Targeted therapeutic management of diabetes using phytoconstituents: molecular mechanisms, evidence map (2015–2025), and translational outlook

Abstract

Background: The root cause of diabetes is dysregulated pathways, including those involving AMP-activated protein kinase (AMPK), GLUT-mediated glucose transport, and the PI3K/AKT pathway. There has been a notable increase in research on phytoconstituents as pathway-specific treatments for diabetes; however, the comprehensiveness of this evidence remains unclear.

Methods: This systematic review followed PRISMA guidelines and was registered on PROSPERO (CRD420251073083). Databases searched included PubMed, Scopus, Google Scholar, and Europe PMC for experimental studies (in vivo, in vitro, and in silico) published between 2015 and 2024. The final search was conducted in April 2025, and 2025 publications available as “early access” before this date were included. Only English-language studies were included. Animal studies (in vivo) were assessed for risk of bias using the SYRCLE tool, while in vitro studies were evaluated using the ToxRTool, based on test substance characterization, test system description, study design, and data reporting. Narrative synthesis was employed due to the heterogeneity of the data.

Results: Out of 3,222 articles, 177 articles met the inclusion criteria. Study types included in vitro (92; 52%), in vivo (66; 37.3%), in silico (15; 8.5%), and other experimental types (4; 2.3%). Phytoconstituents predominantly targeted PI3K/AKT (44.6%), GLUT transporters (19.8%), and AMPK (14.1%) pathways. Rodent models were most used (48.02%). Primary outcomes included improved insulin sensitivity, enhanced glucose homeostasis, and reduced oxidative stress and inflammation. The risk of bias analysis revealed 68.93% of the studies carried a moderate risk, 29.94% a low risk, and 1.13% a high risk.

Discussion: Phytoconstituent activity was consistent with the activation of diabetes-relevant signaling pathways, particularly PI3K/AKT, GLUT transporters, and AMPK cascades. However, most evidence was correlative, with limited loss-of-function validation. Methodological irregularities, moderate risk of bias, and limited translational research reduce the strength and generalizability of these findings.

Keywords

phytoconstituents / diabetes mellitus / molecular mechanisms / in vivo / in vitro / in silico / phytochemicals

References

[1] What is Diabetes? [Internet]. NIDDK; [cited 2023 Apr 1]. Available from: https://www.niddk.nih.gov/health—information/diabetes/overview/what—is—diabetes

[2] Mathew TK, Zubair M, Tadi P. Blood Glucose Monitoring. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.

[3] Vargas E, Joy NV, Carrillo Sepulveda MA. Biochemistry, Insulin Metabolic Effects. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.

[4] Goyal R, Singhal M, Jialal I. Type 2 Diabetes. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.

[5] Nedosugova LV, Markina YV, Bochkareva LA, Kuzina IA, Petunina NA, Yudina IY, et al. Inflammatory Mechanisms of Diabetes and Its Vascular Complications. Biomedicines. 2022; 10: 1168.

[6] Diabetes [Internet]. WHO; c2025 [cited 2024 Nov 14]. Available from: https://www.who.int/news—room/fact—sheets/detail/diabetes

[7] Urgent action needed as global diabetes cases increase four—fold over past decades [Internet]. WHO; c2025 [cited 2024 Nov 13]. Available from: https://www.who.int/news/item/13—11—2024—urgent—action—needed—as—global—diabetes—cases—increase—four—fold—over—past—decades

[8] Wei J, Tian J, Tang C, Fang X, Miao R, Wu H, et al. The Influence of Different Types of Diabetes on Vascular Complications. J Diabetes Res. 2022; 2022: 3448618.

[9] Magliano DJ, Boyko EJ ; IDF Diabetes Atlas 10th edition scientific committee. IDF DIABETES ATLAS [Internet]. 10th edition. Brussels: International Diabetes Federation; 2021. Chapter 3, Global picture. Available from: https://www.ncbi.nlm.nih.gov/books/NBK581940/

[10] Nathan DM. Long—term complications of diabetes mellitus. N Engl J Med. 1993; 328: 1676-85.

[11] Deepa R, Sivasamy A. Advancements in early detection of diabetes and diabetic retinopathy screening using artificial intelligence. AIP Adv. 2023; 13: 115307.

[12] Yang JJ, Yu D, Wen W, Saito E, Rahman S, Shu XO, et al. Association of Diabetes With All—Cause and Cause—Specific Mortality in Asia: A Pooled Analysis of More Than 1 Million Participants. JAMA Netw Open. 2019; 2: e192696.

[13] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372: n71.

[14] Abdel—Rahman RF, Ezzat SM, Ogaly HA, Abd—Elsalam RM, Hessin AF, Fekry MI, et al. Ficus deltoidea extract down—regulates protein tyrosine phosphatase 1B expression in a rat model of type 2 diabetes mellitus: a new insight into its antidiabetic mechanism. J Nutr Sci. 2020; 9: e2.

[15] Abdulmalek SA, Fessal M, El—Sayed M. Effective amelioration of hepatic inflammation and insulin response in high fat diet—fed rats via regulating AKT/mTOR signaling: Role of Lepidium sativum seed extracts. J Ethnopharmacol. 2021; 266: 113439.

[16] Abo—Saif MA, Ragab AE, Ibrahim AO, Abdelzaher OF, Mehanyd ABM, Saber—Ayad M, et al. Pomegranate peel extract protects against the development of diabetic cardiomyopathy in rats by inhibiting pyroptosis and downregulating LncRNA—MALAT1. Front Pharmacol. 2023; 14: 1166653.

[17] Adianingsih OR, Khasanah U, Anandhy KD, Yurina V. In silico ADME—T and molecular docking study of phytoconstituents from Tithonia diversifolia (Hemsl.) A. Gray on various targets of diabetic nephropathy. J Pharm Pharmacogn R. 2022; 14: 572.

[18] Ajiboye BO, Shonibare MT, Oyinloye BE. Antidiabetic activity of watermelon (Citrullus lanatus) juice in alloxan—induced diabetic rats. J Diabetes Metab Disord. 2020; 19: 343-52.

[19] Akomolafe SF, Ajayi OO, Agboola OE, Adewale OO. Comparative evaluation of the antidiabetic potential of three varieties of Ipomoea batatas L. Toxicol Rep. 2025; 14: 102015.

[20] Akoonjee A, Lanrewaju AA, Balogun FO, Makunga NP, Sabiu S. Waste to Medicine: Evidence from Computational Studies on the Modulatory Role of Corn Silk on the Therapeutic Targets Implicated in Type 2 Diabetes Mellitus. Biology (Basel). 2023; 12: 1509.

[21] Alawlaqi MM, Al—Rajhi AMH, Abdelghany TM, Ganash M, Moawad H. Evaluation of Biomedical Applications for Linseed Extract: Antimicrobial, Antioxidant, Anti—Diabetic, and Anti—Inflammatory Activities In Vitro. J Funct Biomater. 2023; 14: 300.

[22] El Allaoui H, Haboubi K, El Ahmadi K, Bouhrim M, ElAbdouni A, Eto B, et al. Comprehensive assessment of antioxidant, antidiabetic, and anti—glycation properties of aqueous and methanolic extracts fromPistacia lentiscus L. leaves: a potential natural source for managing oxidative stress and diabetes—related complications. Front Pharmacol. 2025; 16: 1551841.

