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.
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.
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.
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.
HE3286 (17α-ethynylandrost-5-ene-3β,7β,17β-triol) is a chemical derivative of the natural mammalian sterol androst-5-ene-3β,7β,17β-triol (βAET). βAET exhibits anti-inflammatory activity in rodent models , is elevated in plasma of obese subjects with normal glucose disposal, and may play a compensatory role in preventing development of metabolic syndrome . βAET lacks pharmaceutical suitability, because of poor oral bioavailability and the propensity for inactivation by oxidation with 17β-hydroxysteroid dehydrogenase . The pharmacology of HE3286 has recently been published . HE3286 is orally bioavailable and stabilized against oxidation at position 17. Clinical pharmacokinetics indicated a plasma half-life of ∼7 h. HE3286 does not bind to any known nuclear steroid hormone receptors. HE3286 is pharmacologically unrelated to androgens, estrogens, corticosteroids, or peroxisome proliferators, and it did not alter the concentrations of dehydroepiandrosterone (DHEA), testosterone, estradiol, progesterone, androstenedione, lutenizing hormone, follicle stimulating hormone, or adrenocorticotrophic hormone and did not affect 24-h urinary free cortisol in nonclinical safety studies or clinical trials. HE3286 has shown broad anti-inflammatory activity  in animal models of rheumatoid arthritis , ulcerative colitis, multiple sclerosis , lung inflammation , and autoimmune type 1 diabetes . In these models, nuclear factor kappa B (NFκB) activation and proinflammatory cytokine production were consistently suppressed . Furthermore, HE3286 was not markedly immunosuppressive in ovalbumin immunization, Klebsiella pneumoniae or Pseudomonas aeruginosa infection , Coxsackievirus B3 myocarditis, , delayed-type hypersensitivity, and mitogen-induced proliferation in rodents  or in human mixed lymphocyte reaction assay .
Obesity induces an insulin-resistant state in adipose tissue, liver, and muscle and is a strong risk factor for the development of type 2 diabetes mellitus . Two recent publications report the anti-inflammatory activity of HE3286 in vitro and in rodent models of obesity-induced inflammation and insulin resistance in vivo [12, 13]. HE3286 suppressed endotoxin-induced NFκB activation, reporter gene expression, nuclear localization, and serine phosphorylation in mouse macrophages, and decreased phosphorylation of the proinflammatory extracellular signal-regulated (ERK1/2), IkappaB (IKK), Jun N-terminal (JNK), and p38 mitogen-activated protein (p38 MAPK) kinases. HE3286 also attenuated tumor necrosis factor alpha (TNFα)-stimulated inflammation and TNFα-induced adipocyte-stimulated macrophage chemotaxis [12, 13]. HE3286 treatment of diabetic db/db mice, insulin-resistant diet-induced obese mice, and genetically obese ob/ob mice suppressed progression to hyperglycemia and markedly improved glucose clearance. This effect appeared to be consequent to reduced insulin resistance, because HE3286 lowered blood insulin levels in both db/db and ob/ob mice. HE3286 suppressed levels of the chemokine monocyte chemoattractant protein-1 (MCP-1), along with its cognate receptor, C-C motif chemokine receptor-2, in white adipose tissue . In Zucker diabetic fatty (ZDF) rats, HE3286 downregulated inflammatory cytokine/chemokine expression in liver and adipose tissue, and macrophage migration into adipose tissue. HE3286 normalized fasting and fed glucose levels, improved glucose tolerance, and enhanced skeletal muscle and liver insulin sensitivity, as assessed by hyperinsulinemic, euglycemic clamp studies. Gluconeogenic activity was also reduced by HE3286, as evidenced by a reduced glycemic response during pyruvate tolerance tests and decreased basal hepatic glucose production rates. In addition, HE3286 reduced liver cholesterol and triglyceride content, leading to a feedback elevation of low-density lipoprotein (LDL) receptor and decreased total serum cholesterol .
