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Anti-diabetic effects of benfotiamine on an animal model of type 2 diabetes mellitus

  • Chung, Kang Min (Department of Toxicology and Biochemistry, College of Veterinary Medicine, Jeju National University) ;
  • Kang, Wonyoung (Department of Toxicology and Biochemistry, College of Veterinary Medicine, Jeju National University) ;
  • Kim, Dong Geon (Department of Toxicology and Biochemistry, College of Veterinary Medicine, Jeju National University) ;
  • Hong, Hyun Ju (Department of Toxicology and Biochemistry, College of Veterinary Medicine, Jeju National University) ;
  • Lee, Youngjae (Department of Toxicology and Biochemistry, College of Veterinary Medicine, Jeju National University) ;
  • Han, Chang-Hoon (Department of Toxicology and Biochemistry, College of Veterinary Medicine, Jeju National University)
  • Received : 2013.11.02
  • Accepted : 2014.01.24
  • Published : 2014.03.31

Abstract

Although benfotiamine has various beneficial anti-diabetic effects, the detailed mechanisms underlying the impact of this compound on the insulin signaling pathway are still unclear. In the present study, we evaluated the effects of benfotiamine on the hepatic insulin signaling pathway in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are a type 2 diabetes mellitus model. OLETF rats treated with benfotiamine showed decreased body weight gain and reduced adipose tissue weight. In addition, blood glucose levels were lower in OLETF rats treated with benfotiamine. Following treatment with benfotiamine, the levels of Akt phosphorylation (S473/T308) in the OLETF groups increased significantly compared to the OLETF control group so that they were almost identical to the levels observed in the control group. Moreover, benfotiamine restored the phosphorylation levels of both glycogen synthase kinase (GSK)-$3{\alpha}/{\beta}$ (S21, S9) and glycogen synthase (GS; S641) in OLETF rats to nearly the same levels observed in the control group. Overall, these results suggest that benfotiamine can potentially attenuate type 2 diabetes mellitus in OLETF rats by restoring insulin sensitivity through upregulation of Akt phosphorylation and activation of two downstream signaling molecules, GSK-$3{\alpha}/{\beta}$ and GS, thereby reducing blood glucose levels through glycogen synthesis.