[23] Almomen SM, Guan Q, Liang P, Yang K, Sidiqi AM, Levin A, et al. Daily Intake of Grape Powder Prevents the Progression of Kidney Disease in Obese Type 2 Diabetic ZSF1 Rats. Nutrients. 2017; 9: 345.

[24] Ansari P, Flatt PR, Harriott P, Abdel—Wahab YHA. Insulinotropic and antidiabetic properties of Eucalyptus citriodora leaves and isolation of bioactive phytomolecules. J Pharm Pharmacol. 2021; 73: 1049-61.

[25] Ansari P, Islam SS, Akther S, Khan JT, Shihab JA, Abdel—Wahab YHA. Insulin secretory actions of ethanolic extract of Acacia arabica bark in high fat—fed diet—induced obese Type 2 diabetic rats. Biosci Rep. 2023; 43: BSR20230329.

[26] Antu KA, Riya MP, Nair A, Mishra A, Srivastava AK, Raghu KG. Symplocos cochinchinensis enhances insulin sensitivity via the down regulation of lipogenesis and insulin resistance in high energy diet rat model. J Ethnopharmacol. 2016; 193: 500—9.

[27] Apte MM, Khattar E, Tupe RS. Mechanistic role of Syzygium cumini (L.) Skeels in glycation induced diabetic nephropathy via RAGE—NF—κB pathway and extracellular proteins modifications: A molecular approach. J Ethnopharmacol. 2024; 322: 117573.

[28] Assaggaf H, El Hachlafi N, Elbouzidi A, Taibi M, Alnasser SM, Bendaif H, et al. Exploring the antidiabetic and anti—inflammatory potential of Lavandula officinalis essential oil: In vitro and in silico insights. Heliyon. 2024; 10: e34135.

[29] Ayeleso TB, Ramachela K, Mukwevho E. Aqueous—Methanol Extracts of Orange—Fleshed Sweet Potato (Ipomoeabatatas) Ameliorate Oxidative Stress and Modulate Type 2 Diabetes Associated Genes in Insulin Resistant C2C12 Cells. Molecules. 2018; 23: 2058.

[30] Ayoola MD, Ogundeko YB, Obanleowo TD, Omole DO, Chukwu BN, Faloye KO. Evaluation of the Antidiabetic Activities of the Fruit of Parquetina nigrescens (Afzel.) Bullock and In Silico Identification of Its Antidiabetic Agent. Bioinform Biol Insights. 2024; 18: 11779322231223857.

[31] Babu S, Krishnan M, Rajagopal P, Periyasamy V, Veeraraghavan V, Govindan R, et al. Beta—sitosterol attenuates insulin resistance in adipose tissue via IRS—1/Akt mediated insulin signaling in high fat diet and sucrose induced type—2 diabetic rats. Eur J Pharmacol. 2020; 873: 173004.

[32] Bharadwaja S, Issac PK, Cleta J, Jeganathan R, Chandrakumar SS, Sundaresan S. An in vitro mechanistic approach towards understanding the distinct pathways regulating insulin resistance and adipogenesis by apocynin. J Biosci. 2021; 46: 8.

[33] Buabeid MA, Arafa EA, Hassan W, Murtaza G. In Silico Prediction of the Mode of Action of Viola odorata in Diabetes. Biomed Res Int. 2020; 2020: 2768403.

[34] Cho KH, Lee SH, Lee Y, Bahuguna A, Kim JE. Synergistic Efficacy of Policosanol (Raydel^®) and Banaba Leaf Extract to Treat Hyperglycemia and Dyslipidemia in Streptozotocin—Induced Diabetic and Hyperlipidemic Zebrafish (Danio rerio): Protection of Liver and Kidney with Enhanced Tissue Regeneration. Pharmaceuticals (Basel). 2025; 18: 362.

[35] Chukwuma IF, Nworah FN, Apeh VO, Omeje KO, Nweze EJ, Asogwa CD, et al. Phytochemical Characterization, Functional Nutrition, and Anti—Diabetic Potentials of Leptadenia hastata (pers) Decne Leaves: In Silico and In Vitro Studies. Bioinform Biol Insights. 2022; 16: 11779322221115436.

[36] Cossiga V, Lembo V, Nigro C, Mirra P, Miele C, D’Argenio V, et al. The Combination of Berberine, Tocotrienols and Coffee Extracts Improves Metabolic Profile and Liver Steatosis by the Modulation of Gut Microbiota and Hepatic miR—122 and miR—34a Expression in Mice. Nutrients. 2021; 13: 1281.

[37] Das AK, Hossain U, Ghosh S, Biswas S, Mandal M, Mandal B, et al. Amelioration of oxidative stress mediated inflammation and apoptosis in pancreatic islets by Lupeol in STZ—induced hyperglycaemic mice. Life Sci. 2022; 305: 120769.

[38] de Souza Mesquita LM, Caria CREP, Santos PS, Ruy CC, da Silva Lima N, Moreira DKT, et al. Modulatory Effect of Polyphenolic Compounds from the Mangrove Tree Rhizophora mangle L. on Non—Alcoholic Fatty Liver Disease and Insulin Resistance in High—Fat Diet Obese Mice. Molecules. 2018; 23: 2114.

[39] Ziyanok—Demirtas S. A Holistic In Silico and In Vivo Approach to Exploring the Antidiabetic, Antioxidant, and Hepatoprotective Properties of Rose of Sharon. Life (Basel). 2024; 14: 686.

[40] Derici GE, Özdaş S, Canatar İ, Koç M. Antidiabetic activities of Bolanthus spergulifolius (Caryophyllaceae) extracts on insulin—resistant 3T3—L1 adipocytes. PLoS One. 2021; 16: e0252707.

[41] Ding X, Li S, Huang H, Shen J, Ding Y, Chen T, et al. Bioactive triterpenoid compounds of Poria cocos (Schw.) Wolf in the treatment of diabetic ulcers via regulating the PI3K—AKT signaling pathway. J Ethnopharmacol. 2024; 325: 117812.

[42] Dulala RK, Balraj M, Chandrashekar S, Muninathan N, Rajapandiyan N, Badrachalam R, et al. Phytochemical cocktail of Asanadi gana extract in the management of diabetes. Bioinformation. 2023; 19: 299-306.

[43] Dutta B, Loo S, Kam A, Tam JP. Plant—derived cell—penetrating microprotein α—astratide aM1 targets Akt signaling and alleviates insulin resistance. Cell Mol Life Sci. 2023; 80: 293.

[44] El Azab EF, Alakilli SYM, Saleh AM, Alhassan HH, Alanazi HH, Ghanem HB, et al. Actinidia deliciosa Extract as a Promising Supplemental Agent for Hepatic and Renal Complication—Associated Type 2 Diabetes (In Vivo and In Silico—Based Studies). Int J Mol Sci. 2023; 24: 13759.

[45] Elsayed RH, Kamel EM, Mahmoud AM, El—Bassuony AA, Bin—Jumah M, Lamsabhi AM, et al. Rumex dentatus L. phenolics ameliorate hyperglycemia by modulating hepatic key enzymes of carbohydrate metabolism, oxidative stress and PPARγ in diabetic rats. Food Chem Toxicol. 2020; 138: 111202.

[46] Erukainure OL, Oyebode OA, Chuturgoon AA, Ghazi T, Muhammad A, Aljoundi A, et al. Potential molecular mechanisms underlying the ameliorative effect of Cola nitida (Vent.) Schott & Endl. on insulin resistance in rat skeletal muscles. J Ethnopharmacol. 2024; 319: 117249.

