Insulin Modulates Protease-Activated Receptor 2 Signaling: Implications for the Innate Immune Response

Abstract

Given the anti-inflammatory effects of insulin in human and animal studies done in vivo and given the signaling pathways in common between insulin and the protease-activated receptor 2 (PAR2), a G protein-coupled receptor, we hypothesized that insulin would have an impact on the inflammatory actions of PAR2. We found that low doses or concentrations of insulin in the subnanomolar range reduced PAR2-induced inflammation in a murine paw edema model, attenuated PAR2-induced leukocyte trafficking in mouse intestinal venules, and reduced PAR2 calcium signaling in cultured dorsal root ganglion neurons and endothelial cells. This effect of insulin to attenuate PAR2-mediated inflammation was reversed when cells were preincubated with LY294002 (a PI3K inhibitor) and GF 109203X (a pan-protein kinase C inhibitor). The enhanced inflammatory effect of PAR2 observed in vivo in an insulin-deficient murine type 1 diabetes model was attenuated by the local administration of insulin at the inflammatory site. Our data point to an anti-inflammatory action of insulin that targets the acute innate inflammatory response triggered by PAR2.

C-peptide reduces pro-inflammatory cytokine secretion in LPS-stimulated U937 monocytes in condition of hyperglycemia

“…These findings underscore the role C-peptide may play in the prevention of endothelial dysfunction in T1D which leads to micro-and macrovascular disease, both major causes of morbidity and mortality in T1D. Insulin alone, the mainstay of treatment for T1D, has been shown to exert antiinflammatory properties in a number of settings, including settings designed to simulate T1D [37][38][39]. It is clear that c-peptide also possesses anti-inflammatory properties.…”

β2-Adrenoreceptor blockade improves early posttrauma hyperglycemia and pulmonary injury in obese rats

“…We did not use exogenous insulin to decrease early posttrauma hyperglycemia in OZ rats or to clamp posttrauma glucose at higher levels in LZ rats to confirm the impacts of early hyperglycemia. This is because the innate immune responses after trauma may be differentially affected by preexisting pathophysiological factors in obesity and diabetes (4,25,32,41). Moreover, in addition to the risk of hypoglycemia, insulin treatment has been shown to elicit significant anti-inflammatory effects, which may confound the interpretation of the results (1,14,15,24).…”

Proteinases, Their Extracellular Targets, and Inflammatory Signaling

“…To date, this effect of tissue proteinases on insulin receptor signaling, and by extension, signaling via the insulin-like growth factor-1 receptor, has gone largely unrecognized and has not yet been explored in any depth. In principle, this proteolytic mode of activation of the insulin receptor could play a role in inflammatory disease (Hyun et al, 2010). The impact of proteinases on the regulation of other "growth factor" receptors is a topic of interest for further study.…”