糖尿病是一種代謝性疾病，並與慢性發炎及氧化壓力的上升息息相關。芥子酸(sinapic acid; SA)為肉桂酸(cinnamic acid)的衍生物，並具有抗發炎及抗氧化的能力。然而，芥子酸與糖尿病之間的相關性仍不清楚。在本研究中，我們發現口服給予STZ誘發的糖尿病鼠芥子酸後，會具有降血糖的作用，同時會增加血中β-腦內啡(β-endorphin)的濃度。過去文獻證實，活化腎上腺髓質上的α1-腎上腺素受體(α1-AR)，會促使β-腦內啡的釋放，其透過活化嗎啡μ型受體而產生降血糖的作用。而芥子酸的降血糖作用，能明顯受α1-腎上腺素受體阻斷劑(prazosin)、嗎啡受體阻斷劑(naloxone)及特異性嗎啡μ型受體阻斷劑(nalonxonazine)所抑制。同時，已知β-腦內啡具有增加第四型骨骼肌葡萄糖轉運蛋白(GLUT4)基因的表現及降低肝臟中的磷酸烯醇式丙酮酸羧激酶(PEPCK)基因的表現。在我們實驗中，以芥子酸治療STZ誘發的糖尿病鼠三天後，能提升骨骼肌的GLUT4及降低肝臟PEPCK的表現。此外，活化骨骼肌上的α1-腎上腺素受體會透過PLC-PKC的路徑，增加對葡萄糖的攝取。由芥子酸所刺激的葡萄糖攝取可被prazosin, U73122 及 chelerythrin所抑制。這些結果顯示，芥子酸能透過活化α1-AR，增加β-腦內啡的釋放，進一步加強骨骼肌對葡萄糖的攝取，及降低肝臟醣質新生，而達到降血糖的作用。

Diabetes is a metabolic disorder associated with chronic inflammation and increased oxidative stress. Sinapic acid (SA) is a cinnamic acid derivative that has anti-inflammatory and anti-oxidative capacities. However, the effects of SA on diabetes remain unclear. In the present study, we found that oral administration of SA in streptozocin-induced diabetic rats exerted a blood glucose lowering effect while increased plasma β-endorphin was also observed. Previous studies have been demonstrated that activation of α1-adrenoceptor (α1-AR) in adrenal gland is responsible for β-endorphin secretion, which exerted a function to decrease blood glucose through activation of opioid μ-receptor. The plasma glucose-lowering action of SA was markedly blocked by α1-ARs antagonist (prazosin), opioid receptor antagonist (naloxone) and specific opioid μ-receptor antagonist (nalonxonazine). Also, β-endorphin is known to increase skeletal muscle glucose transporter type 4 (GLUT4) gene expression and attenuate hepatic phosphoenolpyruvatecarboxykinase (PEPCK) gene expression. In our study, administration of SA for 3 days in STZ-induced diabetic rats elevated GLUT4 in muscle and decrease PEPCK expression in liver. In addition, activation of α1-AR increased glucose uptake in isolated skeletal muscle through a PLC-PKC dependent pathway. The SA-induced glucose uptake was blocked by prazosin, U73122 and chelerythrin in mouse skeletal fibroblast cells (C2C12). These results suggested that SA has an ability to decrease blood glucose through activation of α1-AR to increase β-endorphin secretion and this effect further enhance glucose uptake in muscle and decrease hepatic gluconeogenesis.

1. Shepherd PR, Kahn BB: Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. N Engl J Med 341:248-257, 1999

2. Jeffcoate SL: Diabetes control and complications: the role of glycated haemoglobin, 25 years on. Diabet Med 21:657-665, 2004

3. Gianani R, Eisenbarth GS: The stages of type 1A diabetes: 2005. Immunol Rev 204:232-249, 2005

4. Walker CG, Zariwala MG, Holness MJ, Sugden MC: Diet, obesity and diabetes: a current update. Clin Sci (Lond) 112:93-111, 2007

5. Goodyear LJ, Kahn BB: Exercise, glucose transport, and insulin sensitivity. Annu Rev Med 49:235-261, 1998

6. Rathmann W, Giani G: Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:2568-2569; author reply 2569, 2004

7. Masuda T, Akiyama J, Takeda Y, Maekawa T, Sone Y: Identification of the antioxidation reaction products from a sinapic ester in a lipid oxidation system. Biosci Biotechnol Biochem 73:736-739, 2009

