A synthetic anti-inflammatory sterol improves insulin sensitivity in insulin-resistant obese impaired glucose tolerance subjects

Authors


  • Author Contributions: C.R. wrote manuscript and researched data. D.S. designed and monitored studies, reviewed/edited manuscript, and researched data. J.F.-R. researched data and reviewed/edited manuscript. D.D. performed statistical and database analysis. C.A. researched data and reviewed manuscript. J.F. contributed to study design and reviewed/edited manuscript. W.T.C. contributed to study design and reviewed/edited manuscript.

    Disclosure: C.R., D.S., J.F.-R., D.D., C.A., and J.F. are or were employees of Harbor Therapeutics. C.R., D.S., C.A., and J.F. are shareholders. J.F. is a board member. W.T.C. received an investigator grant for clinical studies from Harbor Therapeutics.

  • Additional Supporting Information may be found in the online version of this article.

Correspondence: Christopher L. Reading (creading@harbortx.com)

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).

Design and 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.

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