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Leptolide Improves Insulin Resistance in Diet-Induced Obese Mice

Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid 47005, Spain
Instituto de Productos Naturales y Agrobiología (CSIC), La Laguna 38206, Spain
Instituto Universitario de Bioorgánica “A. González”, University of La Laguna, La Laguna 38206, Spain
School of Nursery, University of Burgos, Burgos 09001, Spain
Author to whom correspondence should be addressed.
Mar. Drugs 2017, 15(9), 289;
Received: 18 July 2017 / Revised: 22 August 2017 / Accepted: 13 September 2017 / Published: 15 September 2017
(This article belongs to the Special Issue Marine Compounds and Inflammation II, 2017)
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Type 2 diabetes (T2DM) is a complex disease linked to pancreatic beta-cell failure and insulin resistance. Current antidiabetic treatment regimens for T2DM include insulin sensitizers and insulin secretagogues. We have previously demonstrated that leptolide, a member of the furanocembranolides family, promotes pancreatic beta-cell proliferation in mice. Considering the beneficial effects of leptolide in diabetic mice, in this study, we aimed to address the capability of leptolide to improve insulin resistance associated with the pathology of obesity. To this end, we tested the hypothesis that leptolide should protect against fatty acid-induced insulin resistance in hepatocytes. In a time-dependent manner, leptolide (0.1 µM) augmented insulin-stimulated phosphorylation of protein kinase B (PKB) by two-fold above vehicle-treated HepG2 cells. In addition, leptolide (0.1 µM) counteracted palmitate-induced insulin resistance by augmenting by four-fold insulin-stimulated phosphorylation of PKB in HepG2 cells. In vivo, acute intraperitoneal administration of leptolide (0.1 mg/kg and 1 mg/kg) improved glucose tolerance and insulin sensitivity in lean mice. Likewise, prolonged leptolide treatment (0.1 mg/kg) in diet-induced obese mice improved insulin sensitivity. These effects were paralleled with an ~50% increased of insulin-stimulated phosphorylation of PKB in liver and skeletal muscle and reduced circulating pro-inflammatory cytokines in obese mice. We concluded that leptolide significantly improves insulin sensitivity in vitro and in obese mice, suggesting that leptolide may be another potential treatment for T2DM. View Full-Text
Keywords: leptolide; insulin resistance; obesity; type 2 diabetes; HepG2 cells leptolide; insulin resistance; obesity; type 2 diabetes; HepG2 cells

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Villa-Pérez, P.; Cueto, M.; Díaz-Marrero, A.R.; Lobatón, C.D.; Moreno, A.; Perdomo, G.; Cózar-Castellano, I. Leptolide Improves Insulin Resistance in Diet-Induced Obese Mice. Mar. Drugs 2017, 15, 289.

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