title: A synthetic anti-inflammatory sterol improves insulin sensitivity in insulin-resistant obese impaired glucose tolerance subjects.
abstract: OBJECTIVE
  To study the activity of HE3286 (17α-ethynylandrost-5-ene-3β,7β,17β-triol), an anti-inflammatory sterol that is active in models of obesity-induced inflammation and insulin resistance in high body mass index (BMI) subjects with impaired glucose tolerance (IGT).
  
  
  METHODS
  HE3286 was explored in high BMI IGT subjects using hyperinsulinemic, euglycemic clamp studies.
  
  
  RESULTS
  In insulin-resistant subjects, HE3286 significantly increased day 29 insulin-stimulated glucose disposal and HDL cholesterol, and decreased C-reactive protein (CRP) compared to placebo. For HE3286, change in M value showed a significant negative correlation with baseline M value. Subjects with baseline M value below the median (4.2 mg/kg/min) had significantly lower adiponectin and higher lipopolysaccharide-stimulated peripheral blood mononuclear cell cytokine secretion. After 28 days of HE3286 treatment, adiponectin levels were significantly increased in insulin-resistant (baseline M < 4.2), but not insulin-sensitive (baseline M > 4.2) subjects, compared to placebo.
  
  
  CONCLUSIONS
  HE3286 significantly increased the frequency of subjects with increased insulin-stimulated glucose disposal and HDL, and decreased CRP compared to placebo, in insulin-resistant, but not insulin-sensitive subjects. Thus, HE3286 may preferentially benefit insulin-resistant, inflamed, high BMI IGT subjects.
authors.affiliation: Harbor Therapeutics, Inc., San Diego, California, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Reading
authors.forename: Dwight R
authors.initials: DR
authors.lastname: Stickney
authors.forename: Jaime
authors.initials: J
authors.lastname: Flores-Riveros
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Destiche
authors.forename: Clarence N
authors.initials: CN
authors.lastname: Ahlem
authors.forename: William T
authors.initials: WT
authors.lastname: Cefalu
authors.forename: James M
authors.initials: JM
authors.lastname: Frincke
mesh_terms: D052242:Adiponectin / Q000097:blood; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D009765:Obesity / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism
chemical_list: C524733:17-ethynyl-5-androstene-3, 7, 17-triol; D052242:Adiponectin; D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D008076:Cholesterol, HDL; D016207:Cytokines; D007004:Hypoglycemic Agents; D007328:Insulin; D008070:Lipopolysaccharides; D003687:Dehydroepiandrosterone; D002097:C-Reactive Protein