[47] Fatimawali, Tallei TE, Kepel BJ, Bodhi W, Manampiring AE, Nainu F. Molecular Insight into the Pharmacological Potential ofClerodendrum minahassae Leaf Extract for Type—2 Diabetes Management Using the Network Pharmacology Approach. Medicina (Kaunas). 2023; 59: 1899.

[48] Gadewar MM, Prashanth GK, Mishra PC, Ashraf GM, Almashjary MN, Harakeh S, et al. Evaluation of Antidiabetic, Antioxidant and Anti—Hyperlipidemic Effects of Solanum indicum Fruit Extract in Streptozotocin—Induced Diabetic Rats. Curr Issues Mol Biol. 2023; 45: 903-17.

[49] Gautam V, Ranjan A, Bajpai KG, Baqri SSR, Saxena AM. Exploring the Therapeutic Potential of Three Cucurbit Plants Involving In Vivo Diabetes Screening. Cureus. 2025; 17: e78861.

[50] Ghaffar S, Waraich RS, Orfali R, Al—Taweel A, Aati HY, Kamran S, et al. New Glycotoxin Inhibitor from Sesuvium sesuvioides Mitigates Symptoms of Insulin Resistance and Diabetes by Suppressing AGE—RAGE Axis in Skeletal Muscle. Molecules. 2024; 29: 3649.

[51] Giannotti L, Stanca E, Di Chiara Stanca B, Spedicato F, Massaro M, Quarta S, et al. Coffee Bioactive N—Methylpyridinium: Unveiling Its Antilipogenic Effects by Targeting De Novo Lipogenesis in Human Hepatocytes. Mol Nutr Food Res. 2024; 68: e2400338.

[52] Ho KL, Yong PH, Wang CW, Lim SH, Kuppusamy UR, Arumugam B, et al. In vitro anti—inflammatory activity and molecular docking of Peperomia pellucida (L.) Kunth extract via the NF—κB and PPAR—γ signalling in human retinal pigment epithelial cells. Bioorg Chem. 2024; 153: 107969.

[53] Holvoet P, Rull A, García—Heredia A, López—Sanromà S, Geeraert B, Joven J, et al. Stevia—derived compounds attenuate the toxic effects of ectopic lipid accumulation in the liver of obese mice: a transcriptomic and metabolomic study. Food Chem Toxicol. 2015; 77: 22-33.

[54] Hong JY, Chung KS, Shin JS, Park G, Jang YP, Lee KT. Anti—Colitic Effects of Ethanol Extract of Persea americana Mill. through Suppression of Pro—Inflammatory Mediators via NF—κB/STAT3 Inactivation in Dextran Sulfate Sodium—Induced Colitis Mice. Int J Mol Sci. 2019; 20: 177.

[55] Hussain A, Yadav MK, Bose S, Wang JH, Lim D, Song YK, et al. Daesiho—Tang Is an Effective Herbal Formulation in Attenuation of Obesity in Mice through Alteration of Gene Expression and Modulation of Intestinal Microbiota. PLoS One. 2016; 11: e0165483.

[56] Iheagwam FN, Iheagwam OT, Onuoha MK, Ogunlana OO, Chinedu SN. Terminalia catappa aqueous leaf extract reverses insulin resistance, improves glucose transport and activates PI3K/AKT signalling in high fat/streptozotocin—induced diabetic rats. Sci Rep. 2022; 12: 10711.

[57] Filfilan WM. Effect of Barley (Hordeum vulgare) on Renal Function in a Diabetic Animal Model: A Study in Experimental Rats. Pakis J Biol Sci. 2024; 27: 298-311.

[58] Ismail Y, Fahmy DM, Ghattas MH, Ahmed MM, Zehry W, Saleh SM, et al. Integrating experimental model, LC—MS/MS chemical analysis, and systems biology approach to investigate the possible antidiabetic effect and mechanisms ofMatricaria aurea (Golden Chamomile) in type 2 diabetes mellitus. Front Pharmacol. 2022; 13: 924478.

[59] Ismawati, Saryono, Mukhyarjon, Romus I, Putri VD, Yanti S, et al. Effect of inulin from dahlia tubers (Dahlia variabilis) extract on insulitis severity and insulin expression in diabetic rats. Biomedicine (Taipei). 2024; 14: 31-9.

[60] Jeon S, Lee H, Kim SY, Lee CH, Lim Y. Effects of Metabolites Derived from Guava (Psidium guajava L.) Leaf Extract Fermented by Limosilactobacillus fermentum on Hepatic Energy Metabolism via SIRT1—PGC1α Signaling in Diabetic Mice. Nutrients. 2024; 17: 7.

[61] Ji J, Yang X, Flavel M, Shields ZP, Kitchen B. Antioxidant and Anti—Diabetic Functions of a Polyphenol—Rich Sugarcane Extract. J Am Coll Nutr. 2019; 38: 670-80.

[62] Johnson R, Dludla PV, Muller CJ, Huisamen B, Essop MF, Louw J. The Transcription Profile Unveils the Cardioprotective Effect of Aspalathin against Lipid Toxicity in an In Vitro H9c2 Model. Molecules. 2017; 22: 219.

[63] Kakouri E, Agalou A, Kanakis C, Beis D, Tarantilis PA. Crocins from Crocus sativus L. in the Management of Hyperglycemia. In Vivo Evidence from Zebrafish. Molecules. 2020; 25: 5223.

[64] Kamga—Simo FY 3rd, Kamatou GP, Kgopa AH, Mokgotho MP, Shai LJ. Evaluation of the Potential Hypoglycaemic Properties of Mimusops zeyheri Sond. and Aloe marlothii A.Berger, Two Plants Used by Traditional Healers in South Africa. Plants (Basel). 2024; 13: 3323.

[65] Kang SY, Kim E, Kang I, Lee M, Lee Y. Anti—Diabetic Effects and Anti—Inflammatory Effects of Laminaria japonica and Hizikia fusiforme in Skeletal Muscle: In Vitro and In Vivo Model. Nutrients. 2018; 10: 491.

[66] Katsa ME, Gil APR, Makri EM, Papadogiannis S, Ioannidis A, Kalliostra M, et al. Effect of oleocanthal—rich olive oil on postprandial oxidative stress markers of patients with type 2 diabetes mellitus. Food Nutr Res. 2024; 68.

[67] Kaur T, Kaur G. Withania somnifera as a potential candidate to ameliorate high fat diet—induced anxiety and neuroinflammation. J Neuroinflammation. 2017; 14: 201.

[68] Kausar MA, Anwar S, Elagib HM, Parveen K, Hussain MA, Najm MZ, et al. GC—MS Profiling of Ethanol—Extracted Polyherbal Compounds from Medicinal Plant (Citrullus colocynthis, Curcuma longa, and Myristica fragrans): In Silico and Analytical Insights into Diabetic Neuropathy Therapy via Targeting the Aldose Reductase. Curr Issues Mol Biol. 2025; 47: 75.

[69] Trichur Khabeer S, Prashant A, Haravey Krishnan M. Dietary fatty acids from pomegranate seeds (Punica granatum) inhibit adipogenesis and impact the expression of the obesity—associated mRNA transcripts in human adipose—derived mesenchymal stem cells. J Food Biochem. 2019; 43: e12739.