References

  1. Alberti KGMM, Zimmet P, Shaw J. The metabolic syndrome-a new worldwide definition. Lancet 2005, 366, 1059-1062. https://doi.org/10.1016/S0140-6736(05)67402-8
  2. Bitsch R, Wolf M, Moller J, Heuzeroth L, Gruneklee D. Bioavailability assessment of the lipophilic benfotiamine as compared to a water-soluble thiamine derivative. Ann Nutr Metab 1991, 35, 292-296. https://doi.org/10.1159/000177659
  3. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976, 72, 248-254. https://doi.org/10.1016/0003-2697(76)90527-3
  4. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001, 414, 813-820. https://doi.org/10.1038/414813a
  5. Ciaraldi TP, Nikoulina SE, Bandukwala RA, Carter L, Henry RR. Role of glycogen synthase kinase-$3{\alpha}$ in insulin action in cultured human skeletal muscle cells. Endocrinology 2007, 148, 4393-4399. https://doi.org/10.1210/en.2006-0932
  6. Cline GW, Johnson K, Regittnig W, Perret P, Tozzo E, Xiao L, Damico C, Shulman GI. Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker diabetic fatty (fa/fa) rats. Diabetes 2002, 51, 2903-2910. https://doi.org/10.2337/diabetes.51.10.2903
  7. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complication in insulin-dependent diabetes mellitus. N Engl J Med 1993, 329, 977-986. https://doi.org/10.1056/NEJM199309303291401
  8. Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A 2000, 97, 12222-12226. https://doi.org/10.1073/pnas.97.22.12222
  9. Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B, Anversa P. Myocardial cell death in human diabetes. Circ Res 2000, 87, 1123-1132. https://doi.org/10.1161/01.RES.87.12.1123
  10. Gadau S, Emanueli C, Van Linthout S, Graiani G, Todaro M, Meloni M, Campesi I, Invernici G, Spillmann F, Ward K, Madeddu P. Benfotiamine accelerates the healing of ischemic diabetic limbs in mice through protein kinase B/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis. Diabetologia 2006, 49, 405-420. https://doi.org/10.1007/s00125-005-0103-5
  11. Gardner CD, Eguchi S, Reynolds CM, Eguchi K, Frank GD, Motley ED. Hydrogen peroxide inhibits insulin signaling in vascular smooth muscle cells. Exp Biol Med 2003, 228, 836-842. https://doi.org/10.1177/15353702-0322807-09
  12. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 2003, 9, 294 -299. https://doi.org/10.1038/nm834
  13. Hays NP, Galassetti PR, Coker RH. Prevention and treatment of type 2 diabetes: current role of lifestyle, natural product, and pharmacological interventions. Pharmacol Ther 2008, 118, 181-191. https://doi.org/10.1016/j.pharmthera.2008.02.003
  14. Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, Stocker R, Van Remmen H, Kraegen EW, Cooney GJ, Richardson AR, James JE. Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci U S A 2009, 106, 17787-17792. https://doi.org/10.1073/pnas.0902380106
  15. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 1992, 41, 1422-1428. https://doi.org/10.2337/diab.41.11.1422
  16. Leng Y, Karlsson HKR, Zierath JR. Insulin signaling defects in type 2 diabetes. Rev Endocr Metab Disord 2004, 5, 111-117. https://doi.org/10.1023/B:REMD.0000021432.84588.f6
  17. MacAulay K, Doble BW, Patel S, Hansotia T, Sinclair EM, Drucker DJ, Nagy A, Woodgett JR. Glycogen synthase kinase $3{\alpha}$-specific regulation of murine hepatic glycogen metabolism. Cell Metab 2007, 6, 329-337. https://doi.org/10.1016/j.cmet.2007.08.013
  18. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000, 404, 787-790. https://doi.org/10.1038/35008121
  19. Nourooz-Zadeh J, Tajaddini-Surmadi J, McCarthy S, Betteridge DJ, Wolff SP. Elevated levels of authentic plasma hydroperoxides in NIDDM. Diabetes 1995, 44, 1054-1058. https://doi.org/10.2337/diab.44.9.1054
  20. Paolisso G, Giugliano D. Oxidative stress and insulin action: is there a relationship? Diabetologia 1996, 39, 357-363. https://doi.org/10.1007/BF00418354
  21. Park JL, Lee YS, Kim BH, Kang YH, Kim IJ, Kim YK, Son SM. Oxidative stress causes vascular insulin resistance in OLETF rat through increased IRS-1 degradation. J Korean Diabetes Assoc 2007, 31, 22-32. https://doi.org/10.4093/jkda.2007.31.1.22
  22. Schenk G, Duggleby RG, Nixon PF. Properties and functions of the thiamine diphosphate dependent enzyme transketolase. Int J Biochem Cell Biol 1998, 30, 1297-1318. https://doi.org/10.1016/S1357-2725(98)00095-8
  23. Schmidt AM, Hori O, Brett J, Yan SD, Wautier JL, Stern D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb 1994, 14, 1521-1528. https://doi.org/10.1161/01.ATV.14.10.1521
  24. Shao J, Yamashita H, Qiao L, Friedman JE. Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice. J Endocrinol 2000, 167, 107-115. https://doi.org/10.1677/joe.0.1670107
  25. Stirban A, Negrean M, Stratmann B, Gawlowski T, Horstmann T, Gotting C, Kleesiek K, Mueller-Roesel M, Koschinsky T, Uribarri H, Vlassara H, TSchoepe D. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care 2006, 29, 2064-2071. https://doi.org/10.2337/dc06-0531
  26. Taniyama Y, Hitomi H, Shah A, Alexander RW, Griendling KK. Mechanisms of reactive oxygen species-dependent downregulation of insulin receptor substrate-1 by angiotensin II. Arterioscler Thromb Vasc Biol 2005, 25, 1142-1147. https://doi.org/10.1161/01.ATV.0000164313.17167.df
  27. Thorburn AW, Gumbiner B, Bulacan F, Wallace P, Henry RR. Intracellular Glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake. J Clin Invest 1990, 85, 522-529. https://doi.org/10.1172/JCI114468
  28. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998, 352, 837-853. https://doi.org/10.1016/S0140-6736(98)07019-6

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