On the basis of these preclinical studies, we hypothesized that HE3286 may ameliorate insulin resistance in obese insulin-resistant subjects by suppression of obesity-induced inflammation that inhibits insulin receptor signaling. We tested this hypothesis by studying impaired glucose tolerance (IGT) participants with a high prevalence of insulin resistance. We also tested whether HE3286 activity would be selective for those with the highest inflammation and insulin resistance.
Methods and Procedures
All manufacturing procedures were performed according to current good manufacturing practices. HE3286, 17α-ethynylandrost-5-ene-3β,7β,17β-triol (Triolex®, Figure 1) active pharmaceutical ingredient was manufactured by Norac, Azuza, CA, and formulated and filled in gelatin capsules by Eminent Services Corporation, Frederick, MD.
The clinical study was approved by the relevant institutional review board and conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization/WHO Good Clinical Practice Standards. Studies were performed at two clinical sites, Pennington Biomedical Research Center, LSU System, Baton Rouge, LA and dgd Research, San Antonio, TX. The trial was registered with ClinicalTrials.gov: HE3286-0102, NCT 00555451.
This was a multicenter, double-blind, dose ranging phase I study designed with five cohorts of obese, IGT but otherwise healthy subjects screened by a fasting blood glucose level of <126 mg/dL and a 140-200 mg/dL 2-h postprandial glucose following a 75-g oral glucose load. Inclusion criteria were male or female 18-65 years, with body mass index (BMI) at least 29 kg/m2, but no more than 35 for females and 37 for males, with fasting triglycerides <350 mg/dL, stable weight (5%), and exercise routine for 3 months prior to screening, and no history of weight loss or gain (>10% body weight) 9 months prior. Oral HE3286 doses of 4 (2 BID), 5 (QD), 10 (5 BID), and 20 (10 BID) mg were administered daily for 28 days.
One-step hyperinsulinemic, euglycemic clamps were performed on the day before the first dose and day 29 in the BID dose groups (Figure 2A). Five-hour clamps were performed after an overnight fast. Two catheters were inserted: one in a retrograde fashion in a hand vein, with the hand placed in a hand warmer for sampling of arterialized blood, and the other with a Y adaptor, into an antecubital vein of the contralateral arm for separate pump-controlled infusion of 20% dextrose solution and 200 mU/mL insulin (Humulin; Eli Lilly, Indianapolis, IN) diluted in 0.9% sodium chloride containing 0.4% autologous serum. Body surface area was calculated, and baseline values for fasting glucose and insulin were obtained. Priming infusion of insulin to raise the plasma insulin concentration to 100 μU/mL, and priming infusion of 20% dextrose to maintain blood sugar between 85 and 95 mg/dL were calculated  for the first 10-min infusion. Subjects with fasting glucose > 95 mg/dL received no glucose infusion during the first 5 min of the insulin priming. Blood samples were drawn every 5 min for 5 h, and glucose measured using a glucose analyzer. Blood samples for glucose and insulin laboratory values were drawn at baseline and every 30 min. At 30 min, the insulin infusion was begun at a rate of 60 μU/m2/min. The glucose infusion rate was varied to maintain blood glucose between 85 and 95 mg/dL .
The M value for each clamp was calculated as mg glucose infusion/kg/min from the means of five 30-min intervals of laboratory glucose and insulin values at a plateau in the glucose infusion curve. The quality of the clamp data was reviewed by three experienced investigators. Clamp data for one subject at baseline and for one subject at day 29 were not interpretable. Dual-energy X-ray absorptiometry scans were not performed in this study; M values were calculated based on total body weight, not corrected for fat-free mass.
