Multi Targeted Activity of Cocculus hirsutus through Modulation of DPP-IV and PTP-1B Leading to Enhancement of Glucose Uptake and Attenuation of Lipid Accumulation.

Multi-targeted therapies are gaining attention in the management of multifactorial diseases due to their poly pharmacology, enhanced potency and reduced toxicity. Metabolic disorders like Type 2 diabetes mellitus (T2DM) and obesity necessitate multi-targeted therapy to improve insulin sensitivity, regulate glucose homeostasis and support weight loss. Medicinal plants rich in bioactive compounds exhibit multi-targetted action with minimal side effects. In the current study, Cocculus hirsutus methanol extract (CME) and its hydromethanolic fraction (HMF) were investigated for their multi-target potential. Significant inhibition of Dipeptidyl peptidase IV (DPP-IV), a key enzyme in glucose metabolism was observed due to CME (54%) and HMF (70%) at 10 µg/ml and 1 µg/ml respectively. Protein Tyrosine Phosphatase 1B (PTP-1B), involved in the regulation of insulin signalling, was also inhibited by CME (67%) and HMF (73%) at 10 µg/ml concentration. An increase in glucose uptake was observed due to CME (62% and 65%) and HMF (63% and 68%) in 3T3-L1 adipocytes and L6 myotubes at 100 ng/ml. Further, investigation of HMF showed a decrease in lipid accumulation by 63% at 1 µg/ml in 3T3-L1 cells. Interestingly, HMF improved insulin sensitivity by upregulating GLUT4 expression (p < 0.05) via the PI3K/AKT pathway in both 3T3-L1 adipocytes and L6 myotubes. An inhibition in lipid accumulation was also observed by suppression of Peroxisome proliferator-activated receptor γ (PPARγ) (p < 0.05), a key regulator of adipogenesis in 3T3-L1 adipocytes. Gas chromatography-mass spectrometry analysis of the HMF showed the major component to be 3-methylmannoside (26.52%).