title: Amelioration of glucose intolerance by the synthetic androstene HE3286: link to inflammatory pathways.
abstract: 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 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 monocyte chemoattractant protein-1 in WAT, along with its cognate receptor C-C motif chemokine receptor-2. Exposure of mouse macrophages to HE3286 in vitro caused partial suppression of endotoxin (lipopolysaccharide)-induced nuclear factor kappa-B (NF-kappaB)-sensitive reporter gene expression, NF-kappaB nuclear translocation, and NF-kappaB/p65 serine phosphorylation. Proinflammatory kinases, including IkappaB kinase, c-Jun NH2-terminal kinase, and p38, were also inhibited by HE3286. In ligand competition experiments HE3286 did not bind to classical sex steroid or corticosteroid receptors, including androgen receptor (AR), progesterone receptor, estrogen receptor (ER) alpha or ERbeta, and glucocorticoid receptor (GR). Likewise, in cells expressing nuclear receptor-sensitive reporter genes HE3286 did not substantially stimulate transactivation of AR, ER, GR, or peroxisome proliferator-activated receptor (PPAR) alpha, 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 classic sex steroid receptors, corticosteroid receptors, or PPARs.
authors.affiliation: Hollis-Eden Pharmaceuticals, Inc., San Diego, CA 92121, USA.
authors.forename: Tianlun
authors.initials: T
authors.lastname: Wang
authors.forename: Sonia
authors.initials: S
authors.lastname: Villegas
authors.forename: Yujin
authors.initials: Y
authors.lastname: Huang
authors.forename: Steve K
authors.initials: SK
authors.lastname: White
authors.forename: Clarence
authors.initials: C
authors.lastname: Ahlem
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.forename: Chris
authors.initials: C
authors.lastname: Reading
authors.forename: James M
authors.initials: JM
authors.lastname: Frincke
authors.forename: David
authors.initials: D
authors.lastname: Alleva
authors.forename: Jaime
authors.initials: J
authors.lastname: Flores-Riveros
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D020869:Gene Expression Profiling; D018149:Glucose Intolerance / Q000378:metabolism / Q000517:prevention & control; D006943:Hyperglycemia / Q000378:metabolism / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007333:Insulin Resistance; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011987:Receptors, Steroid / Q000096:biosynthesis / Q000235:genetics
chemical_list: C524733:17-ethynyl-5-androstene-3, 7, 17-triol; D000893:Anti-Inflammatory Agents; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011987:Receptors, Steroid; D003687:Dehydroepiandrosterone