of salicylate to improve insulin sensitivity in different obese mouse and rat models [138,145,146]. However it should be noted that some models of insulin resistance will often exhibit a relative insulin deficiency and thus drugs with positive effects of on insulin secretion can even be beneficial in insulin resistant models [147,148].…”