Syzygium cumini ameliorates high fat diet induced glucose intolerance, insulin resistance, weight gain, hepatic injury and nephrotoxicity through modulation of PTP1B and PPARγ signaling.

Metabolic disorders are majorly associated with insulin resistance and an impaired glucose tolerance. Since, many of the currently available drugs exhibit adverse effects and are resistant to therapies, natural products are a promising alternate in the alleviation of complex metabolic disorders. In the current study, Syzygium cumini methanolic extract (SCE) was investigated for its anti-diabetic and anti-adipogenic potential using C57BL/6 mice fed on high fat diet (HFD). The HFD fed obese mice were treated with 200 mg/kg SCE and compared with positive controls Metformin, Pioglitazone and Sodium Orthovanadate. The biometabolites in SCE were characterized using Fourier transform infrared and gas chromatography and mass spectroscopy. A reduction in blood glucose levels with improved insulin sensitivity and glucose tolerance was observed in SCE-treated HFD obese mice. Histopathological and biochemical investigations showed a reduction in hepatic injury and nephrotoxicity in SCE-administered HFD mice. Results showed inhibition of PTP1B and an upregulation of IRS1 and PKB-mediated signaling in skeletal muscle. A significant decrease in lipid markers such as TC, TG, LDL-c and VLDL-c levels were observed with increased HDL-c in SCE-treated HFD mice. A significant decrease in weight and adiposity was observed in SCE-administered HFD mice in comparison to controls. This decrease could be due to the partial agonism of PPARγ and an increased expression of adiponectin, an insulin sensitizer. Hence, the dual-modulatory effect of SCE, partly due to the presence of 26% Pyrogallol, could be useful in the management of diabetes and its associated maladies.

Raffinose from Costus speciosus attenuates lipid synthesis through modulation of PPARs/SREBP1c and improves insulin sensitivity through PI3K/AKT.

Among several metabolic disorders, the pathogenesis of insulin resistance is considered to be multifactorial. Raffinose, an oligosaccharide isolated from the rhizome of Costus speciosus showed ≤50% inhibition of lipid accumulation in differentiated HepG2 and 3T3-L1 cells through exhibiting partial agonism to PPARγ, and, an enhanced secretion of adiponectin in 3T3-L1 adipocytes. Raffinose was also observed to attenuate the expression of SREBP1c, ACC and FAS which are involved in the fatty acid synthesis. A corresponding upregulation of PPARα and ACO involved in fatty acid oxidation was observed in steatotic HepG2 hepatocytes and 3T3-L1 adipocytes. In vitro evaluation of its anti-diabetic potential showed a dose dependent enhancement of glucose uptake. Investigation of the insulin sensitizing efficacy of Raffinose revealed an increase in Glut4 translocation via phosphorylation of IRß/PI3K/Akt in differentiated L6 myocytes and 3T3-L1 preadipocytes. In addition, Raffinose was potentially involved in glycogen synthesis by inhibiting the activation of GSK3ß. Hence, Raffinose could be a useful therapeutic agent for metabolic maladies.

Selective Inhibition of PTP1B by Vitalboside A from Syzygium cumini Enhances Insulin Sensitivity and Attenuates Lipid Accumulation Via Partial Agonism to PPARγ: In Vitro and In Silico Investigation.

Although antidiabetic drugs show good insulin-sensitizing property for T2DM, they also exhibit undesirable side-effects. Partial peroxisome proliferator-activated receptor γ agonism with protein tyrosine phosphatase 1B inhibition is considered as an alternative therapeutic approach toward the development of a safe insulin sensitizer. Bioactivity-based fractionation and purification of Syzygium cumini seeds led to the isolation and identification of bifunctional Vitalboside A, which showed antidiabetic and anti-adipogenic activities, as measured by glucose uptake in L6 and 3T3-L1 adipocytes and Nile red assay. A non-competitive allosteric inhibition of protein tyrosine phosphatase 1B by Vitalboside A was observed, which was confirmed by docking studies. Inhibitor studies with wortmannin and genistein showed an IRTK- and PI3K-dependent glucose uptake. A PI3K/AKT-dependent activation of GLUT4 translocation and an inactivation of GSK3ß were observed, confirming its insulin-sensitizing potential. Vitalboside A exhibited partial transactivation of peroxisome proliferator-activated receptor γ with an increase in adiponectin secretion, which was confirmed using docking analysis. Vitalboside A is a bifunctional molecule derived from edible plant showing inhibition of PTP1B and partial agonism to peroxisome proliferator-activated receptor γ which could be a promising therapeutic agent in the management of obesity and diabetes.