[70] Khound P, Deb PK, Bhattacharjee S, Medina KD, Sarma PP, Sarkar B, et al. Phenolic enriched fraction of Clerodendrum glandulosum Lindl. leaf extract ameliorates hyperglycemia and oxidative stress in streptozotocin—nicotinamide induced diabetic rats. J Ayurveda Integr Med. 2024; 15: 100906.

[71] Kim M, Song K, Kim YS. Alantolactone improves palmitate—induced glucose intolerance and inflammation in both lean and obese states in vitro: Adipocyte and adipocyte—macrophage co—culture system. Int Immunopharmacol. 2017; 49: 187-94.

[72] Kim YJ, Choi JY, Ryu R, Lee J, Cho SJ, Kwon EY, et al. Platycodon grandiflorus Root Extract Attenuates Body Fat Mass, Hepatic Steatosis and Insulin Resistance through the Interplay between the Liver and Adipose Tissue. Nutrients. 2016; 8: 532.

[73] Kong ZL, Johnson A, Ko FC, He JL, Cheng SC. Effect of Cistanche Tubulosa Extracts on Male Reproductive Function in Streptozotocin—Nicotinamide—Induced Diabetic Rats. Nutrients. 2018; 10: 1562.

[74] Krstić S, Milanović I, Stilinović N, Vukmirović S, Pavlović N, Berežni S, et al. Health Benefits of Traditional Sage and Peppermint Juices: Simple Solutions for Antioxidant and Antidiabetic Support. Foods. 2025; 14: 1182.

[75] Kumar V, Sharma K, Ahmed B, Al—Abbasi FA, Anwar F, Verma A. Deconvoluting the dual hypoglycemic effect of wedelolactone isolated from Wedelia calendulacea: investigation via experimental validation and molecular docking. RSC Adv. 2018; 8: 18180-96.

[76] Lambert C, Cubedo J, Padró T, Vilahur G, López—Bernal S, Rocha M, et al. Effects of a Carob—Pod—Derived Sweetener on Glucose Metabolism. Nutrients. 2018; 10: 271.

[77] Lee SY, Lai FY, Shi LS, Chou YC, Yen IC, Chang TC. Rhodiola crenulata extract suppresses hepatic gluconeogenesis via activation of the AMPK pathway. Phytomedicine. 2015; 22: 477-86.

[78] Lee YG, Lee SR, Baek HJ, Kwon JE, Baek NI, Kang TH, et al. The Effects of Body Fat Reduction through the Metabolic Control of Steam—Processed Ginger Extract in High—Fat—Diet—Fed Mice. Int J Mol Sci. 2024; 25: 2982.

[79] Leem KH, Kim MG, Hahm YT, Kim HK. Hypoglycemic Effect of Opuntia ficus—indica var. saboten Is Due to Enhanced Peripheral Glucose Uptake through Activation of AMPK/p38 MAPK Pathway. Nutrients. 2016; 8: 800.

[80] Lei S, Zhao S, Huang X, Feng Y, Li Z, Chen L, et al. Chaihu Shugan powder alleviates liver inflammation and hepatic steatosis in NAFLD mice: A network pharmacology study and in vivo experimental validation. Front Pharmacol. 2022; 13: 967623.

[81] Li H, Park HM, Ji HS, Han J, Kim SK, Park HY, et al. Phenolic—enriched blueberry—leaf extract attenuates glucose homeostasis, pancreatic β—cell function, and insulin sensitivity in high—fat diet—induced diabetic mice. Nutr Res. 2020; 73: 83-96.

[82] Li R, Xia Y, Gao Z, Song Y, Guo Z, Yang Y. Transcriptome analysis to reveal the mechanism of the effect of Echinops latifolius polysaccharide B on palmitate—induced insulin—resistant. Biomed Pharmacother. 2021; 143: 112203.

[83] Li W, Sargsyan D, Wu R, Li S, Wang L, Cheng D, et al. DNA Methylome and Transcriptome Alterations in High Glucose—Induced Diabetic Nephropathy Cellular Model and Identification of Novel Targets for Treatment by Tanshinone IIA. Chem Res Toxicol. 2019; 32: 1977—88.

[84] Li Y, Goto T, Ikutani R, Lin S, Takahashi N, Takahashi H, et al. Xanthoangelol and 4—hydroxyderrcin suppress obesity—induced inflammatory responses. Obesity (Silver Spring). 2016; 24: 2351-60.

[85] Lin CH, Shih CC. The Ethyl Acetate Extract of Phyllanthus emblica L. Alleviates Diabetic Nephropathy in a Murine Model of Diabetes. Int J Mol Sci. 2024; 25: 6686.

[86] Li H, Gao Y, Li M, Dong Y, Chen J, Zhang B, et al. Cai’s herbal tea enhances mitochondrial autophagy of type 1 diabetic mellitus β cells through the AMPK/mTOR pathway and alleviates inflammatory response. Acta Diabetol. 2024; 61: 1553—67.

[87] Lin Y, Qiu L, Zhang M, Zhang C, Qin Y, Yu H, et al. Comprehensive evaluation on nutritional characteristics and anti—hyperglycemic active ingredients of different varieties of Yam. Sci Rep. 2025; 15: 12609.

[88] Lin ZX, Wang CJ, Tu HW, Tsai MT, Yu MH, Huang HP. The Neuroprotective Effects of Primary Functional Components Mulberry Leaf Extract in Diabetes—Induced Oxidative Stress and Inflammation. J Agric Food Chem. 2025; 73: 3680-91.

[89] Liu Y, Sun D, Xing D, Rui Y, Jin Y, Wang P, et al. Mechanism of the Traditional Chinese Medicine Simiao Biejia Decoction Improves the Diabetes Mellitus—Induced Erectile Dysfunction in Rats. Drug Des Devel Ther. 2025; 19: 2609-28.

[90] Lu J, Wang H, Chen X, Zhang K, Zhao X, Xiao Y, et al. Exploration of potential antidiabetic and antioxidant components from the branches of Mitragyna diversifolia and possible mechanism. Biomed Pharmacother. 2024; 180: 117450.

[91] Lv Y, Zhao P, Pang K, Ma Y, Huang H, Zhou T, et al. Antidiabetic effect of a flavonoid—rich extract from Sophora alopecuroides L. in HFD— and STZ—induced diabetic mice through PKC/GLUT4 pathway and regulating PPARα and PPARγ expression. J Ethnopharmacol. 2021; 268: 113654.

[92] Ma C, Yu H, Xiao Y, Wang H. Momordica charantia extracts ameliorate insulin resistance by regulating the expression of SOCS—3 and JNK in type 2 diabetes mellitus rats. Pharm Biol. 2017; 55: 2170—7.

[93] Okokon JE, Nyong ME. Antidiabetic and hypolipidemic activities of Zea mays husk extract and fractions. J Herbs Spices Med P. 2018; 24: 134-50.

[94] Mayasankaravalli C, Deepika K, Esther Lydia D, Agada R, Thagriki D, Govindasamy C, et al. Profiling the phyto—constituents of Punica granatum fruits peel extract and accessing its in—vitro antioxidant, anti—diabetic, anti—obesity, and angiotensin—converting enzyme inhibitory properties. Saudi J Biol Sci. 2020; 27: 3228-34.

