Modified Si-Miao-San () regulates adipokine expression and ameliorates insulin resistance by targeting IKKβ/Insulin receptor substrate-1 in mice.

Abstract

To evaluate modified Si-Miao-San (mSMS, ) regulation of insulin sensitivity and explore the molecular mechanism by which mSMS inhibits inflammation and improves insulin action in mice. Insulin resistant model in mice was prepared by stimulation with macrophage-derived condition medium (Mac-CM) and the effects of mSMS on oral glucose tolerance, insulin sensitivity and liver glycogen content in mice was observed. The mice adipose tissue was isolated and the regulation of inflammation-related adipokine expression and insulin phosphatidylinositol 3-kinase (PI3K) signaling transduction by mSMS was investigated. Effect of mSMS on insulin-mediated glucose uptake was also investigated in adipocytes. Oral administration of mSMS improved glucose tolerance in mice. Treatment of mice with Mac-CM resulted in glucose intolerance in mice and this change was effectively reversed by mSMS. Meanwhile, mSMS enhanced insulin sensitivity and increased glucose load-stimulated liver glycogen when mice were exposed to Mac-CM. Mac-CM stimulation induced dysregulation of adipokine expression in adipose tissue of mice. mSMS downregulated tumor necrosis factor α and interleukin 6 (IL-6) overexpression and upregulated adiponectin and peroxisomal proliferator activated receptor γ with inhibition of inhibitory kappa B kinase-β (IKKβ) and p65 phophsphorylation. Meanwhile, mSMS inhibited IL-6 production and increased adiponectin secretion in adipocytes against Mac-CM insult. Mac-CM challenge impaired insulin phosphatidylinositol 3 kinase (PI3K) signaling in adipose tissue. Oral administration mSMS inhibited inflammation-induced serine phosphorylation of insulin receptor substrate-1 (IRS-1) and restored insulin-mediated tyrosine phosphorylation, and thereby facilitated insulin PI3K signaling manifested by restoration of Akt phosphorylation. The resultant improvement of insulin sensitivity promoted insulin-stimulated glucose uptake when adipocytes were exposed to Mac-CM. mSMS improves glucose tolerance in mice by enhancing insulin sensitivity in mice. mSMS inhibits IKKβ/NF κ B (p65)-dependent inflammatory response with beneficial regulation of adipokine expression in adipose tissue. mSMS inhibits inflammation and improves insulin sensitivity by blocking inflammatory interaction between IKKβ/IRS-1.