Acalypha Indica Attenuates Insulin Resistance In Stz-Induced Type 2 Diabetic Male Rats: Mechanistic Study

Background: Type 2 diabetes mellitus (t2dm) is characterised by progressive peripheral insulin resistance manifesting as dysregulated skeletal muscle glucose metabolism, including depletion of glycogen stores, suppression of glycolytic enzyme activities, and constitutive overexpression of gluconeogenic enzymes. At the molecular level, failure of the ir/irs1/irs2-pi3k-akt signalling cascade leads to aberrant activation of gsk3β and pkc, transcriptional suppression of pparγ, and upregulation of srebp1c, collectively perpetuating hyperglycaemia and metabolic dysfunction. Acalypha indica linn. (euphorbiaceae), a herb widely used in ayurvedic and siddha medicine, possesses a diverse phytochemical profile including flavonoids, tannins, phenols, and polyphenolic compounds demonstrating established antioxidant, anti-inflammatory, and insulin-sensitising bioactivities. However, its mechanistic effects on skeletal muscle glycogen metabolism, glycolytic and gluconeogenic enzyme activities, and insulin signalling gene expression have not been systematically investigated. Aim: The current investigation aimed to assess the dose-dependent effects of acalypha indica's ethanolic extract at 100, 200, and 400 mg/kg body weight on tissue glycogen content, glycolytic enzymes (hexokinase and pyruvate kinase), gluconeogenic enzymes (pepck and g6pase), and the mrna expression of key insulin signalling and metabolic genes (ir, irs1, irs2, gsk3β, pkc, pparγ, and srebp1c) in the gastrocnemius muscle of stz-induced t2dm male wistar rats, with metformin (50 mg/kg) as the reference standard. Results: Stz-induced diabetic rats exhibited significantly depleted muscle glycogen content, markedly reduced hexokinase and pyruvate kinase activities, and substantially elevated pepck and g6pase activities compared to normal controls (p < 0.05). At the transcriptional level, ir, irs1, irs2, and pparγ mrna were significantly downregulated, while gsk3β, pkc, and srebp1c mrna were markedly overexpressed in the diabetic group. Treatment with acalypha indica produced consistent, dose-dependent reversal of all these alterations. Muscle glycogen content was progressively restored, glycolytic enzyme activities were significantly elevated, and gluconeogenic enzyme activities were significantly suppressed across all treatment doses. The downregulated insulin signalling genes were progressively restored toward control levels while the overexpressed genes were correspondingly suppressed in a dose-dependent manner. At 400 mg/kg, all enzymatic and gene expression parameters were restored to levels which are similar to that of reference drug treated and healthy control groups, indicating near-complete normalisation of skeletal muscle glucose metabolic dysfunction. Conclusion: Acalypha indica exerts potent, dose-dependent, and mechanistically integrated anti-diabetic effects in stz-induced t2dm rats, restoring skeletal muscle glycogen metabolism, reinstating glycolytic enzyme activity, suppressing gluconeogenic enzyme overactivity, and normalising the transcriptional landscape of insulin signalling and lipid metabolic gene networks. The 400 mg/kg dose demonstrated efficacy comparable to metformin across all measured endpoints, providing a comprehensive mechanistic approach for the traditional use of a. Indica in diabetes management and warranting further investigation into its active constituents and translational therapeutic potential.