8. Bozcali E, Suzer O, Gursoy HN, Atukeren P, Gumustas KM: Effects of erucic acid supplemented feeding on chronic doxorubucin toxicity in rats. Int J Clin Exp Med 2:337-347, 2009

9. Mattila P, Pihlava JM, Hellstrom J: Contents of phenolic acids, alkyl- and alkenylresorcinols, and avenanthramides in commercial grain products. J Agric Food Chem 53:8290-8295, 2005

10. Kern SM, Bennett RN, Mellon FA, Kroon PA, Garcia-Conesa MT: Absorption of hydroxycinnamates in humans after high-bran cereal consumption. J Agric Food Chem 51:6050-6055, 2003

11. Zou Y, Kim AR, Kim JE, Choi JS, Chung HY: Peroxynitrite scavenging activity of sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid) isolated from Brassica juncea. J Agric Food Chem 50:5884-5890, 2002

12. Kikuzaki H, Hisamoto M, Hirose K, Akiyama K, Taniguchi H: Antioxidant properties of ferulic acid and its related compounds. J Agric Food Chem 50:2161-2168, 2002

13. Yun KJ, Koh DJ, Kim SH, Park SJ, Ryu JH, Kim DG, Lee JY, Lee KT: Anti-inflammatory effects of sinapic acid through the suppression of inducible nitric oxide synthase, cyclooxygase-2, and proinflammatory cytokines expressions via nuclear factor-kappaB inactivation. J Agric Food Chem 56:10265-10272, 2008

14. Yoon BH, Jung JW, Lee JJ, Cho YW, Jang CG, Jin C, Oh TH, Ryu JH: Anxiolytic-like effects of sinapic acid in mice. Life Sci 81:234-240, 2007

15. Hegadoren KM, O'Donnell T, Lanius R, Coupland NJ, Lacaze-Masmonteil N: The role of beta-endorphin in the pathophysiology of major depression. Neuropeptides 43:341-353, 2009

16. Cheng JT, Liu IM, Tzeng TF, Tsai CC, Lai TY: Plasma glucose-lowering effect of beta-endorphin in streptozotocin-induced diabetic rats. Horm Metab Res 34:570-576, 2002

17. Cheng JT, Huang CC, Liu IM, Tzeng TF, Chang CJ: Novel mechanism for plasma glucose-lowering action of metformin in streptozotocin-induced diabetic rats. Diabetes 55:819-825, 2006

18. Liu IM, Cheng JT: Mediation of endogenous {beta}-endorphin in the plasma glucose-lowering Action of herbal products observed in type 1-like diabetic rats. Evid Based Complement Alternat Med, 2008

19. Hieble JP, Bylund DB, Clarke DE, Eikenburg DC, Langer SZ, Lefkowitz RJ, Minneman KP, Ruffolo RR, Jr.: International Union of Pharmacology. X. Recommendation for nomenclature of alpha 1-adrenoceptors: consensus update. Pharmacol Rev 47:267-270, 1995

20. Docherty JR: Subtypes of functional alpha1- and alpha2-adrenoceptors. Eur J Pharmacol 361:1-15, 1998

21. Furuta H: [Direct evidence of alpha-adrenoceptor binding in rat and human adrenal glands]. Nippon Hinyokika Gakkai Zasshi 81:161-169, 1990

22. Faintrenie G, Geloen A: Alpha-1 adrenergic stimulation of glucose uptake in rat white adipocytes. J Pharmacol Exp Ther 286:607-610, 1998

23. Cheng JT, Liu IM, Yen ST, Chen PC: Role of alpha1A-adrenoceptor in the regulation of glucose uptake into white adipocyte of rats in vitro. Auton Neurosci 84:140-146, 2000

24. Cheng JT, Liu IM: Stimulatory effect of caffeic acid on alpha1A-adrenoceptors to increase glucose uptake into cultured C2C12 cells. Naunyn Schmiedebergs Arch Pharmacol 362:122-127, 2000

25. Hutchinson DS, Bengtsson T: alpha1A-adrenoceptors activate glucose uptake in L6 muscle cells through a phospholipase C-, phosphatidylinositol-3 kinase-, and atypical protein kinase C-dependent pathway. Endocrinology 146:901-912, 2005

26. Szkudelski T: The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50:537-546, 2001

27. Okada S, Yamaguchi-Shima N, Shimizu T, Arai J, Yorimitsu M, Yokotani K: Centrally administered N-methyl-d-aspartate evokes the adrenal secretion of noradrenaline and adrenaline by brain thromboxane A2-mediated mechanisms in rats. Eur J Pharmacol 586:145-150, 2008

