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J Pharmacol Exp Ther. 2014 May;349(2):248-57. doi: 10.1124/jpet.113.208728. Epub 2014 Feb 18.

Novel curcumin derivative CNB-001 mitigates obesity-associated insulin resistance.

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  • 1Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, College of Health Sciences, Laramie, Wyoming (E.P., Y.H., J.R., S.N.); Cedars-Sinai Medical Center, Department of Neurology and Neurosurgery, Burns and Allen Research Institute, Los Angeles, California (P.A.L.); and Chemistry Department, University of Wyoming, Laramie, Wyoming (E.T., T.E.L.).

Abstract

Type 2 diabetes is growing at epidemic proportions, and pharmacological interventions are being actively sought. This study examined the effect of a novel neuroprotective curcuminoid, CNB-001 [4-((1E)-2-(5-(4-hydroxy-3-methoxystyryl-)-1-phenyl-1H-pyrazoyl-3-yl)vinyl)-2-methoxy-phenol], on glucose intolerance and insulin signaling in high-fat diet (HFD)-fed mice. C57BL6 mice (5-6 weeks old) were randomly assigned to receive either a HFD (45% fat) or a low-fat diet (LFD, 10% fat) for 24 weeks, together with CNB-001 (40 mg/kg i.p. per day). Glucose tolerance test revealed that the area under the curve of postchallenge glucose concentration was elevated on HF-feeding, which was attenuated by CNB-001. CNB-001 attenuated body weight gain, serum triglycerides, and IL-6, and augmented insulin signaling [elevated phosphoprotein kinase B (p-Akt), and phosphoinsulin receptor (p-IR)β, lowered endoplasmic reticulum (ER) stress, protein-tyrosine phosphatase 1B (PTP1B)] and glucose uptake in gastrocnemius muscle of HFD-fed mice. Respiratory quotient, measured using a metabolic chamber, was elevated in HFD-fed mice, which was unaltered by CNB-001, although CNB-001 treatment resulted in higher energy expenditure. In cultured myotubes, CNB-001 reversed palmitate-induced impairment of insulin signaling and glucose uptake. Docking studies suggest a potential interaction between CNB-001 and PTP1B. Taken together, CNB-001 alleviates obesity-induced glucose intolerance and represents a potential candidate for further development as an antidiabetic agent.

PMID:
24549372
PMCID:
PMC3989800
DOI:
10.1124/jpet.113.208728
[PubMed - indexed for MEDLINE]
Free PMC Article
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