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 ⌬ 5 -androstene-17␣-ethynyl-3␤,7␤,17␤-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 -B (NF-B)-sensitive reporter gene expression, NF-B nuclear translocation, and NF-B/ p65 serine phosphorylation. Proinflammatory kinases, including IB kinase, c-Jun NH 2 -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) ␣ or ER␤, 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) ␣, PPAR␦, and PPAR␥. 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.

Pharmacology and immune modulating properties of 5-androstene-3β,7β,17β-triol, a DHEA metabolite in the human metabolome

“…Importantly, the effects are not immunosuppressive. The mechanism of action by which this occurs is not known, although it is reasonable to assume that ␤AET acts similarly to a closely related compound, 17␣-alkynyl-␤AET (HE3286), which has been reported to modulate the TNF␣ and MAP kinase signal transduction pathways [37,56].…”

“…Nuclear hormone receptor interactions were measured as previously described [37]. Binding interactions for androgen receptor (AR), estrogen receptor alpha (ER␣), estrogen receptor beta (ER␤), glucocorticoid receptor (GR), and the progesterone receptor (PR) were quantified in homogeneous competition assays using the PolarScreen TM fluorescence polarization system (Invitrogen, Carlsbad, CA).…”

17α-Alkynyl 3α, 17β-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism

“…Nuclear hormone receptor interaction profile Assessment of binding and transactivation for various nuclear receptors was performed as previously described [6]. 13 Fig.…”

Molecular Targets for 17α-Ethynyl-5-Androstene-3β,7β,17β-Triol, an Anti-Inflammatory Agent Derived from the Human Metabolome

“…HE3286, an orally bioavailable synthetic compound (Figure 1), is pharmacologically distinct from androgens, estrogens, corticosteroids, and peroxisome proliferators [10]. HE3286 has demonstrated anti-inflammatory activities similar to β-AET in murine models of ulcerative colitis [4], multiple sclerosis [4], type 1 diabetes mellitus [11], chronic obstructive pulmonary disease [12], and rheumatoid arthritis [4], [13], [14], [15].…”

“…All of these models involve attenuation of NF-κB activity and decreased levels of pro-inflammatory cytokines, including TNFα. HE3286 exhibits anti-inflammatory and insulin sensitizing activities in preclinical db/db and ob/ob mouse, fa/fa ZDF rat models of diabetes [10], [16], and in a rare example of species translation for sterols, in contrast to DHEA or β-AET, HE3286 is active in impaired glucose tolerant and type 2 diabetes mellitus human subjects [17].…”