28. Sato K, Iemitsu M, Aizawa K, Ajisaka R: DHEA improves impaired activation of Akt and PKC zeta/lambda-GLUT4 pathway in skeletal muscle and improves hyperglycaemia in streptozotocin-induced diabetes rats. Acta Physiol (Oxf) 197:217-225, 2009

29. Gliemann J, Rees WD, Foley JA: The fate of labelled glucose molecules in the rat adipocyte. Dependence on glucose concentration. Biochim Biophys Acta 804:68-76, 1984

30. Davis RM, Richard JL: Production of [14C]rubratoxin B. Mycopathologia 67:35-38, 1979

31. Adisakwattana S, Moonsan P, Yibchok-Anun S: Insulin-releasing properties of a series of cinnamic acid derivatives in vitro and in vivo. J Agric Food Chem 56:7838-7844, 2008

32. Adisakwattana S, Roengsamran S, Hsu WH, Yibchok-anun S: Mechanisms of antihyperglycemic effect of p-methoxycinnamic acid in normal and streptozotocin-induced diabetic rats. Life Sci 78:406-412, 2005

33. Balasubashini MS, Rukkumani R, Viswanathan P, Menon VP: Ferulic acid alleviates lipid peroxidation in diabetic rats. Phytother Res 18:310-314, 2004

34. Jung EH, Kim SR, Hwang IK, Ha TY: Hypoglycemic effects of a phenolic acid fraction of rice bran and ferulic acid in C57BL/KsJ-db/db mice. J Agric Food Chem 55:9800-9804, 2007

35. Liu IM, Hsu FL, Chen CF, Cheng JT: Antihyperglycemic action of isoferulic acid in streptozotocin-induced diabetic rats. Br J Pharmacol 129:631-636, 2000

36. Cheng JT, Liu IM, Tzeng TF, Chen WC, Hayakawa S, Yamamoto T: Release of beta-endorphin by caffeic acid to lower plasma glucose in streptozotocin-induced diabetic rats. Horm Metab Res 35:251-258, 2003

37. Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM: Endogenous opioids: biology and function. Annu Rev Neurosci 7:223-255, 1984

38. Bhathena SJ, Velasquez MT: Beneficial role of dietary phytoestrogens in obesity and diabetes. Am J Clin Nutr 76:1191-1201, 2002

39. DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP: The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30:1000-1007, 1981

40. Lauritzen HP: In vivo imaging of GLUT4 translocation. Appl Physiol Nutr Metab 34:420-423, 2009

41. Giffin BF, Drake RL, Morris RE, Cardell RR: Hepatic lobular patterns of phosphoenolpyruvate carboxykinase, glycogen synthase, and glycogen phosphorylase in fasted and fed rats. J Histochem Cytochem 41:1849-1862, 1993

42. Hsu JH, Wu YC, Liou SS, Liu IM, Huang LW, Cheng JT: Mediation of endogenous beta-endorphin by tetrandrine to lower plasma glucose in streptozotocin-induced diabetic rats. Evid Based Complement Alternat Med 1:193-201, 2004

43. Hwang SL, Liu IM, Tzeng TF, Cheng JT: Activation of imidazoline receptors in adrenal gland to lower plasma glucose in streptozotocin-induced diabetic rats. Diabetologia 48:767-775, 2005

44. Yu BC, Hung CR, Chen WC, Cheng JT: Antihyperglycemic effect of andrographolide in streptozotocin-induced diabetic rats. Planta Med 69:1075-1079, 2003

45. Chan P, Wong KL, Liu IM, Tzeng TF, Yang TL, Cheng JT: Antihyperglycemic action of angiotensin II receptor antagonist, valsartan, in streptozotocin-induced diabetic rats. J Hypertens 21:761-769, 2003

46. Hofmann C, Lorenz K, Williams D, Palazuk BJ, Colca JR: Insulin sensitization in diabetic rat liver by an antihyperglycemic agent. Metabolism 44:384-389, 1995

47. Crist GH, Xu B, Lanoue KF, Lang CH: Tissue-specific effects of in vivo adenosine receptor blockade on glucose uptake in Zucker rats. FASEB J 12:1301-1308, 1998

48. Barnett AH: Treating to goal: challenges of current management. Eur J Endocrinol 151 Suppl 2:T3-7; discussion T29-30, 2004

49. Tominaga H, Kobayashi Y, Goto T, Kasemura K, Nomura M: DPPH radical-scavenging effect of several phenylpropanoid compounds and their glycoside derivatives. Yakugaku Zasshi 125:371-375, 2005