# Resveratrol: A Review on the Biological Activity and Applications
## 5 Metabolic Disturbances
### Antidiabetic Properties  
Diabetic complications, such as cataracts and nephropathy, have numerous and complex mechanisms. RSV was investigated for its inhibitory effect versus rat lens and kidney aldose reductase in vitro, together with its capacity to block the generation of advanced glycation end products. The phytoalexin considerably amended glycemic status and renal function in diabetic rats, with an important reduction in the production of advanced glycation end products in the kidneys. This evidence highlights the capability of RSV as a potential therapeutic factor as opposed to long-term diabetic complications [144].  
The protective effects of RSV treatment against diabetes and cardiovascular complications of diabetes are based on modulation of cell and molecular signaling pathways, such as improvement of insulin sensitivity, reduction in oxidative stress and inflammation, lipid metabolism regulation, increase in glucose transporter (GLUT) 4 expression, autophagy induction, regulation of SIRT1/AMPK axis [145].  
In an experimental model of obese mice with type 2 diabetes mellitus (T2 DM), 60-day RSV oral administration increased the nuclear amount of SIRT1 and restored glycemic control, as well as the normal values of GLUT (\(Glc2a2\) gene) and GLUT4 (\(Glc2a4\) gene) proteins in liver and muscle, respectively [146].  
Quercetin and RSV have well-known favorable actions on diabetes and diabetic complications; nevertheless, the results of mixed treatment of these phytochemicals on diabetes are not completely elucidated. The combined treatment guarded the functions of hepatic glucose metabolic enzymes and the structure of pancreatic \(\beta\)-cells from diabetes, and it is remarkable that this octreatment exhibited the most beneficial action on diabetic rats [147]. Other assays proved that the nutritional polyphenols RSV and piceatannol reduce postprandial hyperglycemia and suggest that suppression of intestinal \(\alpha\)-glucosidase function can be a possible mechanism associated with their antidiabetic effect [148].  
Various clinical trials highlighted the beneficial effects of RSV treatment against diabetes. In a preliminary investigation on 13 patients with type 1 diabetes mellitus (T1 DM), RSV 500 mg capsules supplementation, twice daily for 60 days, significantly decreased the values of fasting blood sugar (FBS) and hemoglobin A1c (HDA1c) compared to baseline. Moreover, in this exploratory clinical trial, RSV treatment also decreased the level of oxidative stress marker malondialdehydehyde (MDA) and increased the total antioxidant capacity (TAC) in T1D patients [149]. In a 4-week double-blind trial, which included 10 T2 DM patients who received oral RSV treatment, 5 mg twice daily, a significant decrease in the homeostatic model assessment of insulin resistance (HOMA-IR) index and urinary excretion of _ortho_-tyrosine was found [150; 151; 152]. Also, compared with a placebo, in T2 DM elderly patients, RSV oral supplementation, 200 mg once daily for six months, significantly improved glucose homeostasis, HOMA-IR index, lipid profile, renal function, and inflammatory status by decreasing the level of proinflammatory cytokines [153]. In T2 DM patients, RSV co-administration with oral hypoglycemic drugs for 24 weeks improved oxidative stress status, significantly decreasing plasma levels of MDA, high-sensitive C-reactive protein (hs-CRP), TNF-\(\alpha\), and IL-6 [154; 155].