Asiaticoside ameliorates type 2 diabetes mellitus in rats by modulating carbohydrate metabolism and regulating insulin signaling

Abstract

Objective: To evaluate the effect of asiaticoside on streptozotocin (STZ) and nicotinamide (NAD)-induced carbohydrate metabolism abnormalities and deregulated insulin signaling pathways in rats. Methods: Asiaticoside (50 and 100 mg/kg body weight) was administered to STZ-NAD-induced diabetic rats for 45 days, and its effects on hyperglycaemic, carbohydrate metabolic, and insulin signaling pathway markers were examined. Results: Asiaticoside increased insulin production, lowered blood glucose levels, and enhanced glycolysis by improving hexokinase activity and suppressing glucose-6-phosphatase and fructose-1,6-bisphosphatase activities. Abnormalities in glycogen metabolism were mitigated by increasing glycogen synthase activity and gluconeogenesis was decreased by decreasing glycogen phosphorylase activity. Furthermore, asiaticoside upregulated the mRNA expressions of IRS-1, IRS-2, and GLUT4 in STZ-NAD-induced diabetic rats and restored the beta cell morphology to normal. Conclusions: Asiaticoside has the potential to ameliorate type 2 diabetes by improving glycolysis, gluconeogenesis, and insulin signaling pathways.

Keywords

Asiaticoside / Type 2 diabetes mellitus / Metabolic disorders / Carbohydrate metabolism / Insulin signaling

Conflict of interest statement

The authors have no conflicts of interest.

Funding

The authors received no extramural funding for the study.

Data availability statement

The data supporting the findings of this study are available from the corresponding authors upon request.

Authors’ contributions

BP wrote the manuscript; BP, VS, KD, and PS performed experiments and collected the data; BP, VS, KD, and PS analyzed the data; BP and VS designed the study; KD and PS reviewed the manuscript. All authors read and approved the final manuscript.

References

[1] Sathibabu Uddandrao VV, Brahmanaidu P, Ravindarnaik R, Suresh P, Vadivukkarasi S, Saravanan G. Restorative potentiality of S-allylcysteine against diabetic nephropathy through attenuation of oxidative stress and inflammation in streptozotocin-nicotinamide-induced diabetic rats. Eur J Nutr 2019; 58(6): 2425-2437.

[2] Swapna K, Sathibabu Uddandrao VV, Parim B, Ravindarnaik R, Suresh P, Ponmurugan P, et al. Effects of asiatic acid, an active constituent in Centella asiatica (L.): Restorative perspectives of streptozotocin-nicotinamide induced changes on lipid profile and lipid metabolic enzymes in diabetic rats. Comp Clin Pathol 2019; 28: 1321-1329.

[3] Antony Rathinasamy JIR, Uddandrao VVS, Raveendran N, Sasikumar V. Antiobesity effect of biochanin-A: Effect on trace element metabolism in high fat diet-induced obesity in rats. Cardiovasc Hematol Agents Med Chem 2020; 18(1): 21-30.

[4] Sethumathi PP, Sathibabu Uddandrao VV, Chandrasekaran P, Sengottuvelu S, Tamilmani P, Ponmurugan P, et al. Biochanin-A attenuates high-fat diet and streptozotocin-induced hyperlipidemia and oxidative stress in rats by improving antioxidant status and lipid metabolic markers. Asian Pac J Trop Biomed 2023; 13(11): 460-468.

[5] Pudhupalayam SP, Uddandrao VVS, Ponnusamy C, Sengottuvelu S, Tamilmani P, Ponmurugan P, et al. Biochanin A attenuates hyperglycemia in high-fat diet-streptozotocin-induced diabetic rats by modulating the activities of carbohydrate-metabolizing enzymes in vital organs. Rev Bras Farmacogn 2022; 32: 608-617.

