Dual actions of gallic acid and andrographolide trigger AdipoR1 to stimulate insulin secretion in a streptozotocin-induced diabetes rat model

10.1016/j.jtcme.2022.09.002

Tet Soon Wong；Fatahiya Mohamed Tap；Zanariah Hashim；Fadzilah Adibah Abdul Majid；Nor Hafizah Zakaria；Parsaoran Siahaan；Abeer Mogadem

Gallic acid ； Andrographolide ； adipoR1 ； Insulin ； Diabetes mellitus

Journal of Traditional and Complementary Medicine

13卷1期（2023 / 01 / 01）

11 - 19

英文

Common treatments for the management of diabetes have limitations due to side effects, hence the need for continuous research to discover new remedies with better therapeutic efficacy. Previously, we have reported that the combination treatment of gallic acid (20 mg/kg) and andrographolide (10 mg/kg) for 15 days demonstrated synergistic hypoglycemic activity in the streptozotocin (STZ)-induced insulindeficient diabetes rat model. Here, we attempt to further elucidate the effect of this combination therapy at the biochemical, histological and molecular levels. Our biochemical analyses showed that the combination treatment significantly increased the serum insulin level and decreased the total cholesterol and triglyceride level of the diabetic animals. Histological examinations of H&E stained pancreas, liver, kidney and adipose tissues of combination-treated diabetic animals showed restoration to the normalcy of the tissues. Besides, the combination treatment significantly enhanced the level of glucose transporter-4 (GLUT4) protein expression in the skeletal muscle of treated diabetic animals compared to single compound treated and untreated diabetic animals. The molecular docking analysis on the interaction of gallic acid and/or andrographolide with the adiponectin receptor 1 (AdipoR1), a key component in the regulation of pancreatic insulin secretion, revealed a greater binding affinity of AdipoR1 to both compounds compared to individual compounds. Taken together, these findings suggest the combination of gallic acid and andrographolide as a potent therapy for the management of diabetes mellitus.