[95] Mazibuko—Mbeje SE, Mthembu SXH, Tshiitamune A, Muvhulawa N, Mthiyane FT, Ziqubu K, et al. Orientin Improves Substrate Utilization and the Expression of Major Genes Involved in Insulin Signaling and Energy Regulation in Cultured Insulin—Resistant Liver Cells. Molecules. 2021; 26: 6154.

[96] Mihailović M, Arambašić Јovanović J, Uskoković A, Grdović N, Dinić S, Vidović S, et al. Protective Effects of the Mushroom Lactarius deterrimus Extract on Systemic Oxidative Stress and Pancreatic Islets in Streptozotocin—Induced Diabetic Rats. J Diabetes Res. 2015; 2015: 576726.

[97] Modi S, Yaluri N, Kokkola T, Laakso M. Plant—derived compounds strigolactone GR24 and pinosylvin activate SIRT1 and enhance glucose uptake in rat skeletal muscle cells. Sci Rep. 2017; 7: 17606.

[98] Mokashi P, Khanna A, Pandita N. Flavonoids from Enicostema littorale blume enhances glucose uptake of cells in insulin resistant human liver cancer (HepG2) cell line via IRS—1/PI3K/Akt pathway. Biomed Pharmacother. 2017; 90: 268—77.

[99] Mouhid L, Gómez de Cedrón M, Quijada—Freire A, Fernández—Marcos PJ, Reglero G, Fornari T, et al. Yarrow Supercritical Extract Ameliorates the Metabolic Stress in a Model of Obesity Induced by High—Fat Diet. Nutrients. 2019; 12: 72.

[100] Mu J, Xin G, Zhang B, Wang Y, Ning C, Meng X. Beneficial effects of Aronia melanocarpa berry extract on hepatic insulin resistance in type 2 diabetes mellitus rats. J Food Sci. 2020; 85: 1307—18.

[101] Nag S, Stany B, Mishra S, Kumar S, Mohanto S, Ahmed MG, et al. Multireceptor Analysis for Evaluating the Antidiabetic Efficacy of Karanjin: A Computational Approach. Endocrinol Diabetes Metab. 2024; 7: e509.

[102] Nahar N, Nazmul Hasan Zilani M, Biswas P, Morsaline Billah M, Bibi S, Albekairi NA, et al. Profiling of secondary metabolite and evaluation of anti—diabetic potency of Crotalaria quinquefolia (L): In—vitro, in—vivo, and in—silico approaches. Saudi Pharm J. 2024; 32: 101887.

[103] Naowaboot J, Wannasiri S, Pannangpetch P. Vernonia cinerea water extract improves insulin resistance in high—fat diet—induced obese mice. Nutr Res. 2018; 56: 51-60.

[104] Nethengwe M, Kerebba N, Okaiyeto K, Opuwari CS, Oguntibeju OO. Antioxidant, Anti—Diabetic, and Anti—Inflammation Activity of Garcinia livingstonei Aqueous Leaf Extract: A Preliminary Study. Int J Mol Sci. 2024; 25: 3184.

[105] Noor F, Rehman A, Ashfaq UA, Saleem MH, Okla MK, Al—Hashimi A, et al. Integrating Network Pharmacology and Molecular Docking Approaches to Decipher the Multi—Target Pharmacological Mechanism of Abrus precatorius L. Acting on Diabetes. Pharmaceuticals (Basel). 2022; 15: 414.

[106] Oh KK, Adnan M, Cho DH. Network pharmacology of bioactives from Sorghum bicolor with targets related to diabetes mellitus. PLoS One. 2020; 15: e0240873.

[107] Ojo OA, Amanze JC, Oni AI, Grant S, Iyobhebhe M, Elebiyo TC, et al. Antidiabetic activity of avocado seeds (Persea americana Mill.) in diabetic rats via activation of PI3K/AKT signaling pathway. Sci Rep. 2022; 12: 2919.

[108] Ooi DJ, Adamu HA, Imam MU, Ithnin H, Ismail M. Polyphenol—rich ethyl acetate fraction isolated from Molineria latifolia ameliorates insulin resistance in experimental diabetic rats via IRS1/AKT activation. Biomed Pharmacother. 2018; 98: 125-33.

[109] Oyedemi SO, Eze K, Aiyegoro OA, Ibeh RC, Ikechukwu GC, Swain SS, et al. Computational, chemical profiling and biochemical evaluation of antidiabetic potential of Parkia biglobosa stem bark extract in type 2 model of rats. J Biomol Struct Dyn. 2022; 40: 9948-61.

[110] Patibandla C, Khan ZI, MacGregor L, Campbell MJ, Patterson S. Costus pictus D. Don leaf extract stimulates GLP—1 secretion from GLUTag L—cells and has cytoprotective effects in BRIN—BD11 β—cells. J Ethnopharmacol. 2020; 260: 112970.

[111] Peng CY, Xie QY, Xie X, Tang LY, Ma TX, Ke DW, et al. Extraction, phytochemicals characterization, in vivo and in vitro anti—diabetic ability of non—extractable polyphenols from Undaria pinnatifida. Food Res Int. 2024; 196: 115021.

[112] Ponnulakshmi R, Shyamaladevi B, Vijayalakshmi P, Selvaraj J. In silico and in vivo analysis to identify the antidiabetic activity of beta sitosterol in adipose tissue of high fat diet and sucrose induced type—2 diabetic experimental rats. Toxicol Mech Methods. 2019; 29: 276-90.

[113] Pringle NA, van de Venter M, Koekemoer TC. Comprehensive in vitro antidiabetic screening of Aspalathus linearis using a target—directed screening platform and cellomics. Food Funct. 2021; 12: 1020-38.

[114] Puopolo T, Li H, Ma H, Schrader JM, Liu C, Seeram NP. Uncovering the anti—inflammatory mechanisms of phenolic—enriched maple syrup extract in lipopolysaccharide—induced peritonitis in mice: insights from data—independent acquisition proteomics analysis. Food Funct. 2023; 14: 6690-706.

[115] Puppala ER, Yalamarthi SS, Aochenlar SL, Prasad N, Syamprasad NP, Singh M, et al. Mesua assamica (King&Prain) kosterm. Bark ethanolic extract attenuates chronic restraint stress aggravated DSS—induced ulcerative colitis in mice via inhibition of NF—κB/STAT3 and activation of HO—1/Nrf2/SIRT1 signaling pathways. J Ethnopharmacol. 2023; 301: 115765.

[116] Qin T, He Z, Hassan HM, Wang Q, Shi L, Yu Y, et al. Taohe Chengqi decoction improves diabetic cognitive dysfunction by alleviating neural stem cell senescence through HIF1α—driven metabolic signaling. Phytomedicine. 2024; 135: 156219.

[117] Qiu D, Hu J, Zhang S, Cai W, Miao J, Li P, et al. Fenugreek extract improves diabetes—induced endothelial dysfunctionvia the arginase 1 pathway. Food Funct. 2024; 15: 3446-62.

[118] Malarvizhi R, Mani S, Sali VK, Bhardwaj M, Vasanthi HR. Macrotyloma uniflorum a plant food alleviates the metabolic syndrome through modulation of adipokines and PPARs. J Food Biochem. 2021; 45: e13595.

