LAUSR

BACKGROUND AND PURPOSE Chemokines are known to play essential roles mediating immunity and inflammation in many physiological and pathophysiological processes, with reports linking their action to the development of obesity, insulin resistance and type 2 diabetes (T2D). Given our findings of highly upregulated mRNA expression of the chemokine receptor CCR9 in islets from obese human donors, we have determined the effects of CCR9 activation by CCL25 on islet function and viability. BASIC PROCEDURES RT-qPCR was used to measure expression of 384 GPCR mRNAs in human islets from organ donors with normal and elevated BMI. mRNA encoding CCR9, a receptor that was highly upregulated in islets from obese donors, was also quantified in islets from lean and high-fat diet (HFD) mice. The effects of CCR9 activation by exogenous CCL25 in human and mouse islets and its inhibition by the CCR9 antagonist vercirnon on insulin secretion, apoptosis and cAMP accumulation were examined using standard techniques. MAIN FINDINGS The qPCR analysis showed altered expression of several GPCRs in islets isolated from lean and obese donors. CCR9 displayed over 90-fold upregulation in islets from obese individuals, and it was also significantly upregulated in islets from obese mice. In isolated human and mouse islets exogenous CCL25 inhibited glucose-induced insulin secretion in a concentration-dependent manner, enhanced cytokine-induced apoptosis and significantly reduced forskolin-induced elevation in cAMP levels. These detrimental effects of CCL25 in islets were blocked by vercirnon, which had no effect on its own. PRINCIPAL CONCLUSIONS We have shown that CCL25 acts via the Gαi-coupled receptor CCR9 to impair beta-cell function by inhibiting insulin secretion and promoting cytokine-induced apoptosis. Upregulation of CCR9 in islets in obesity, possibly secondary to accumulation of passenger immune cells, may predispose to metabolic dysfunction and our data suggest that CCL25 downregulation or CCR9 inhibition could be explored to treat T2D.