1. Arora, SK,Verma, PR,Itankar, PR,Prasad, SK,Nakhate, KT(2021).Evaluation of pancreatic regeneration activity of Tephrosia purpurea leaves in rats with streptozotocin-induced diabetes.J Tradit Complement Med,11(5),435-445.
   連結：
2. Choudhury, H,Pandey, M,Hua, CK(2018).An update on natural compounds in the remedy of diabetes mellitus: a systematic review.J Tradit Complement Med,8(3),361-376.
   連結：
3. Ismail, HF,Hashim, Z,Soon, WT,Rahman, NSA,Zainudin, AN,Majid, FAA(2017).Comparative study of herbal plants on the phenolic and flavonoid content, antioxidant activities and toxicity on cells and zebrafish embryo.J Tradit Complement Med,7(4),452-465.
   連結：
4. Polyphenols in Human Health and Disease.
5. (2019).Classification of Diabetes Mellitus.World Health Organization.
6. Ab Rahman, NS,Abdul Majid, FA,Abd Wahid, ME(2020).Molecular docking analysis and anti-hyperglycaemic activity of SynacinnTM in streptozotocininduced rats.RSC Adv,10(57),34581-34594.
7. Aktaş, ŞH,Pençe, HH,Özçelik, F(2020).Vaspin, adiponectin and leptin levels in type 1 diabetic rats induced by streptozotocin.Acta Endocrinol,16(2),136-141.
8. Aleidi, S,Issa, A,Bustanji, H,Khalil, M,Bustanji, Y(2015).Adiponectin serum levels correlate with insulin resistance in type 2 diabetic patients.Saudi Pharmaceut J,23(3),250-256.
9. Belayneh, YM,Birru, EM,Ambikar, D(2019).Evaluation of hypoglycemic, anti-hyperglycemic and antihyperlipidemic activities of 80% methanolic seed extract of calpurnia aurea (Ait.) benth. (fabaceae) in mice.J Exp Pharmacol,11,73-83.
10. Cetto, AA(2015).Diabetes and metabolic disorders: an ethnopharmacological perspective.Ethnopharmacology
11. Deeds, MC,Anderson, JM,Armstrong, AS(2011).Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models.Lab Anim,45(3),131-140.
12. Du, YT,Rayner, CK,Jones, KL,Talley, NJ,Horowitz, M(2018).Gastrointestinal symptoms in diabetes: prevalence, assessment, pathogenesis, and management.Diabetes Care,41(3),627-637.
13. Furman, BL(2021).Streptozotocin-induced diabetic models in mice and rats.Curr Protoc,1(4),1-21.
14. Gargouri, M,Magné, C,El Feki, A(2016).Hyperglycemia, oxidative stress, liver damage and dysfunction in alloxan-induced diabetic rat are prevented by Spirulina supplementation.Nutr Res,36(11),1255-1268.
15. Gu, W,Li, X,Liu, C(2006).Globular adiponectin augments insulin secretion from pancreatic Islet b cells at high glucose concentrations.Endocrine,30(2),217-221.
16. Gylling, H,Tuominen, JA,Koivisto, VA,Miettinen, TA(2004).Cholesterol metabolism in type 1 diabetes.Diabetes,53(9),2217-2222.
17. Hurren, KM,Dunham, MW(2018).Understanding the impact of commonly utilized, non-insulin, glucose-lowering drugs on body weight in patients with type 2 diabetes.Expet Opin Pharmacother,19(10),1087-1095.
18. Jha, JC,Banal, C,Chow, BSM,Cooper, ME,Jandeleit-Dahm, K(2016).Diabetes and kidney disease: role of oxidative stress.Antioxidants Redox Signal,25(12),657-684.
19. Kade, IJ,Ogunbolude, Y,Kamdem, JP,Rocha, JBT(2014).Influence of gallic acid on oxidative stress-linked streptozotocin-induced pancreatic dysfunction in diabetic rats.J Basic Clin Physiol Pharmacol,25(1),35-45.
20. Kahn, BB,Rossetti, L,Lodish, HF,Charron, MJ.Decreased in vivo glucose uptake but normal expression of GLUT1 and GLUT4 in skeletal muscle of diabetic rats.J Clin Invest
21. Komolafe, OA,Adeyemi, DO,Adewole, SO,Obuotor, EM(2010).Streptozotocin-induced diabetes alters the serum lipid profiles of adult wistar rats.Internet J Cardiovasc Res,7(1)
22. Latha, RC,Daisy, P(2011).Insulin-secretagogue, antihyperlipidemic and other protective effects of gallic acid isolated from Terminalia bellerica Roxb. In streptozotocin-induced diabetic rats.Chem Biol Interact,189(1-2),112-118.
23. Leto, D,Saltiel, AR(2012).Regulation of glucose transport by insulin: traffic control of GLUT4.Nat Rev Mol Cell Biol,13(6),383-396.
24. Loganadan, NK,Huri, HZ,Vethakkan, SR,Hussein, Z(2020).Clinical and genetic predictors of secondary sulfonylurea failure in Type 2 diabetes patients: the SUCLINGEN study.Pharmacogenomics,21(9),587-600.
25. Mohamed, J,Nazratun Nafizah, AH,Zariyantey, AH,Budin, SB(2016).Mechanisms of diabetes-induced liver damage: the role of oxidative stress and inflammation.Sultan Qaboos Univ Med J,16(2),e132-e141.
