A new antidiabetic compound attenuates inflammation and insulin resistance in Zucker diabetic fatty rats.

Abstract

Tissue macrophage inflammatory pathways contribute to obesity-associated insulin resistance. Here, we have examined the efficacy and mechanisms of action of a novel anti-inflammatory compound (HE3286) in vitro and in vivo. In primary murine macrophages, HE3286 attenuates LPS- and TNFalpha-stimulated inflammation. In Zucker diabetic fatty rats, inflammatory cytokine/chemokine expression was downregulated in liver and adipose tissue by HE3286 treatment, as was macrophage infiltration into adipose tissue. In line with reduced inflammation, HE3286 treatment normalized fasting and fed glucose levels, improved glucose tolerance, and enhanced skeletal muscle and liver insulin sensitivity, as assessed by hyperinsulinemic euglycemic clamp studies. In phase 2 clinical trials, HE3286 treatment led to an enhancement in insulin sensitivity in humans. Gluconeogenic capacity was also reduced by HE3286 treatment, as evidenced by a reduced glycemic response during pyruvate tolerance tests and decreased basal hepatic glucose production (HGP) rates. Since serum levels of gluconeogenic substrates were decreased by HE3286, it indicates that the reduction of both intrinsic gluconeogenic capacity and substrate availability contributes to the decrease in HGP. Lipidomic analysis revealed that HE3286 treatment reduced liver cholesterol and triglyceride content, leading to a feedback elevation of LDL receptor and HMG-CoA reductase expression. Accordingly, HE3286 treatment markedly decreased total serum cholesterol. In conclusion, HE3286 is a novel anti-inflammatory compound, which displays both glucose-lowering and cholesterol-lowering effects.

• Authors: Min Lu, David Patsouris, Pingping Li, Jaime Flores-Riveros, James M Frincke, Steve Watkins, Simon Schenk, Jerrold M Olefsky
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 298 Issue 5 Pg. E1036-48 (May 2010) ISSN: 1522-1555 [Electronic] United States
• PMID: 20159859 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 17-ethynyl-5-androstene-3, 7, 17-triol
• Blood Glucose
• Chemokines
• Cytokines
• Lipids
• Lipopolysaccharides
• Dehydroepiandrosterone

Topics

• Adult
• Analysis of Variance
• Animals
• Blood Glucose (metabolism)
• Blotting, Western
• Cell Movement (drug effects)
• Chemokines (metabolism)
• Cytokines (metabolism)
• Dehydroepiandrosterone (analogs & derivatives, pharmacology)
• Female
• Gene Expression
• Gluconeogenesis (drug effects)
• Glucose Clamp Technique
• Glucose Tolerance Test
• Humans
• Immunohistochemistry
• Inflammation (drug therapy, metabolism)
• Insulin Resistance
• Lipids (blood)
• Lipopolysaccharides
• Liver (drug effects, metabolism)
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Middle Aged
• Muscle, Skeletal (drug effects, metabolism)
• Obesity (drug therapy, metabolism)
• Rats
• Rats, Zucker