just found out why...
thanks to immunotrade guy on yahoo (I guess he calls himself "immuno" because he knows something about inflamation and immunology. I like the way they chopped up macrophages treated with drug and looked at all the gene pathway changes)
:
J Pharmacol Exp Ther. 2010 Jan 12. [Epub ahead of print]
Amelioration of Glucose Intolerance by the Synthetic Androstene HE3286: Link to Inflammatory Pathways.
Wang T, Villegas S, Huang Y, White SK, Ahlem C, Lu M, Olefsky JM, Reading C, Frincke JM, Alleva D, Flores-Riveros J.
1 Hollis-Eden Pharmaceuticals, Inc.;
Insulin resistance, the major metabolic abnormality underlying type 2 diabetes, is associated with chronic inflammation and heavy macrophage infiltration in white adipose tissue (WAT). The therapeutic properties of the synthetic adrenal steroid Delta(5)-androstene-17alpha-ethynyl-3beta,7beta,17beta-triol (HE3286) were characterized in metabolic disease models. Treatment of diabetic db/db mice with HE3286 suppressed progression to hyperglycemia and markedly improved glucose clearance. Similar effects were also observed in insulin resistant, diet-induced obese C57BL/6J mice and in genetically obese ob/ob mice. This effect appeared to be a consequence of reduced insulin resistance because HE3286 lowered blood insulin levels in db/db and ob/ob mice. Treatment with HE3286 was accompanied by suppressed expression of the prototype macrophage-attracting chemokine MCP-1 in WAT, along with its cognate receptor CCR2. Exposure of mouse macrophages to HE3286 in vitro caused partial suppression of endotoxin (LPS)-induced NF-kappaB-sensitive reporter gene expression, NF-kappaB nuclear translocation and NF-kappaB/p65 serine phosphorylation. Proinflammatory kinases including IkappaB kinase (IKK), c-Jun NH(2)-terminal kinase (JNK) and p38, were also inhibited by HE3286. In ligand competition experiments, HE3286 did not bind to classical sex steroid or corticosteroid receptors, including AR, PR, ERalpha or ERbeta and GR. Likewise, in cells expressing nuclear receptor-sensitive reporter genes, HE3286 did not substantially stimulate transactivation of AR, ER, GR or PPARalpha, PPARdelta and PPARgamma. These findings indicate that HE3286 improves glucose homeostasis in diabetic and insulin resistant mice, and suggest that the observed therapeutic effects result from attenuation of proinflammatory pathways, independent of classical sex steroid, corticosteroid or PPAR nuclear receptors.
AI
