1H NMR metabolomics techniques demonstrated the effectiveness of methoxy substituted 2-benzylidene-1-indanone, A1 and A2A Adenosine Receptor antagonists, in modulating glucose production in the liver of diabetic rats

Abstract

The physiological function of the liver in the overall disposal of postprandial glucose is important in the management of diabetes. Our recent research showed that benzylidene indanone derivative 2-(3,4-dihydroxybenzylidene)-4-methoxy-2,3-dihydro-1H-inden-1-one (2-BI) showed antihyperglycemic activity, but its role in glucose homeostasis in the liver is unknown. ¹H NMR metabolomics approach was used to unravel the effectiveness of 2-BI, on hepatic glucose production in fructose-streptozotocin (STZ) diabetics. Diabetes was induced in Sprague–Dawley rats using fructose-streptozotocin. Metabolites were extracted from the liver tissue and analyzed by ¹H NMR spectroscopy. Pathway analysis was performed on the identified metabolites. The unsupervised principal components analysis score plot showed clear differentiation. The control group (NC) was clearly separated from the diabetic group (DBC) and was clustered near the treated diabetic groups (DBI and DGT). There is a significant (p < 0.01) increased level of 12 metabolites in diabetes rats that are crucial in liver glucose homeostasis. Treatment with 2-BI was able to lower the level of these metabolites. Detailed pathway analysis of the spiked metabolite levels shows an effect on the glycolysis/gluconeogenesis, butanoate, amino acid, nitrogen, and nucleotide (pyrimidine) metabolism. 2-BI reduced hyperglycemia in diabetic rats via the attenuation of hepatic glucose production and advancement of liver insulin sensitivity.