Numbers of subjects at each dose group are shown in Figure 2B. Clamp studies were not performed on the 5-mg QD subjects (two placebo and 10 HE3286 subjects), and therefore, they were not included in the analysis of insulin sensitivity efficacy. One subject with a baseline clamp withdrew consent. Baseline and day 29 clamps were performed on 11 placebos, and 25 HE3286 subjects, for a total of 36 clamp patients. Results from two clamps were not interpretable (one HE3286 subject at baseline, and one at day 29), yielding day 29 M values change for 34 subjects (11 randomized to placebo [0 mg BID], 4-2 mg BID, 8-5 mg BID, and 11-10 mg BID). There were no significant differences between doses, and HE3286 responses were combined for analyses. For parameters other than M value and insulin, baseline analyses were performed on all 48 randomized subjects. Two subjects withdrew consent (Figure 2B). On day 28, analyses were performed on the remaining 46 subjects, except for missing values.
Inflammatory cytokine secretion was measured in peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide (LPS), using enzyme-linked immunosorbent assay to determine the levels of secreted cytokines and chemokines MCP-1, interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and TNFα.
Statistics and analysis
All analyses were performed using Prism Graph Pad (San Diego, CA). Changes from baseline in laboratory values were calculated from day 28 measurements. The relationship of day 29 change in M value versus baseline M value was analyzed using standard linear regression. Data sets were tested for normal distributions using the Shapiro–Wilks W test. Because of the frequency of significantly abnormal distributions, nonparametric analyses were used for comparisons. Baseline parameters were tested for balance, and day 28 laboratory value changes were tested for activity between treatment and placebo with the Mann–Whitney test. Correlations between baseline M value or day 29 change in M value and other baseline parameters were analyzed using the Spearman correlation. Treatment effects for all subjects and for insulin-resistant (baseline M value < 4.2) and insulin-sensitive (baseline M value > 4.2) subjects were analyzed using Fisher's exact test. Because of the exploratory nature of these hypothesis-testing studies, P values were not adjusted for multiple comparisons.
HE3286 was well tolerated. Ninety-six percent of the randomized subjects completed the study. Two subjects withdrew consent for personal reasons unrelated to study treatment (Figure 2B). There was no trend in adverse events (AEs) to differentiate between placebo- and HE3286-treated subjects, nor was there an increase in AEs with dose escalation. No patient died while on study.
Correlations of baseline M value with other baseline parameters are presented in Table 1. Baseline M values were significantly positively correlated with adiponectin (P < 0.0001) and glycated albumin (P = 0.02), and negatively with insulin (P = 0.001) and the inflammatory parameters (LPS-stimulated MCP-1 [P = 0.008], IL6 [P = 0.009], TNFα [P = 0.03], and IL-1β [P = 0.02]; and WBC [P = 0.02] and monocyte count [P = 0.02]). Day 29 change in M value was significantly correlated with baseline M value (P = 0.0001) and with its correlates, adiponectin, PBMC IL-6, MCP-1, TNFα, and WBC.
Table 1. Correlation of M values with other baseline parameters
Other baseline (n)
Spearman r (95% CI)
Spearman correlations of hyperinsulinemic, euglycemic clamp M values with other parameters at baseline or day 29 (clamp study performed on day 29, laboratory values from day 28).
The relationship of day 29 M value change with baseline M value is presented in Figure 3.
All placebo- and insulin-sensitive HE3286 participants showed a decrease in M value on day 29 compared to their baseline values. The underlying reasons for decreases in M values in 29 days in placebo and in insulin-sensitive participants are unknown. HE3286 treatment resulted in a significant negative correlation (r2 = 0.54, P < 0.0001), with increased day 29 M values for insulin-resistant participants, but placebo treatment left the parameters uncorrelated (r2 = 0.004, P = 0.9).
Baseline M value was a significant predictor of increased insulin-stimulated glucose disposal for HE3286, but not for placebo. To further examine the hypothesis that HE3286 would benefit insulin-resistant subjects, the subjects were stratified by the median baseline M value (4.2 mg/kg/min). At baseline, 18 subjects (before randomization) had M values < 4.2 (operationally defined as insulin-resistant) and 17 had M values ≥ 4.2 (operationally defined as insulin-sensitive).