[119] Rahman SS, Klamrak A, Mahat NC, Rahat RH, Nopkuesuk N, Kamruzzaman M, et al. Thyroid Stimulatory Activity of Houttuynia cordata Thunb. Ethanolic Extract in 6—Propyl—Thiouracil—Induced Hypothyroid and STZ Induced Diabetes Rats: In Vivo and In Silico Studies. Nutrients. 2025; 17: 594.

[120] Rahman SS, Klamrak A, Nopkuesuk N, Nabnueangsap J, Janpan P, Choowongkomon K, et al. Impacts of Plu kaow (Houttuynia cordata Thunb.) Ethanolic Extract on Diabetes and Dyslipidemia in STZ Induced Diabetic Rats: Phytochemical Profiling, Cheminformatics Analyses, and Molecular Docking Studies. Antioxidants (Basel). 2024; 13: 1064.

[121] Rahman MA, Uddin MN, Babteen NA, Alnajeebi AM, Zakaria ZA, Aboelenin SM. Natural Compounds from Hatikana Extract Potentiate Antidiabetic Actions as Displayed by In Vivo Assays and Verified by Network Pharmacological Tools. Biomed Res Int. 2021; 2021: 6978450.

[122] Rakotondrabe TF, Fan M, Guo M. Exploring potential antidiabetic and anti—inflammatory flavonoids from Euphorbia humifusa with an integrated strategy. Front Pharmacol. 2022; 13: 980945.

[123] Rashid K, Sil PC. Curcumin enhances recovery of pancreatic islets from cellular stress induced inflammation and apoptosis in diabetic rats. Toxicol Appl Pharmacol. 2015; 282: 297-310.

[124] Rather IA, Khan N, Kushwah AS, Surampalli G, Kumar M. Nephroprotective effects of honokiol in a high—fat diet—streptozotocin rat model of diabetic nephropathy. Life Sci. 2023; 320: 121543.

[125] Roy JR, Janaki CS, Jayaraman S, Periyasamy V, Balaji T, Vijayamalathi M, et al. Effect of Carica papaya on IRS—1/Akt Signaling Mechanisms in High—Fat—Diet—Streptozotocin—Induced Type 2 Diabetic Experimental Rats: A Mechanistic Approach. Nutrients. 2022; 14: 4181.

[126] Roy JR, Janaki CS, Jayaraman S, Periyasamy V, Balaji T, Vijayamalathi M, et al. Carica papaya Reduces Muscle Insulin Resistance via IR/GLUT4 Mediated Signaling Mechanisms in High Fat Diet and Streptozotocin—Induced Type—2 Diabetic Rats. Antioxidants (Basel). 2022; 11: 2081.

[127] Rozenberg K, Rosenzweig T. Sarcopoterium spinosum extract improved insulin sensitivity in mice models of glucose intolerance and diabetes. PLoS One. 2018; 13: e0196736.

[128] Sajal H, Patil SM, Raj R, Shbeer AM, Ageel M, Ramu R. Computer—Aided Screening of Phytoconstituents from Ocimum tenuiflorum against Diabetes Mellitus Targeting DPP4 Inhibition: A Combination of Molecular Docking, Molecular Dynamics, and Pharmacokinetics Approaches. Molecules. 2022; 27: 5133.

[129] Saleem M, Mazhar Fareed M, Salman Akbar Saani M, Shityakov S. Network pharmacology and multitarget analysis of Nigella sativa in the management of diabetes and obesity: a computational study. J Biomol Struct Dyn. 2024; 42: 4800—16.

[130] Scott NJA, Ellmers LJ, Pilbrow AP, Thomsen L, Richards AM, Frampton CM, et al. Metabolic and Blood Pressure Effects of Walnut Supplementation in a Mouse Model of the Metabolic Syndrome. Nutrients. 2017; 9: 722.

[131] Shah MS, Talukder MSH, Uddin AMK, Hasan MN, Sayem SAJ, Mostafa—Hedeab G, et al. Comparative Assessment of Three Medicinal Plants against Diabetes and Oxidative Stress Using Experimental and Computational Approaches. Evid Based Complement Alternat Med. 2023; 2023: 6359818.

[132] Shahzad A, Liu W, Hussain S, Ni Y, Cui K, Sun Y, et al. Integrated in vitro, in silico, and in vivo approaches to elucidate the antidiabetic mechanisms of Cicer arietinum and Hordeum vulgare extract and secondary metabolites. Sci Rep. 2025; 15: 6620.

[133] Shang N, Saleem A, Musallam L, Walshe—Roussel B, Badawi A, Cuerrier A, et al. Novel Approach to Identify Potential Bioactive Plant Metabolites: Pharmacological and Metabolomics Analyses of Ethanol and Hot Water Extracts of Several Canadian Medicinal Plants of the Cree of Eeyou Istchee. PLoS One. 2015; 10: e0135721.

[134] Sharma P, Joshi T, Joshi T, Chandra S, Tamta S. In silico screening of potential antidiabetic phytochemicals from Phyllanthus emblica against therapeutic targets of type 2 diabetes. J Ethnopharmacol. 2020; 248: 112268.

[135] Sharma S, Choudhary M, Sharma O, Injeti E, Mittal A. Mechanistic insights into antidiabetic potential of Ficus viren against multi organ specific diabetic targets: molecular docking, MDS, MM—GBSA analysis. Comput Biol Chem. 2024; 113: 108185.

[136] Sharma S, Pathak S, Gupta G, Sharma SK, Singh L, Sharma RK, et al. Pharmacological evaluation of aqueous extract of syzigium cumini for its antihyperglycemic and antidyslipidemic properties in diabetic rats fed a high cholesterol diet—Role of PPARγ and PPARα. Biomed Pharmacother. 2017; 89: 447-53.

[137] Shen CL, Wankhade UD, Shankar K, Najjar RS, Feresin RG, Elmassry MM, et al. Effects of Statin and Annatto—extracted Tocotrienol Supplementation on Glucose Homeostasis, Bone Microstructure, and Gut Microbiota Composition in Obese Mice. In Vivo. 2024; 38: 1557-70.

[138] Shi Y, Sheng P, Guo M, Chen K, Zhao Y, Wang X, et al. Banxia Xiexin Decoction Prevents HT22 Cells from High Glucose—induced Neurotoxicity via JNK/SIRT1/Foxo3a Signaling Pathway. Curr Comput Aided Drug Des. 2024; 20: 911-27.

[139] Shinohara S, Gu Y, Yang Y, Furuta Y, Tanaka M, Yue X, et al. Ethanol extracts of chickpeas alter the total lipid content and expression levels of genes related to fatty acid metabolism in mouse 3T3—L1 adipocytes. Int J Mol Med. 2016; 38: 574-84.

[140] Singh G. Insilico screening and pharmacokinetic properties of phytoconstituents from Ferula asafoetida H.Karst. (Heeng) as potential inhibitors of α—amylase and α—glucosidase for Type 2 Diabetes Mellitus. J Diabetes Metab Disord. 2022; 21: 1339—47.

[141] Sorrenti V, Consoli V, Grosso S, Raffaele M, Amenta M, Ballistreri G, et al. Bioactive Compounds from Lemon (Citrus limon) Extract Overcome TNF—α—Induced Insulin Resistance in Cultured Adipocytes. Molecules. 2021; 26: 4411.

[142] Srivastava S, Shree P, Pandey H, Tripathi YB. Incretin hormones receptor signaling plays the key role in antidiabetic potential of PTY—2 against STZ—induced pancreatitis. Biomed Pharmacother. 2018; 97: 330—8.

