Table 2.
List of flavonoids targeting signaling pathways in diabetes.
| Flavonoids | Glucose transporter isoforms | Pathways/target molecules | Experimental model | Targets | Comments | References |
|---|---|---|---|---|---|---|
| Anthocyanins | ||||||
| Anthocyanin | GLUT-4 | IRS1, PI3k/AKT pathway, Antiinflamtroy pathway | HFD-treated mice | Liver | Suppressed reactive oxygen species, restored the impairment of PI3k/AKT pathway, suppressed the JNK, NF- κB and IKKβ activation. | 78 |
| Anthocyanin | GLUT-4 | AMPK pathway, glucose uptake | In vitro | Adipocyte 3T3-L1, C2C12 muscle cells and β TC-tetcells | Enhanced glucose uptake, insulin-like activities, insulin-sensitizing properties, PPARγ agonist activity, increased insulin secretion. | 182 |
| Anthocyanin | GLUT-4 | Glucose uptake | STZ-induced diabetic rats | Heart, skeletal muscle, pancreatic tissues and serum | Antioxidant activity, prevent pancreatic apoptosis, decreased glucose levels, Increased insulin secretion, activated insulin receptor phosphorylation and increased GLUT-4 expression. | 163 |
| Anthocyanin | GLUT-4 | AMPK, insulin sensitivity, PPAR | diabetic mic | White adipose tissue, skeletal muscle, and the liver | hyperglycemia and insulin sensitivity via activation of AMPK, upregulation of glucose transporter 4 in WAT and skeletal muscle, suppression of glucose production and inactivation of acetyl-CoA carboxylase in the liver. | 164 |
| Cyanidin 3-glucoside | GLUT-4 | Antiinflamtroy pathway, glucose uptake, GLUT 4 regulation, | KK-Ay diabetic mice | White adipose tissue | Ameliorated hyperglycemia and insulin sensitivity, upregulated the GLUT 4,downregulated the inflammatory adipocytokines (TNF-α and MCP-1). | 183 |
| Cyanidin 3-glucoside | GLUT-4 | Antiinflamtroy pathway, modulating the JNK/FoxO1 signaling pathway | C57BL/Ks db/db | White adipose tissue and blood | Lowered fasting glucose levels, improved the insulin sensitivity, reduced inflammatory cytokines (TNF-α, IL-6, and MCP-1). | 184 |
| Cyanidin 3-Glucoside | GLUT-4 | Glucose uptake | In vitro | Adipocyte 3T3-L1 | Insulin-like activities, increased adipocyte glucose uptake, GLUT-4 expression and translocation, increased nuclear PPARg activity, improve insulin resistance. | 161, 185 |
| Flavon-3-ols | ||||||
| Catechin | GLUT-4 | Enhanced GLUT4 mRNA and protein expression | STZ-induced diabetic rats | Liver, muscle and blood | Hypo-glycemic, Glucose oxidizing and insulin mimetic activities. | 186 |
| (-)-epicatechin(EP) | GLUT-4 | Glucose uptake, PI3K | In vitro | 3T3-L1 adipocytes | Promote the translocation of GLUT-4 through activation of PI3K, increased phosphorylation of PKCλ/ζ. | 187 |
| (-)-epigallocatechin (EGC) | GLUT-4 | Glucose uptake, PI3K | In vitro | 3T3-L1 adipocytes | Promote the translocation of GLUT-4 through activation of PI3K, increased phosphorylation of PKCλ/ζ. | 187 |
| (-)-epigallocatechin-3-gallate (EGCG) | GLUT-4 | Suppressed JNK pathway | In vitro and obese KK-ay mice,HFD-induced obese rats | Adipocytes tissue, 3T3-L1 adipocytes | Decreased JNK phosphorylation and promoted GLUT-4 translocation. | 188 |
| (-)-epigallocatechin-3-gallate (EGCG) | GLUT-4 | AMPK, insulin signaling pathway | In vivo | Skeletal muscle and adipose tissue | Activated AMPK pathway, improving insulin signaling pathway, decrease oxidative stress, membrane translocation and Ser307 phosphorylation of IRS-1, increase in Ser473 phosphorylation of Akt and GLUT-4 translocation in skeletal muscle and adipose tissue. | 150 |