Baseline laboratory values were balanced between HE3286 and placebo randomization with the exception of cholesterol and HDL, which were lower in HE3286 participants (Supporting Information Table S1). Overall, HE3286 subjects had a significantly different changes than placebo in day 29 M value (0 vs. −1.3), and in insulin (3 vs. 2 μU/mL), HDL (−0.4 vs. −4.3 mg/dL), and C-reactive protein (CRP, −0.6 vs. 0.6, P = 0.03). Fasting glucose decreased nonsignificantly with HE3286 for all subjects (median −0.5 vs. +4.5 mg/dL for placebo). Cholesterol and LDL decreased in both HE3286 and placebo without significant differences. There were no significant differences for triglycerides between HE3286 and placebo in all subjects. There were no significant weight changes, nor weight change differences between HE3286 and placebo in any group. There was no evidence for a treatment center effect on M value change.
Supporting Information Table S1 also indicates baseline and day 28 changes for laboratory values in insulin-resistant and insulin-sensitive subjects. HE3286 showed a significant difference for median day 29 M value change (0.7 vs. −1.2), HDL (0.6 vs. −4.3), triglycerides (6 vs. −37), and adiponectin (1.6 vs. 0) in insulin-resistant subjects. There was a trend for decreased CRP by HE3286 compared to placebo in insulin-resistant subjects (−0.7 vs. +1.7). Fasting glucose decreased nonsignificantly with HE3286 for insulin-resistant (−5 vs. +4.5) and for insulin-sensitive (−1.5 vs. +7) subjects. Cholesterol and LDL decreased in both HE3286 and placebo without significant differences. There were no significant differences between HE3286 and placebo for triglycerides in insulin-sensitive subjects. There were no significant weight changes, nor weight change differences between HE3286 and placebo in any group.
Baseline adiponectin and log10-normalized LPS-stimulated PBMC cytokines from all insulin-resistant versus insulin-sensitive subjects are summarized in Table 2. Baseline adiponectin was significantly lower in insulin-resistant than insulin-sensitive subjects (5.6 vs. 11, P = 0.0009). There were significantly higher baseline LPS-stimulated PBMC inflammatory cytokines in insulin-resistant than in insulin-sensitive subjects for IL-1β (P = 0.03), IL-6 (P = 0.04), MCP-1 (P = 0.045), and a trend for TNFα (P = 0.05).
Table 2. Baseline adiponectin and LPS-stimulated PBMC cytokines in insulin-resistant and insulin-sensitive subjects
We tested the hypothesis that HE3286 would benefit inflamed insulin-resistant subjects by comparing the treatment effect on insulin-resistant and insulin-sensitive subjects (Table 3).
Table 3. HE3286 treatment effects
Median (IQR) [n]
Fisher's exact test
⇑, proportion of subjects with increase; ⇓, proportion of subjects with decrease; IQR, inter quartile range; M, mg/kg/min glucose infusion.
Additional Supporting Information may be found in the online version of this article.
0.0 (−0.89 to 0.90) 
P = 0.003
−1.3 (−1.9 to −0.8) 
0.64 (−0.12 to 1.3) 
P = 0.009
−1.2 (−1.6 to −6.4) 
−0.74 (−1.3 to 0.02) 
−1.5 (−2.7 to −0.5) 
0.5 (−2.5 to 2.0) 
P = 0.02
−4.3 (−8.7 to −1.4) 
0.6 (−2.2 to 1.6) 
P = 0.04
−4.3 (−8.7 to −1.5) 
−0.15 (−2.9 to 3.1) 
−5.2 (−11 to 0.9) 
−0.4 (−2.6 to 0.7) 
P = 0.048
1.7 (−0.9 to 2.6) 
−0.7 (−3.6 to −0.2) 
P = 0.02
1.7 (−1.8 to 2.3) 
−0.1 (−2.2 to 0.9) 
0.55 (−1.2 to 8.9) 
There were significant HE3286 treatment responses compared to placebo in all subjects for change in day 29 M value (12/23 vs. 0/11, 0.003), HDL (12/23 vs. 1/11, P = 0.02), and CRP (16/22 vs. 4/11, P = 0.048). HE3286 significantly increased day 29 M value (9/12 vs. 0/5, P = 0.009) and HDL (7/12 vs. 0/5, P = 0.04), and decreased CRP (10/11 vs. 1/5, P = 0.02) in insulin-resistant, but not insulin-sensitive subjects, compared to placebo. Although median adiponectin change in insulin-resistant subjects was significant by Mann–Whitney test (Supporting Information Table 1), the frequency of subjects with increased day 28 adiponectin (7/10 vs. 1/4) did not reach significance by Fisher's exact test.
