Table 3.

Collected studies of pure compounds suggesting antidiabetic activity of hesperidin and hesperetin.

Hesperidin
Model	Observations/proposed mechanism	Reference
Rat skeletal muscle cell lines, L6 myoblasts	-Antioxidant—free radicals scavenging; increase in glutathione levels -Increased glucose uptake—up-regulation of GLUT-4 receptors and down-regulation of PI3 kinase	[141]
Male Sprague Dawley rats	-α-glucosidase inhibition	[142]
In vitro In silico	-Dipeptidyl peptidase-4 inhibition	[143]
In vitro—Caco-2/TC7 cells and Xenopus laevis oocytes In vivo—human	-Decrease in sugar absorption rate by inhibition of GLUT 2 and GLUT 5 transporters	[144]
Male Sprague Dawley rats	-Regulation of glycolysis and gluconeogenesis—induction of glucokinase and decrease in glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activity -Improved insulin sensitivity by activating the IR/PDK1 pathway -Improved glucose uptake	[145]
Male Wistar rats	-Up-regulation of GLUT 4 translocation -Anti-apoptotic effect—increase in antiapoptotic Bcl-2 protein and decrease in pro-apoptotic protein Bax levels -Increased PPAR-γ expression	[146]
In silico In vitro—pancreas of male BALB/c mice	-Glucose-dependent insulinotropic effect by PKA-dependent mode of action	[147]
White male albino rats	-Reduction in oxidative stress—enhanced antioxidant enzymes (CAT, GPx, GR, SOD) levels -Anti-inflammatory—suppression in the production of pro-inflammatory cytokines—TNF-α, IL-6 -Decreased glucose, glycosylated hemoglobin, and increased insulin plasma levels	[148]
Male Wistar albino rats	-Reduction in insulin, total cholesterol, triglyceride, low-density lipoprotein cholesterol serum levels -Improved histological structure -Anti-inflammatory—decreased pro-inflammatory cytokines (TNF-α, IL-6) levels	[149]
Retinal ganglion cell 5 (RGC-5) cells	-Antioxidant—enhancement in SOD, GPx, CAT activities -Anti-apoptotic—stabilization of mitochondrial membrane potential, inhibition of caspase-3, -9, and Bax expression, enhancement in Bcl-2 expression, suppression in pro-apoptotic p38 and JNK MAPK pathways activation	[150]
Male albino rats	-Decrease in fasting blood glucose and glycosylated hemoglobin levels -Increase in insulin secretion—protective action on β-cells and stimulatory effect on the insulin secretory response of islets of the pancreas -Decrease in gluconeogenic enzymes -Anti-hyperglycemic—increased GLUT 4 expression	[151]
Hesperetin
Rat skeletal muscle cell lines, L6 myoblasts	-Antioxidant—free radicals scavenging; increase in glutathione levels -Increased glucose uptake—up-regulation of GLUT-4 receptors and down-regulation of PI3 kinase	[141]
Male albino Wistar rats	-Reduction in glucose plasma and increase in insulin levels similar to glibenclamide -Recuperation of pancreatic β-cells -Improvement in glucokinase activity and glucose-6-phosphate dehydrogenase -Inhibition of hepatic gluconeogenesis—decrease in the level of gluconeogenic enzymes—glucose-6-phosphatase and fructose-1,6-bisphosphatase -Increased glycogen content in hepatocytes -Antioxidant—increase in activity of enzymic antioxidants -Anti-hyperlipidemic effect—enhanced insulin secretion, which led to a reduction in cholesterol synthesis and due to the ability of hesperetin to bind bile acids, which resulted in a decrease in the cholesterol absorption -Protective effect on hepatic damage -Renoprotective effect	[152]
Wistar rats	-Attenuation of gluconeogenesis by inhibition of mitochondrial pyruvate carrier, uncoupling of mitochondrial oxidative phosphorylation, inhibition of mitochondrial respiratory chain at Complex I, and deviation of NADH supply for gluconeogenesis and mitochondria due to a prooxidant action, deviation of glucose 6-phosphate for glucuronidation reactions	[153]
Adult male Wistar albino rats	-Reduction of plasma glucose because of the increased release of insulin from the existing β-cells and/or regenerated β-cells of the pancreas, restored insulin sensitivity or inhibition of intestinal absorption of glucose, or enhanced the utilization of glucose by peripheral tissues -Improved lipid profile -Improved pancreatic islets’ morphology	[154]
Male mice	-Anti-hyperglycemic—increased insulin production and reduced blood glucose levels	[155]
Wistar rats	-Anti-hyperglycemic—decrease in glucose levels -Antioxidant—increase in antioxidant enzymes—SOD, CAT, GSH, GPx activity -Anti-inflammatory—decrease in pro-inflammatory cytokines levels—TNF-α, IL-17 -Anti-apoptotic—suppression of caspase-3 and maintenance of mitochondrial membrane potential	[156]
In vitro In silico	-α-glucosidase inhibition	[157]
In vitro In silico	-Dipeptidyl peptidase-4 inhibition	[143]
HepG2 cells	-Increase in protein level and direct activation of SIRT1, which was accompanied by induction of AMPK phosphorylation	[158]
RAW264.7 cells	-Inhibitory effect on oxidative stress and inflammation induced by AGEs	[159]
Male Sprague Dawley rats	-Up-regulation and Increased Glo-1 enzymatic activity -Anti-inflammatory—decreased level of pro-inflammatory cytokines (IL-1β, TNF-α) -Enhancement of Nrf2/ARE pathway	[160]