Pancreastatin inhibitor PSTi8 attenuates hyperinsulinemia induced obesity and inflammation mediated insulin resistance via MAPK/NOX3-JNK pathway.

Pancreastatin (PST), a chromogranin A derived peptide has anti-insulin effects and plays a significant role in obesity-induced insulin resistance. In obesity and type 2 diabetes mellitus, both insulin and PST level are elevated, but it is not clearly understood how anti-insulin effect of PST get regulated in hyperinsulinemic state. Simultaneously we have explored pancreastatin inhibitor PSTi8 against the native PST in the same hyperinsulinemic state. In in-vitro studies, we found that PST treatment increases lipid droplets and reactive oxygen species production in 3T3L1 adipocyte cells and theses effects of PST was found synergistic with chronic-insulin treatment. Treatment of PSTi8 in 3T3L1 adipocytes attenuates PST effect on lipid droplet formation and reactive oxygen species production. We further validated these findings in epididymal white adipose tissue of C57BL/6 mice, implanted with mini-osmotic insulin pump with and without PSTi8 for 4 weeks. We found that chronic hyperinsulinemia enhanced PST levels in circulation which in turn induces expression of various pro-inflammatory cytokines and oxidative stress. In addition, it also stimulated the expression of lipogenic genes, fat mass and body weight gain through the regulation of circulating adiponectin level. The change in PST mediated inflammatory and lipogenic parameters were attenuated by PSTi8 treatment, leading to enhanced insulin sensitivity and improved glucose homeostasis. PSTi8 rescue from PST mediated insulin resistance in adipose via inhibition of MAPK and NOX3-JNK stress signalling pathway which stimulates GLUT4 expression through activation of AKT-AS160 pathway. Thus PSTi8 may be a novel therapeutic agent for the treatment of hyperinsulinemia induced obesity and inflammation mediated insulin resistance.