At baseline in this clinical study, high BMI IGT subjects with lower M values (insulin-resistant) correlated with higher baseline inflammatory status and fasting insulin levels, as seen in animal models . They also had elevated monocytes and WBC (chronic low-grade inflammation), and decreased adiponectin (known to be low in obesity). Adiponectin is a key determinant of insulin sensitivity and protection against obesity-associated metabolic syndrome .
We sought to test the hypothesis that the anti-inflammatory activity of HE3286 [12, 13] would improve glucose disposal parameters in humans with elevated BMI, insulin resistance, and obesity-induced inflammatory status. At day 29, increased insulin-stimulated glucose disposal by HE3286 was significantly different than by placebo, with an overall change of zero compared to −1.3. The overall average difference in M value compared to placebo by HE3286 was 33% in this 28-day treatment study. This compares favorably with a meta-analysis of 23 studies evaluating thiazolidinediones involving 342 type 2 diabetes patients having an average increase in glucose disposal of 34% . HE3286 change in day 29 M value correlated inversely with baseline M values. For insulin-sensitive subjects, HE3286 had no significant effect compared to placebos. The underlying reasons for decreases in M value from baseline in 29 days in placebos and in insulin-sensitive HE3286-treated subjects are unknown.
On the basis of the correlation of change in M value versus baseline M value, we stratified the subjects by the median M value of 4.2. These strata had a significant difference in baseline inflammatory status. Analysis of the treatment effect indicated that the activity of HE3286 was significant only in the insulin-resistant strata, which showed an increase in day 29 M value of +1.9 (+0.7 vs. −1.2 for placebo). Compared to placebo, the absolute magnitude of the change from baseline in insulin-resistant subjects (M value increase of 1.9, day 29) is also similar to the increase seen in a 12-week study with troglitazone in both obese and diabetic subjects . HE3286 treatment was well tolerated and did not cause hypoglycemia.
HE3286 treatment effects were also seen in the overall subjects for changes in HDL and CRP, with significant changes in insulin-resistant, but not in insulin-sensitive subjects. The anti-inflammatory activity of HE3286 in this active phenotype improved glucose disposal parameters, increased HDL, and reduced CRP. HE3286 was not active in non-inflamed, insulin-sensitive IGT subjects. CRP is a known cardiovascular risk factor, and HDL inhibits oxidation and inflammation, with higher levels correlating to decreased heart disease rates . These HE3286-mediated changes in CRP and HDL are the first demonstrations of anti-inflammatory activity in humans by a member of the DHEA metabolome. In addition to the insulin-sensitizing effects, HE3286 might lower cardiovascular risk in high BMI glucose intolerant subjects.
HE3286-mediated decreases for fasting glucose did not reach statistical significance, but these subjects had an inclusion criterion of <126 mg/dL, and had baseline medians of 102 for HE3286 and 101 for placebo. These IGT subjects had less metabolically dysregulated glucose and lipids than db/db, ob/ob, and diet-induced obesity mice and ZDF rats used in the preclinical studies.
Changes in body composition were not measured in this study. Serum adiponectin is an insulin-sensitizing cytokine  that activates AMPK , and its concentration is inversely correlated with body fat composition in adults . HE3286 significantly increased serum adiponectin in insulin-resistant, but not in insulin-sensitive subjects compared to placebo. This action may be due, in part, to effects on the expression of 11β-hydroxysteroid dehydrogenase (11β-HSD1) by HE3286, a synthetic derivative of the antiglucocorticoid βAET . 11β-HSD1 overexpression is reported to decrease adiponectin serum levels in obese subjects .
