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Although single-target therapies effectively reduce glucose levels, they seldom address oxidative stress or adipocyte dysfunction. Polyherbal formulations (PHFs) harness synergistic phytochemicals for multimodal intervention; however, many lack mechanistic transparency owing to excessive inclusion of diverse botanical bioactives, suffer from non-standardized composition, and underexplore volatile antidiabetic constituents. Confronting these challenges, we developed Gluco Balance V (GB5), a cold-percolated ethanolic extract comprising equal proportions of bio-effective parts of\n                      <jats:italic>Asparagus racemosus<\/jats:italic>\n                      ,\n                      <jats:italic>Cyperus rotundus<\/jats:italic>\n                      ,\n                      <jats:italic>Tinospora cordifolia<\/jats:italic>\n                      ,\n                      <jats:italic>Terminalia arjuna<\/jats:italic>\n                      , and\n                      <jats:italic>Mimosa pudica<\/jats:italic>\n                      . These botanicals were selected for complementary antidiabetic, antioxidant, and adiporegulatory activities documented in preclinical and clinical settings, indicating balanced, synergistic, and safe bioactivity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>GB5\u2019s phytochemical composition was standardized using gas chromatography\u2013mass spectrometry (GC\u2013MS) fingerprinting. In vitro assays assessed 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) scavenging capacity, inhibition of carbohydrate-digesting enzymes (\u03b1-amylase, \u03b1-glucosidase), enzyme kinetics, and effects on glucose uptake (GU) and lipid accumulation (LA) in yeast and 3T3-L1 adipocytes. Computational network pharmacology, molecular docking, and pharmacokinetic analyses elucidated molecular targets and bioavailability. Statistical analyses employed robust dose-response modelling, analysis of variance with Dunnett\u2019s T3 test, and t-tests with false discovery rate correction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      GC\u2013MS identified 21 bioactive compounds, including phytol, fatty acids, and sterols, driving GB5\u2019s therapeutic synergy. GB5 showed robust antioxidant activity (DPPH and NO; half-maximal inhibitory concentration (IC\n                      <jats:sub>50<\/jats:sub>\n                      ) 88.6 and 74.8\u00a0\u00b5g\/mL) and mixed-type inhibition of \u03b1-amylase and \u03b1-glucosidase (IC\n                      <jats:sub>50<\/jats:sub>\n                      71.6 and 174\u00a0\u00b5g\/mL). At sub-inhibitory doses, it outperformed ascorbic acid (ASA) and acarbose. In 3T3-L1 adipocytes, GB5 increased GU by 32.3% at 2.0\u00a0mg\/mL, comparable to rosiglitazone, and reduced lipid accumulation by 18.6% (90% effective concentration (EC\n                      <jats:sub>90<\/jats:sub>\n                      ) 0.742\u00a0mg\/mL). Network pharmacology and molecular docking implicated peroxisome proliferator-activated receptor gamma (PPAR\u03b3), protein tyrosine phosphatase 1B (PTP1B), cyclooxygenase-2 (COX-2), and advanced glycation end-products\u2013receptor for advanced glycation end-products (AGE\u2013RAGE) pathways with 9,12-octadecadienoic acid and cholestan-3-ol, 2-methylene-, (3\u03b2,5\u03b1)- as key associates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>GB5\u2019s multi-targeted efficacy against hyperglycaemia, oxidative stress, and adipocyte dysfunction positions it as a promising complementary therapy for T2DM, meriting further in vivo evaluation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s12906-025-05192-3","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T13:47:21Z","timestamp":1765460841000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["GB5, a synergistic phytotherapy for type 2 diabetes mellitus management: an integrated polyherbal approach from phytochemical profiling to network pharmacology"],"prefix":"10.1186","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5717-1498","authenticated-orcid":false,"given":"Arghadip","family":"Das","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1459-9216","authenticated-orcid":false,"given":"Narmadha Chinnadurai","family":"Rajeswari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2217-7448","authenticated-orcid":false,"given":"Priyadharshini","family":"Palani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9789-0798","authenticated-orcid":false,"given":"Navaneedhakrishnan","family":"Manigandan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6130-5412","authenticated-orcid":false,"given":"Sujatha","family":"Kuppusamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8995-7882","authenticated-orcid":false,"given":"Gayatri","family":"Sukumaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9764-0140","authenticated-orcid":false,"given":"Gayathri","family":"Veeraraghavan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7013-8732","authenticated-orcid":false,"given":"Raman Lakshmi","family":"Sundaram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"5192_CR1","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1038\/s41392-024-01951-9","volume":"9","author":"X Lu","year":"2024","unstructured":"Lu X, Xie Q, Pan X, Zhang R, Zhang X, Peng G, et al. 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