| dc.description.abstract | Type 2 diabetes is characterized by insulin resistance and beta-cell dysfunction[1]. Macrophages are a major source of inflammatory cytokine IL-1β, which is a major regulator of inflammation in the pancreatic beta-cells [2, 3]. IL-1Ra antagonizes the activity of IL-1β[4]. Beta-cells are the primary source for islet IL-1Ra expression, and IL-1Ra expression in islets diminishes following T2D onset [5]. Ghrelin is nutrient sensor and metabolic regulator. Ghrelin’s known receptor is growth hormone secretagogue receptor (GHS-R), reported to govern glucose homeostasis and inflammation under both physiological and pathological conditions[6, 7]. However, little is known of the role of macrophage GHS-R in glycemic regulation of T2D conditions, and its effect on the IL-1Ra:IL-1β ratio is totally unknown. In this study we utilized Western diet + multiple low dose streptozotocin to generate an experimental T2D model to evaluate the effects of myeloid-specific inhibition of GHS-R (LysM-Cre;Ghsr^f/f). We determined that the WD/STZ model emulated the natural pathogenesis of T2D, the severity of which was attenuated in LysM-Cre;Ghsr^f/f mice. We detected attenuated hyperglycemia, increased circulating insulin, reduced glucagon, improved hepatic glucose production, and improved glucose tolerance in vivo; as well as enhanced insulin secretion ex vivo. Furthermore, gene expression of whole islets exhibited increased insulin signaling genes and an increased ratio of IL-1Ra:IL-1β, suggesting increased IL-1Ra activity. In conclusion, myeloid-specific inhibition of GHS-R mitigated the severity of T2D via improvements of regulation of glucoregulatory hormones, hepatic glucose metabolism, and islet insulin signaling, at least in part due to increased IL-1Ra activity. | |
