Improvement of Insulin Sensitivity in Obese Zucker Rats by Myricetin Extracted from Abelmoschus moschatus

Abstract

In an attempt to develop new substances for treating insulin resistance, obese Zucker rats were employed to screen the effect of myricetin, an active principle of Abelmoschus moschatus (Malvaceae), on insulin resistance. Myricetin purified from the aerial portion of the plant was administered intravenously (i. v.) into animals. A dose-dependent decrease in the plasma glucose concentration of obese Zucker rats was observed 30 min following an i. v. injection. Moreover, repeated i. v. injection of myricetin (1 mg/kg) into obese Zucker rats 3 times daily for 1 week reduced the value of the glucose-insulin index, an index of insulin resistance calculated from the areas under the curve of glucose and insulin during the intraperitoneal glucose tolerance test. Additionally, repeated myricetin treatments overturned the inability of insulin to increase the expression of glucose transporter subtype 4 (GLUT 4) and to increase the protein levels and phosphorylation of insulin receptor substrate-1 (IRS-1) in soleus muscle of these obese rats. The inability of insulin to increase expression of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and to promote Akt serine phosphorylation in soleus muscle of these rats were also overturned by repeated myricetin treatments. These findings indicate that myricetin improves insulin sensitivity through increased post-receptor insulin signaling mediated by enhancements in IRS-1-associated PI3-kinase and GLUT 4 activity in muscles of obese Zucker rats. Myricetin might be used as a model substance for the development of antidiabetic compounds.

Key words

Akt - glucose transporter subtype 4 - insulin receptor - insulin receptor substrate-1 - myricetin - phosphatidylinositol 3-kinase - obese Zucker rat - Abelmoschus moschatus - Malvaceae

References

• 1 Shulman G I. Cellular mechanisms of insulin resistance.  J Clin Invest. 2000;  106 171-6.
• 2 Younis N, Soran H, Farook S. The prevention of type 2 diabetes mellitus: recent advances.  QJM. 2004;  97 451-5.
• 3 Bown D. Encyclopaedia of Herbs and their Uses. London; Dorling Kindersley 1995.
• 4 Ong K C, Khoo H E. Biological effects of myricetin.  Gen Pharmacol. 1997;  29 121-6.
• 5 Ong K C, Khoo H E. Insulinomimetic effects of myricetin on lipogenesis and glucose transport in rat adipocytes but not glucose transport translocation.  Biochem Pharmacol. 1996;  51 423-9.
• 6 Ong K C, Khoo H E. Effects of myricetin on glycemia and glycogen metabolism in diabetic rats.  Life Sci. 2000;  67 1695-705.
• 7 Liu I M, Liou S S, Lan T W, Hsu F L, Cheng J T. Myricetin as the active principle of Abelmoschus moschatus to lower plasma glucose in streptozotocin-induced diabetic rats.  Planta Med. 2005;  71 617-21.
• 8 Liu I M, Liou S S, Lan T W, Hsu F L, Cheng J T. Mediation of β-endorphin by myricetin to lower plasma glucose in streptozotocin-induced diabetic rats.  J Ethnopharmacol. 2006;  104 199-206.
• 9 Bray G A. The Zucker-fatty rat: a review.  Fed Proc. 1977;  36 148-53.
• 10 Griffiths L A, Smith G E. Metabolism of myricetin and related compounds in the rat. Metabolite formation in vivo and by the intestinal microflora in vitro .  Biochem J. 1972;  130 141-51.
• 11 Rouru J, Huupponen R, Pesonen U, Koulu M. Subchronic treatment with metformin produces anorectic effect and reduces hyperinsulinemia in genetically obese Zucker rats.  Life Sci. 1992;  50 1813-20.
• 12 Cefalu W T, Wang Z Q, Zhang X H, Baldor L C, Russell J C. Oral chromium picolinate improves carbohydrate and lipid metabolism and enhances skeletal muscle Glut-4 translocation in obese, hyperinsulinemic (JCR-LA corpulent) rats.  J Nutr. 2002;  132 1107-11.
• 13 Ahren B, Pacini G. Importance of quantifying insulin secretion in relation to insulin sensitivity to accurately assess beta cell function in clinical studies.  Eur J Endocrinol. 2004;  150 97-104.
• 14 Christ C Y, Hunt D, Hancock J, Garcia-Macedo R, Mandarino L J, Ivy J L. Exercise training improves muscle insulin resistance but not insulin receptor signaling in obese Zucker rats.  J Appl Physiol. 2002;  92 736-44.
• 15 Giorgino F, Laviola L, Leonardini A. Pathophysiology of type 2 diabetes: rationale for different oral antidiabetic treatment strategies.  Diabetes Res Clin Pract. 2005;  68 S22-9.
• 16 Hundal R S, Inzucchi S E. Metformin: new understandings, new uses.  Drugs. 2003;  63 1879-94.
• 17 Petersen K F, Shulman G I. Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus.  Am J Cardiol. 2002;  90 G11-8.
• 18 Song X M, Ryder J W, Kawano Y, Chibalin A V, Krook A, Zierath J R. Muscle fiber type specificity in insulin signal transduction.  Am J Physiol. 1999;  277 R1690-6.
• 19 Sesti G, Federici M, Hribal M L, Lauro D, Sbraccia P, Lauro R. Defects of the insulin receptor substrate (IRS) system in human metabolic disorders.  FASEB J. 2001;  15 2099-111.
• 20 Anai M, Funaki M, Ogihara T, Terasaki J, Inukai K, Katagiri H. et al . Altered expression levels and impaired steps in the pathway to phosphatidylinositol 3-kinase activation via insulin receptor substrates 1 and 2 in Zucker fatty rats.  Diabetes. 1998;  47 13-23.
• 21 Carvalho E, Rondinone C, Smith U. Insulin resistance in fat cells from obese Zucker rats-evidence for an impaired activation and translocation of protein kinase B and glucose transporter 4.  Mol Cell Biol. 2000;  206 7-16.
• 22 Kern M, Wells J A, Stephens J M, Elton C W, Friedman J E, Tapscott E B. et al . Insulin responsiveness in skeletal muscle is determined by glucose transporter (Glut4) protein level.  Biochem J. 1999;  270 397-400.
• 23 Ivy J L. Muscle insulin resistance amended with exercise training: role of GLUT4 expression.  Med Sci Sports Exerc. 2004;  36 1207-11.