Kakkalide ameliorates endothelial insulin resistance by suppressing reactive oxygen species-associated inflammation.

Abstract

BACKGROUND:

Kakkalide is the predominant isoflavone derived from the flowers of Pueraria lobata (Willd.) Ohwi. The aim of the present study was to investigate the effects of kakkalide on insulin resistance in the endothelium.

METHODS:

Human umbilical vein endothelial cells (HUVEC) were stimulated with 100 μmol/L palmitate (PA) for 30 min and the effects of 30 min pretreatment with 0.1-10 μmol/L kakkalide on reactive oxygen species (ROS)-associated inflammation in cells were evaluated by western blot analysis and reverse transcription-polymerase chain reaction. Furthermore, we investigated the biomodulation of insulin signaling by kakkalide along the insulin receptor substrate (IRS)-1/Akt/endothelial nitric oxide synthase (eNOS) pathway. We also determined the effects of 30 min pretreatment with 0.1-10 μmol/L kakkalide on insulin-mediated endothelium-dependent vasodilation of rat aorta in vitro following stimulation with 100 μmol/L PA.

RESULTS:

Kakkalide inhibited ROS overproduction and effectively restored mitochondrial membrane potential, demonstrating its chemoprotection of mitochondrial function. In addition, kakkalide inhibited ROS-associated inflammation in the endothelium by inhibiting tumor necrosis factor-α and interleukin-6 production and gene expression, as well as suppressing the phosphorylation of c-Jun N-terminal kinase and IκB kinase β/nuclear factor-κB. Inflammation impaired insulin phosphatidylinositol 3-kinase (PI3K) signaling and reduced insulin-mediated NO production in endothelial cells. Kakkalide facilitated PI3K signaling by positively regulating serine/tyrosine phosphorylation of IRS-1.

CONCLUSIONS:

Kakkalide inhibited ROS-associated inflammation and ameliorated insulin-resistant endothelial dysfunction by beneficial effects on IRS-1 function.

• Authors: Dongyan Zhang, Xuejiao Gao, Qi Wang, Minjian Qin, Kang Liu, Fang Huang, Baolin Liu
• Journal: Journal of diabetes (J Diabetes) Vol. 5 Issue 1 Pg. 13-24 (Mar 2013) ISSN: 1753-0407 [Electronic] Australia
• PMID: 23190749 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Chemical References

• DNA Primers
• Glycosides
• IRS1 protein, human
• Insulin
• Insulin Receptor Substrate Proteins
• Isoflavones
• Reactive Oxygen Species
• Nitric Oxide
• kakkalide
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Base Sequence
• Blotting, Western
• Cells, Cultured
• DNA Primers
• Endothelium, Vascular (cytology, drug effects, metabolism)
• Glycosides (pharmacology)
• Humans
• Insulin (metabolism, physiology)
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin Resistance
• Isoflavones (pharmacology)
• Membrane Potential, Mitochondrial (drug effects)
• Nitric Oxide (biosynthesis)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Vasodilation (drug effects, physiology)