[6] Sankaranarayanan C, Nishanthi R, Pugalendi P. Ameliorating effect of berbamine on hepatic key enzymes of carbohydrate metabolism in high-fat diet and streptozotocin induced type 2 diabetic rats. Biomed Pharmacother 2018; 103: 539-545.

[7] Rahman MS, Hossain KS, Das S, Kundu S, Adegoke EO, Rahman MA, et al. Role of insulin in health and disease: An update. Int J Mol Sci 2021; 22(12). doi: 10.3390/ijms22126403.

[8] Feraco A, Gorini S, Armani A, Camajani E, Rizzo M, Caprio M. Exploring the role of skeletal muscle in insulin resistance: Lessons from cultured cells to animal models. Int J Mol Sci 2021; 22(17). doi: 10.3390/ijms22179327.

[9] Uddandrao VVS, Parim B, Singaravel S, Ponnusamy P, Ponnusamy C, Sasikumar V, et al. Polyherbal formulation ameliorates diabetic cardiomyopathy through attenuation of cardiac inflammation and oxidative stress via NF-κB/Nrf-2/HO-1 pathway in diabetic rats. J Cardiovasc Pharmacol 2022; 79(1): e75-e86.

[10] Uddandrao VVS, Parim B, Ramavat R, Pothani S, Vadivukkarasi S, Ponmurugan P, et al. Effect of S-allylcysteine against diabetic nephropathy via inhibition of MEK1/2-ERK1/2-RSK2 signalling pathway in streptozotocin-nicotinamide-induced diabetic rats. Arch Physiol Biochem 2023; 129(1): 213-221.

[11] Parim B, Sathibabu Uddandrao VV, Saravanan G. Diabetic cardiomyopathy: Molecular mechanisms, detrimental effects of conventional treatment, and beneficial effects of natural therapy. Heart Fail Rev 2019; 24(2): 279-299.

[12] Kalaivani A, Uddandrao VVS, Parim B, Ganapathy S, Nivetha PR, Kancharla SC, et al. Reversal of high fat diet-induced obesity through modulating lipid metabolic enzymes and inflammatory markers expressions in rats. Arch Physiol Biochem 2019; 125(3): 228-234.

[13] Kotturu SK, Uddandrao VVS, Ghosh S, Parim B. Bioactive compounds in diabetic cardiomyopathy: Current approaches and potential diagnostic and therapeutic targets. Cardiovasc Hematol Agents Med Chem 2021; 19(2): 118-130.

[14] Raziani Y, Karami K, Mohammadi HR, Mahmoudvand H, Moradi MN, Yadegari JG. Astragalus adscendens extract shows antidiabetic effects through controlling oxidative stress, inflammation and apoptosis in streptozotocin-induced diabetic rats. Asian Pac J Trop Biomed 2023; 13(6): 242-249.

[15] Tan SC, Bhattamisra SK, Chellappan DK, Candasamy M. Actions and therapeutic potential of madecassoside and other major constituents of Centella asiatica: A review. Appl Sci 2021; 11(18). doi: 10.3390/app11188475.

[16] Luo J, Zhang T, Zhu C, Sun J, Zhu W, Ai W, et al. Asiaticoside might attenuate bleomycin-induced pulmonary fibrosis by activating cAMP and Rap1 signalling pathway assisted by A2AR. J Cell Mol Med 2020; 24(14): 8248-8261.

[17] Tosapol A, Mayuree HT, Tsutomu S, Yoshimichi S, Phisit K. Multiple oral dosing pharmacokinetics of standardized extract of Centella asiatica ECa 233 and its inductive effect on efflux transporters in rats. Planta Med Int Open 2017; 4: e66-e73.

[18] Naidu PB, Sathibabu Uddandrao VV, Naik RR, Pothani S, Munipally PK, Meriga B, et al. Effects of S-allylcysteine on biomarkers of the polyol pathway in rats with type 2 diabetes. Can J Diabetes 2016; 40(5): 442-448.

