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.
Footnotes
- Received August 13, 2013.
- Accepted February 13, 2014.
This work was supported in part by the National Institutes of Health National Center for Research Resources [Grant P20-RR016474]; and the National Institutes of Health National Institute of General Medical Sciences [Grant P20-GM103432] (to S.N. and J.R.); the National Institutes of Health National Institute of General Medical Sciences Wyoming INBRE Bioinformatics Core [Grant 8P20-GM103432] (to S.N.); and the National Institutes of Health National Institute of Neurologic Disorders and Stroke [Grant U01-NS060685] (to P.A.L.). S.N. is the guarantor of this work, had full access to all the data, and takes full responsibility for the integrity of data and the accuracy of data analysis.
Portions of this article were presented: Panzhinskiy E, Lapchak PA, Ren J, and Nair S (2012) A novel neuroprotective curcuminoid alleviates glucose intolerance and improves insulin signaling. FASEB J 26:672.7; Experimental Biology 2012; 21–25 Apr 2012; San Diego, CA, for which E.P. received the travel award from ASPET.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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