PROJECT SUMMARY/ABSTRACT
The nature of obesity-associated islet inflammation and its impact on ß cell abnormalities remain poorly defined.
In this application, we explore the immune cell components of islet inflammation and define their roles in
regulating ß cell function. Islet inflammation in obese mice is dominated by macrophages. We identified that G
protein-coupled receptor 92 (GPR92) is exclusively expressed in islet macrophages and its expression level is
regulated by high fat diet (HFD)-feeding in mice. Our computer simulation modeling combined with site-directed
mutagenesis of GPR92 has revealed the sites responsible for binding to farnesyl pyrophosphate (FPP)
activation, which portend various biological and medicinal functions for GPR92. Although GPR92 agonists have
been reported, their physiological function has not yet been studied. In several studies, the GPR92 locus
(12q13.31) has been linked by a genome-wide association study (GWAS) to type 1 and type 2 diabetes (T2D).
However, the role of GPR92 in this field is largely unknown. Since obesity induces expansion of islet
macrophages and increased pro-inflammatory status which impair ß cell function, we hypothesize whether islet
macrophage GPR92 and its activation affect nearby ß cell function in obesity. Our recent publication revealed
that GPR92 global knockout mice exhibited reduced insulin+ ß cells as well as lower insulin levels, but increased
macrophages in the islets compared to those of WT mice in both normal chow diet (NCD)- and HFD-fed groups.
In this application, we propose a novel approach to harness islet macrophages via a specific molecular target,
GPR92, to regulate intercellular communication with ß cells. This strategy proposes to simultaneously regulate
islet inflammation and ß cell function in a diet-induced obese condition using genetic and pharmacological means
to alter GPR92 function and further identify the molecular and cellular mechanism of islet macrophage-ß cell
communication via GPR92 activation. If successful, this approach will have a significant impact on T2D-mediated
islet dysfunction. Furthermore, insulin insufficiency and beta cell failure occur in all forms of diabetes. This
macrophage-based ß cell regulation strategy may also have a broader application potential for other types of
diabetes.