26. Morris, GM,Huey, R,Lindstrom, W(2009).AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility.J Comput Chem,2785-2791.
27. Muratore, M,Komai, AM(2020).Theoretical study of the adiponectin receptors: binding site characterization and molecular dynamics of possible ligands for drug design.SN Appl Sci,2(4),1-14.
28. Nugroho, AE,Rais, IR,Setiawan, I(2014).Pancreatic effect of andrographolide isolated from Andrographis paniculata (Burm. f.) Nees.Pakistan J Biol Sci,17(1),22-31.
29. Okamoto, M,Ohara-Imaizumi, M,Kubota, N(2008).Adiponectin induces insulin secretion in vitro and in vivo at a low glucose concentration.Diabetologia,51(5),827-835.
30. Poonuru, S,Pathak, SR,Vats, HS,Pathak, RD(2011).Rapid reduction of severely elevated serum triglycerides with insulin infusion, gemfibrozil and niacin.Clin Med Res,9(1),38-41.
31. Punithavathi, VR,Stanely Mainzen Prince, P,Kumar, MR,Selvakumari, CJ(2011).Protective effects of gallic acid on hepatic lipid peroxide metabolism, glycoprotein components and lipids in streptozotocin-induced type II diabetic wistar rats.J Biochem Mol Toxicol,25(2),68-76.
32. Richardson, JM,Balon, TW,Treadway, JL,Pessin, JE(1991).Differential regulation of glucose transporter activity and expression in red and white skeletal muscle.J Biol Chem,266(19),12690-12694.
33. Roy, B,Palaniyandi, SS(2021).Tissue-specific role and associated downstream signaling pathways of adiponectin.Cell Biosci,11(1)
34. Sankar, P,Subhashree, S,Sudharani, S(2012).Effect of Trigonella foenum-graecum seed powder on the antioxidant levels of high fat diet and low dose streptozotocin induced type II diabetic rats.Eur Rev Med Pharmacol Sci,16(SUPPL. 3),10-17.
35. Santini, SA,Marra, G,Giardina, B(1997).Defective plasma antioxidant defenses and enhanced susceptibility to lipid peroxidation in uncomplicated IDDM.Diabetes,46(11),1853-1858.
36. Sun, H,Saeedi, P,Karuranga, S(2022).IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045.Diabetes Res Clin Pract,183,109119.
37. Szkudelski, T(2001).The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas.Physiol Res,50(6),537-546.
38. Trott, O,Olson, AJ(2010).AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.J Comput Chem,31(2),455-461.
39. Vargas E, Podder V, Carrillo Sepulveda MA. Physiology, glucose transporter type 4 [Updated]. In: StatPearls. StatPearls Publishing; 2021 May 9 [Internet] https://www.ncbi.nlm.nih.gov/books/NBK537322/. Accessed September 19, 2021. Published 2021.
40. Vergès, B(2009).Lipid disorders in type 1 diabetes.Diabetes Metab,35(5),353-360.
41. Wang, J,Wang, H(2017).Oxidative stress in pancreatic beta cell regeneration.Oxid Med Cell Longev,1930261.
42. Weiss, T,Iglay, K,Gulati, T,Rajpathak, S,Yang, L,Blonde, L(2021).Secondary metformin monotherapy failure in individuals with type 2 diabetes mellitus.BMJ Open Diabetes Res Care,9(1)
43. Whitehead, JP,Richards, AA,Hickman, IJ,Macdonald, GA,Prins, JB(2006).Adiponectin - a key adipokine in the metabolic syndrome.Diabetes Obes Metabol,8(3),264-280.
44. Whitlock, RH,Hougen, I,Komenda, P,Rigatto, C,Clemens, KK,Tangri, N(2020).A safety comparison of metformin vs sulfonylurea initiation in patients with type 2 diabetes and chronic kidney disease: a retrospective cohort study.Mayo Clin Proc,95(1),90-100.
45. Wijesekara, N,Krishnamurthy, M,Bhattacharjee, A,Suhail, A,Sweeney, G,Wheeler, MB(2010).Adiponectin-induced ERK and Akt phosphorylation protects against pancreatic beta cell apoptosis and increases insulin gene expression and secretion.J Biol Chem,285(44),33623-33631.
46. Wong, TS,Hassan Fahmi, I,Zanariah, H,Fadzilah Adibah, AM(2019).Synergistic antihyperglycaemic effect of combination therapy with gallic acid and androgra-pholide in streptozotocin-induced diabetic rats.Biocatal Agric Biotechnol,18,101048.
47. Young, NL,Lopez, DH,McNamara, DJ(1988).Contributions of absorbed dietary cholesterol and cholesterol synthesized in small intestine to hypercholester-olemia in diabetic rats.Diabetes,37(8),1151-1156.
48. Zhang, Z,Jiang, J,Yu, P,Zeng, X,Larrick, JW,Wang, Y(2009).Hypoglycemic and beta cell protective effects of andrographolide analogue for diabetes treatment.J Transl Med,7,62.

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