[143] Stojković D, Gašić U, Uba AI, Zengin G, Rajaković M, Stevanović M, et al. Chemical profiling of Anthriscus cerefolium (L.) Hoffm., biological potential of the herbal extract, molecular modeling and KEGG pathway analysis. Fitoterapia. 2024; 177: 106115.

[144] Subramaniam S, Sabaratnam V, Heng CK, Kuppusamy UR. The Medicinal Mushroom Ganoderma neo—japonicum (Agaricomycetes) from Malaysia: Nutritional Composition and Potentiation of Insulin—Like Activity in 3T3—L1 Cells. Int J Med Mushrooms. 2020; 22: 65-78.

[145] Sun S, Yang S, Cheng Y, Fang T, Qu J, Tian L, et al. Jinlida granules alleviate podocyte apoptosis and mitochondrial dysfunction via the AMPK/PGC1α pathway in diabetic nephropathy. Int J Mol Med. 2025; 55: 26.

[146] Sunil V, Shree N, Venkataranganna MV, Bhonde RR, Majumdar M. The anti diabetic and anti obesity effect of Memecylon umbellatum extract in high fat diet induced obese mice. Biomed Pharmacother. 2017; 89: 880—6.

[147] Takahashi H, Hara H, Goto T, Kamakari K, Wataru N, Mohri S, et al. 13—Oxo—9(Z),11(E),15(Z)—octadecatrienoic Acid Activates Peroxisome Proliferator—Activated Receptor γ in Adipocytes. Lipids. 2015; 50: 3-12.

[148] Tang S, Wei K, Xu Y, Xu R, Wan W, Sun Y, et al. Network pharmacology combines cellular experiments to investigate the anti—inflammatory phytochemicals of vine of Pueraria montana var. lobata and their mechanism. J Ethnopharmacol. 2025; 345: 119592.

[149] Teng Y, Li D, Guruvaiah P, Xu N, Xie Z. Dietary Supplement of Large Yellow Tea Ameliorates Metabolic Syndrome and Attenuates Hepatic Steatosis in db/db Mice. Nutrients. 2018; 10: 75.

[150] Tijani RO, Molina—Tijeras JA, Vezza T, Ruiz—Malagón AJ, Cádiz—Gurrea ML, Segura—Carretero A, et al. Myrianthus arboreus P. Beauv improves insulin sensitivity in high fat diet—induced obese mice by reducing inflammatory pathways activation. J Ethnopharmacol. 2022; 282: 114651.

[151] Tomar R, Mishra SS, Sahoo J, Rath SK. Computational and in—vitro Investigation of Phytochemicals from Allamanda cathartica as a Potential Candidate for the Treatment of Type 2 Diabetes mellitus. J Comput Biophys Chem. 2024; 23: 901-23.

[152] Vandanmagsar B, Yu Y, Simmler C, Dang TN, Kuhn P, Poulev A, et al. Bioactive compounds from Artemisia dracunculus L. activate AMPK signaling in skeletal muscle. Biomed Pharmacother. 2021; 143: 112188.

[153] Variya BC, Bakrania AK, Patel SS. Antidiabetic potential of gallic acid from Emblica officinalis: Improved glucose transporters and insulin sensitivity through PPAR—γ and Akt signaling. Phytomedicine. 2020; 73: 152906.

[154] Veeramani C, Alsaif MA, Al—Numair KS. Lavatera critica controls systemic insulin resistance by ameliorating adipose tissue inflammation and oxidative stress using bioactive compounds identified by GC—MS. Biomed Pharmacother. 2018; 106: 183-91.

[155] Venkatesan S, Rajagopal A, Muthuswamy B, Mohan V, Manickam N. Phytochemical Analysis and Evaluation of Antioxidant, Antidiabetic, and Anti—inflammatory Properties of Aegle marmelos and Its Validation in an In—Vitro Cell Model. Cureus. 2024; 16: e70491.

[156] Vijh D, Gupta P. GC—MS analysis, molecular docking, and pharmacokinetic studies on Dalbergia sissoo barks extracts for compounds with anti—diabetic potential. Sci Rep. 2024; 14: 24936.

[157] Vujicic M, Nikolic I, Kontogianni VG, Saksida T, Charisiadis P, Orescanin—Dusic Z, et al. Methanolic extract of Origanum vulgare ameliorates type 1 diabetes through antioxidant, anti—inflammatory and anti—apoptotic activity. Br J Nutr. 2015; 113: 770-82.

[158] Wang Y, Cai S, Wen W, Tan Y, Wang W, Xu J, et al. A Network Pharmacology Study and In Vitro Evaluation of the Bioactive Compounds of Kadsura coccinea Leaf Extract for the Treatment of Type 2 Diabetes Mellitus. Molecules. 2025; 30: 1157.

[159] Wang Z, Wang X, Fu L, Xu S, Wang X, Liao Q, et al. Shengmai San formula alleviates high—fat diet—induced obesity in mice through gut microbiota—derived bile acid promotion of M2 macrophage polarization and thermogenesis. Phytomedicine. 2024; 133: 155938.

[160] Wang Z, Li R, Chen X, Ren H, Wang C, Min R, et al. Network pharmacology, molecular docking and experimental validation to elucidate the anti—T2DM mechanism of Lanxangia tsaoko. Fitoterapia. 2024; 178: 106117.

[161] Guo Y, Yu XR, Gu HD, Wang YJ, Yang ZG, Chi JF, et al. Farrerol ameliorates diabetic cardiomyopathy by inhibiting ferroptosis via miR—29b—3p/SIRT1 signaling pathway in endothelial cells. World J Diabetes. 2025; 16: 109553.

[162] Wang N, Zhang C, Xu Y, Li S, Tan HY, Xia W, et al. OMICs approaches—assisted identification of macrophages—derived MIP—1γ as the therapeutic target of botanical products TNTL in diabetic retinopathy. Cell Commun Signal. 2019; 17: 81.

[163] Wang H, Tan H, Zhan W, Song L, Zhang D, Chen X, et al. Molecular mechanism of Fufang Zhenzhu Tiaozhi capsule in the treatment of type 2 diabetes mellitus with nonalcoholic fatty liver disease based on network pharmacology and validation in minipigs. J Ethnopharmacol. 2021; 274: 114056.

[164] Wang G, Xu J, Ma H, Mu Y, Xu W, Yan N, et al. Phenolipid JE improves metabolic profile and inhibits gluconeogenesis via modulating AKT—mediated insulin signaling in STZ—induced diabetic mice. Pharmacol Res. 2023; 187: 106569.

[165] Wei W, Wang L, Zhou K, Xie H, Zhang M, Zhang C. Rhapontin ameliorates colonic epithelial dysfunction in experimental colitis through SIRT1 signaling. Int Immunopharmacol. 2017; 42: 185-94.

[166] Wei S, Li J, Han DW, Fu Q, Hao F. Mechanism of Astragali Radix—Puerariae Lobatae Radix combination in regulating type 2 diabetes mellitus through AMPK signaling pathway: based on network pharmacology and experimental verification. Zhongguo Zhong Yao Za Zhi. 2022; 47: 2738—49. Chinese.

[167] Wu R, Jian T, Ding X, Lv H, Meng X, Ren B, et al. Total Sesquiterpene Glycosides from Loquat Leaves Ameliorate HFD—Induced Insulin Resistance by Modulating IRS—1/GLUT4, TRPV1, and SIRT6/Nrf2 Signaling Pathways. Oxid Med Cell Longev. 2021; 2021: 4706410.

