Inhibitory Effects on the Polyol Pathway in Type 2 Diabetic Rats by Chickpea Flavonoid Extract

Chickpea is an important source of plant flavonoids in the diet, and flavonoids from chickpea have hypoglycemic activity. In this study, a male SD rat model of type 2 diabetes mellitus (T2DM) induced by a high-fat high-sugar diet combined with streptozotocin (STZ) was used to investigate the inhibitory effects on the polyol pathway (a branch of glucose metabolism) by chickpea flavonoid extract (CFE). The results demonstrated that CFE significantly lowered fasting blood glucose (FBG) level, and reduced insulin resistance in diabetic rats by elevating the homeostasis model assessment of insulin sensitivity (HOMA-IS) and decreasing the homeostasis model assessment of insulin resistance (HOMA-IR). And CFE relieved oxidative stress through reducing H₂O_2, malondialdehyde (MDA) and carbonylated protein levels, and increasing the activity of glutathione peroxidase (GSH-Px). Moreover, CFE inhibited the polyol pathway by downregulating the aldose reductase (AR) and sorbitol dehydrogenase (SDH) activities, as well as reducing the sorbitol and fructose levels. Meanwhile, CFE also enhanced the antioxidant defense capacity through increasing glutathione reductase (GR) activity and the glutathione (GSH) level, while decreasing the oxidized glutathione (GSSG) level. Further results showed that CFE mitigated reductive stress in T2DM rats via increasing intracellular NAD⁺ content and the NAD⁺/NADH ratio, due to suppressing PARP activity and upregulating Sirt3 activity. Furthermore, CFE regulated the levels of metabolites such as nicotinamide and β-aminobutyric acid, and modulated seven metabolic pathways closely associated with the improvement of diabetes and its complications. Ten key differential metabolites were reversed after CFE intervention, which were strongly correlated with the polyol pathway and oxidative stress in T2DM rats. In summary, CFE possessed hypoglycemic activity and could inhibit the polyol pathway, which was considered a promising natural product for diabetes prevention.