In 28 days of treatment, HE3286 did not significantly decrease ex vivo LPS-stimulated PBMC cytokine production. As the samples were shipped overnight, and cultured in the absence of HE3286, the data are unlikely to reflect in vivo effects of HE3286 on cytokine secretion. Serum cytokines were below the limits of detection in these patients. We favor the hypothesis that the increases in insulin-stimulated glucose disposal, adiponectin, and HDL, and decrease in CRP likely reflect its activity to decrease inflammatory-mediated hyperactivation of NFκB, with consequent restoration of insulin signaling [12, 13]. Increased adiponectin and decreased CRP may reflect decreased inflammatory status in adipose tissue. White adipose tissue is the site of production of elevated TNFα, IL-1β, IL-6, and MCP-1 in obese individuals . TNFα antagonizes the adiponectin promoter , and IL6 increases hepatic synthesis of CRP . Salsalate, an anti-inflammatory insulin sensitizer, dosed at 4 g/day also increased adiponectin and decreased CRP .
The selectivity of HE3286 responses may be better understood based on recent investigations of HE3286-binding partners, which were discovered using affinity chromatography and SILAC (stable-isotope labeling in culture) proteomic analysis tools . We have evidence for direct interactions between HE3286 and both extracellular receptor kinase (ERK) 1 and 2, in addition to other binding partners. ERK1 is important in adipocyte differentiation , inflammation-induced insulin resistance , insulin receptor substrate (IRS)-1 serine (inhibitory) phosphorylation, and the inhibitory effect of TNFα on insulin signaling . HE3286 does not inhibit insulin-mediated ERK activation, but inhibits LPS- and TNFα-stimulated ERK activation, and IRS-1 serine phosphorylation mediated by IKK and JNK [12, 13]. Tumor promotion locus 2 (Tpl2) kinase is upregulated in adipose tissue in mice and human subjects, and is reported to mediate NFκB and TNFα effects on ERK activation and IRS-1 serine phosphorylation . HE3286-mediated changes in signal transduction of ERK, IKK, JNK, and p38 MAPK may explain the preferential responses observed in obese subjects. Signal transduction pathways in omental fat are altered in obese, compared to lean individuals. In humans, activation of JNK and p38 MAPK was increased in omental (compared to paired subcutaneous) fat from obese, but not lean individuals, and this hyperphosphorylation correlated with clinical parameters of glycemia and insulin sensitivity . It will be important to further clarify the role of ERK in the activity of HE3286.
Our hypotheses tested in this study appear to be borne out. High BMI, IGT, insulin-resistant subjects have significantly elevated LPS-stimulated PBMC IL-1β, IL-6, MCP-1, and TNFα cytokine secretion compared to insulin-sensitive subjects (chronic low-grade inflammation). HE3286 treatment results in decreased CRP and increased HDL (anti-inflammatory). As in rodents, HE3286 significantly improves insulin-stimulated glucose disposal (increased insulin sensitivity) in high BMI, inflamed insulin-resistant subjects. HE3286 does not have significant activity in insulin-sensitive, high BMI IGT subjects (lacking chronic, low-grade inflammation). These findings support our hypothesis that the anti-inflammatory activity of HE3286 results in decreased NFκB- and TNFα-stimulated inhibition of insulin signaling, thereby restoring insulin-stimulated glucose disposal. Furthermore, subjects lacking chronic, low-grade inflammation lack the lesion in insulin receptor signaling, are glucose intolerant for other reasons, and therefore are unaffected by HE3286.
HE3286 is active at low doses and is the first anti-inflammatory insulin sensitizer with a toxicology profile consistent with chronic daily use . Because insulin resistance presages conversion of IGT subjects to type 2 diabetes mellitus, further studies of HE3286 activity in the obese, inflamed, insulin-resistant IGT population might uncover a promising intervention to prevent disease progression. In addition, these results justify exploration of HE3286 in obese, inflamed insulin-resistant type 2 diabetes mellitus subjects.