[168] Wu F, Shao Q, Xia Q, Hu M, Zhao Y, Wang D, et al. A bioinformatics and transcriptomics based investigation reveals an inhibitory role of Huanglian—Renshen—Decoction on hepatic glucose production of T2DM mice via PI3K/Akt/FoxO1 signaling pathway. Phytomedicine. 2021; 83: 153487.

[169] Xu W, Lu Z, Wang X, Cheung MH, Lin M, Li C, et al. Gynura divaricata exerts hypoglycemic effects by regulating the PI3K/AKT signaling pathway and fatty acid metabolism signaling pathway. Nutr Diabetes. 2020; 10: 31.

[170] Yan F, Dai G, Zheng X. Mulberry anthocyanin extract ameliorates insulin resistance by regulating PI3K/AKT pathway in HepG2 cells and db/db mice. J Nutr Biochem. 2016; 36: 68-80.

[171] Yang Z, Wu F, He Y, Zhang Q, Zhang Y, Zhou G, et al. A novel PTP1B inhibitor extracted from Ganoderma lucidum ameliorates insulin resistance by regulating IRS1—GLUT4 cascades in the insulin signaling pathway. Food Funct. 2018; 9: 397-406.

[172] Yang J, Bi Y, Liang S, Gu Z, Cheng L, Li C, et al. The in vivo digestibility study of banana flour with high content of resistant starch at different ripening stages. Food Funct. 2020; 11: 10945-53.

[173] Ye C, Li Y, Shi J, He L, Shi X, Yang W, et al. Network pharmacology analysis revealed the mechanism and active compounds of jiao tai wan in the treatment of type 2 diabetes mellitus via SRC/PI3K/AKT signaling. J Ethnopharmacol. 2025; 337: 118898.

[174] Yin Y, Nie W, Tang ZQ, Zhu SJ. Flavonoid—Rich Extracts from Chuju (Asteraceae Chrysanthemum L.) Alleviate the Disturbance of Glycolipid Metabolism on Type 2 Diabetic Mice via Modulating the Gut Microbiota. Foods. 2025; 14: 765.

[175] Yu Y, Simmler C, Kuhn P, Poulev A, Raskin I, Ribnicky D, et al. The DESIGNER Approach Helps Decipher the Hypoglycemic Bioactive Principles of Artemisia dracunculus (Russian Tarragon). J Nat Prod. 2019; 82: 3321—9.

[176] Yu W, Fan L, Wang M, Cao B, Hu X. Pterostilbene Improves Insulin Resistance Caused by Advanced Glycation End Products (AGEs) in Hepatocytes and Mice. Mol Nutr Food Res. 2021; 65: e2100321.

[177] Zhang YY, Tan RZ, Zhang XQ, Yu Y, Yu C. Calycosin Ameliorates Diabetes—Induced Renal Inflammation via the NF—κB Pathway In Vitro and In Vivo. Med Sci Monit. 2019; 25: 1671-8.

[178] Zhang Y, Li L, Chai T, Xu H, Du H, Jiang Y. Mulberry leaf multi—components exert hypoglycemic effects through regulation of the PI—3K/Akt insulin signaling pathway in type 2 diabetic rats. J Ethnopharmacol. 2024; 319: 117307.

[179] Zhang X, Sun Z, Sun W, Li Y, Gao F, Teng F, et al. Bioinformatics Analysis and Experimental Findings Reveal the Therapeutic Actions and Targets of Cyathulae Radix Against Type 2 Diabetes Mellitus. J Diabetes Res. 2024; 2024: 5521114.

[180] Zhang X, Lv Q, Jia S, Chen Y, Sun C, Li X, et al. Effects of flavonoid—rich Chinese bayberry (Morella rubra Sieb. et Zucc.) fruit extract on regulating glucose and lipid metabolism in diabetic KK—A(y) mice. Food Funct. 2016; 7: 3130-40.

[181] Zhang S, Shao Y, Jin R, Ma B. Combining Network Pharmacology, Molecular Docking, Molecular Dynamics Simulation, and Experimental Validation to Uncover the Efficacy and Mechanisms of Si—Miao—Yong—An Decoction in Diabetic Wound Healing. J Inflamm Res. 2025; 18: 4087-101.

[182] Zhong Y, Xiao Y, Gao J, Zheng Z, Zhang Z, Yao L, et al. Curcumin improves insulin sensitivity in high—fat diet—fed mice through gut microbiota. Nutr Metab (Lond). 2022; 19: 76.

[183] Zhang Z, Deng X, Chen R, Li Q, Sun L, Cao J, et al. Effect of Black Tea Polysaccharides on Alleviating Type 2 Diabetes Mellitus by Regulating PI3K/Akt/GLUT2 Pathway. Foods. 2024; 13: 1908.

[184] Zhao C, Zhao H, Zhang CC, Yang XH, Chen K, Xue Y, et al. Impact of Lycium barbarum polysaccharide on the expression of glucagon—like peptide 1 in vitro and in vivo. Int J Biol Macromol. 2023; 224: 908-18.

[185] Zhao P, Zhong S, Liao J, Tao J, Yao Y, Song P, et al. Caragana jubata ethanol extract ameliorates the symptoms of STZ—HFD—induced T2DM mice by PKC/GLUT4 pathway. J Ethnopharmacol. 2025; 339: 119171.

[186] Zheng M, Wang L, Sun Y, Pi X, Zhang W, Gao P, et al. Hypoglycemic effect of the Phellinus baumii extract with α—glucosidase—inhibited activity and its modulation to gut microbiota in diabetic patients. Biomed Pharmacother. 2023; 158: 114130.

[187] Zhu J, Yu C, Zhou H, Wei X, Wang Y. Comparative evaluation for phytochemical composition and regulation of blood glucose, hepatic oxidative stress and insulin resistance in mice and HepG2 models of four typical Chinese dark teas. J Sci Food Agric. 2021; 101: 6563—77.

[188] Zhu D, Du Y, Zhu L, Alahmadi TA, Hussein—Al—Ali SH, Wang Q. Testosterone with Silymarin Improves Diabetes—obesity Comorbidity Complications by Modulating Inflammatory Responses and CYP7A1/ACC Gene Expressions in Rats. Comb Chem High Throughput Screen. 2024; 27: 1999-2012.

[189] Zhuang P, Zhang J, Wang Y, Zhang M, Song L, Lu Z, et al. Reversal of muscle atrophy by Zhimu and Huangbai herb pair via activation of IGF—1/Akt and autophagy signal in cancer cachexia. Support Care Cancer. 2016; 24: 1189-98.

[190] Zuhri UM, Purwaningsih EH, Fadilah F, Yuliana ND. Network pharmacology integrated molecular dynamics reveals the bioactive compounds and potential targets of Tinospora crispa Linn. as insulin sensitizer. PLoS One. 2022; 17: e0251837.

[191] Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006; 7: 85-96.

[192] Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46: 3-26.

[193] Domingueti CP, Dusse LMS, Carvalho MdG, de Sousa LP, Gomes KB, Fernandes AP. Diabetes mellitus: The linkage between oxidative stress, inflammation, hypercoagulability and vascular complications. J Diabetes Complications. 2016; 30: 738—45.