[19] Kalidhindi S, Uddandrao VVS, Sasikumar V, Raveendran N, Ganapathy S. Mitigating perspectives of asiatic acid in the renal derangements of streptozotocin-nicotinamide induced diabetic rats. Cardiovasc Hematol Agents Med Chem 2020; 18(1): 37-44.

[20] Hatting M, Tavares CDJ, Sharabi K, Rines AK, Puigserver P. Insulin regulation of gluconeogenesis. Ann N Y Acad Sci 2018; 1411(1): 21-35.

[21] Cao R, Tian H, Zhang Y, Liu G, Xu H, Rao G, et al. Signaling pathways and intervention for therapy of type 2 diabetes mellitus. MedComm (2020) 2023; 4(3). doi: 10.1002/mco2.283.

[22] Sathibabu Uddandrao VV, Brahmanaidu P, Nivedha PR, Vadivukkarasi S, Saravanan G. Beneficial role of some natural products to attenuate the diabetic cardiomyopathy through Nrf2 pathway in cell culture and animal models. Cardiovasc Toxicol 2018; 18(3): 199-205.

[23] Brahmanaidu P, Uddandrao VVS, Sasikumar V, Naik RR, Pothani S, Begum MS, et al. Reversal of endothelial dysfunction in aorta of streptozotocin-nicotinamide-induced type-2 diabetic rats by S-allylcysteine. Mol Cell Biochem 2017; 432(1-2): 25-32.

[24] Lewis GF, Carpentier AC, Pereira S, Hahn M, Giacca A. Direct and indirect control of hepatic glucose production by insulin. Cell Metab 2021; 33(4): 709-720.

[25] Rines AK, Sharabi K, Tavares CD, Puigserver P. Targeting hepatic glucose metabolism in the treatment of type 2 diabetes. Nat Rev Drug Discov 2016; 15(11): 786-804.

[26] Bouvet BR, Paparella CV, Arriaga SM, Monje AL, Amarilla AM, Almará AM. Evaluation of urinary N-acetyl-beta-D-glucosaminidase as a marker of early renal damage in patients with type 2 diabetes mellitus. Arq Bras Endocrinol Metabol 2014; 58(8): 798-801.

[27] Chou KM, Lee CC, Chen CH, Sun CY. Clinical value of NGAL, L-FABP and albuminuria in predicting GFR decline in type 2 diabetes mellitus patients. PLoS One 2013; 8(1). doi: 10.1371/journal.pone.0054863.

[28] Chang AS, Hathaway CK, Smithies O, Kakoki M. Transforming growth factor-β1 and diabetic nephropathy. Am J Physiol Renal Physiol 2016; 310(8): F689-F696.

[29] Röder PV, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med 2016; 48(3): e219. doi: 10.1038/emm.2016.6.

[30] Devi RC, Ramesh B. Amelioration of streptozotocin-induced diabetes by Bougainvillea spectabilis leaf extract through modulation of carbohydrate metabolic enzymes and oxidative stress in rats. Biosc Biotech Res Comm 2021; 14(2): 842-852.

[31] Sylow L, Tokarz VL, Richter EA, Klip A. The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia. Cell Metab 2021; 33(4): 758-780.

[32] Atmodjo WL, Larasati YO, Jo J, Nufika R, Naomi S, Winoto I. Relationship between insulin-receptor substrate 1 and Langerhans’ islet in a rat model of type 2 diabetes mellitus. In Vivo 2021; 35(1): 291-297.

[33] Zhao X, An X, Yang C, Sun W, Ji H, Lian F. The crucial role and mechanism of insulin resistance in metabolic disease. Front Endocrinol (Lausanne) 2023; 14. doi: 10.3389/fendo.2023.1149239.

[34] Chadt A, Al-Hasani H. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Arch 2020; 472(9): 1273-1298.

[35] Kandasamy N, Ashokkumar N. Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin-cadmium induced diabetic nephrotoxic rats. Toxicol Appl Pharmacol 2014; 279(2): 173-185.