| (-)-epigallocatechin-3-gallate (EGCG) | GLUT-4 | PI3K/aPKCλ, AMPK and NF- κB signaling pathways | In vitro | H4IIE cells | Stimulates the PI3K/aPKCλ, AMPK and NF- κB pathways. | 149 |
| (-)-epigallocatechin-3-gallate (EGCG) | GLUT-4 | inflammatory response pathway | HFD rats | adipose tissues | Decreasing the levels of toll-like receptor 4, IKKβ, NF- κB, TNF-α, and IL-6, decreased the level of phosphorylated insulin receptor substrate 1 and increased phosphoinositide-3-kinase and GLUT-4 in adipose tissues of HFD rats. | 189 |
| (-)-epigallocatechin-3-gallate (EGCG) | GLUT-4 | Glucose uptake and GLUT-4 translocation | In vitro and ratEx vivo | Insulin-resistant L6 myotubes and skeletal muscle of mice | Increased glucose uptake and promoted translocation of GLUT-4 to plasma membrane in skeletal muscle. | 131 |
| (-)-epigallocatechin-3-gallate (EGCG) | GLUT-4 | IRS1, AMPK | In vitro | HepG2 | Attenuates insulin signaling blockade by reducing IRS-1 Ser307 phosphorylation through the AMPK activation pathway. | 139 |
| (-)-epigallocatechin-3-gallate (EGCG) | GLUT-4 | AMPK, insulin signaling pathway | FFAs-induced peripheral insulin resistance in rats | Skeletal muscle cells and adipose tissue | Decreased oxidative stress and PKCθ membrane translocation activated the AMPK pathway and improved insulin signaling pathway. | 140 |
| (-)-epigallocatechin-3-gallate (EGCG) | - | AMPK pathway | In vitro and BALB/c mice | Mouse hepatoma (Hepa 1-6) cells, rat myotube L6 cells, and 3T3-L1 adipocytes cells and liver of mice | Increased in AMPK and the downstream target acetyl-CoA carboxylase (ACC) phosphorylation. |
151 |
| (-)-epigallocatechin-3-gallate (EGCG) | GLUT-4 | AMPK and PI3K/Akt pathway. | In vitro | L6 cells | Improved insulin-stimulated glucose uptake by increasing GLUT-4 translocation to plasma membrane. | 141 |
| Procyanidins | GLUT-4 | signaling pathway (PI3K and p38 MAPK), glucose uptake, glucose transporter-4 translocation | In vitro and STZ-induced diabetic rats | L6E9 myotubes and 3T3-L1 adipocytes, Blood sample | Antihyperglycemic effect, insulinomimetic activity, stimulated glucose uptake, stimulated GLUT-4 expression and translocation. | 147 |
| Flavanones | ||||||
| Hesperidin | GLUT-2 and GLUT-4 | GLUT 4 expression, increasing hepatic glycolysis and lowering hepatic gluconeogenesis | C57BL/KsJ-db/db mice | Liver and adipocyte | Reduced blood glucose, reduced protein expression of GLUT-2 in hepatocyte, elevated GLUT-4 in adipocyte and hepatocyte. | 80, 110 |
| Naringenin | GLUT-4 | AMPK, glucose uptake, | In vitro | L6 myotubes | Stimulated glucose uptake, increased AMPK phosphorylation/activation. | 132 |
| Naringin | GLUT-2 and GLUT-4 | GLUT 4 expression, increasing hepatic glycolysis and lowering hepatic gluconeogenesis | C57BL/KsJ-db/db mice | Liver and adipocyte | Reduced blood glucose, lowered the mRNA expression of PEPCKand G6Pase in the liver, reduced protein expression of GLUT-2 in hepatocyte, elevated GLUT-4 in adipocyte and hepatocyte. | 80, 110 |
| Naringin | GlUT-4 | AMPK-dependent mechanism and Anti-oxidative stress | HFD in C57BL/6 mice | Liver, white adipose tissue and Blood | Regulated of PEPCK and G6pase, improvement of insulin resistance, protective by phosphorylating AMPKa and IRS1. | 152 |
| Naringin | GLUT-4 | AMPK Pathway, glucose uptake | In vitro | L6 myotubes | Stimulated glucose uptake, increased AMPK phosphorylation/activation. | 132 |
| Flavones | ||||||
| Apigenin | GLUT-4 | GLUT-4 translocation | STZ-induced diabetic rats | Liver and pancreas | Antioxidant effect, effective control of blood glucose level along, enhanced GLUT-4 translocation. | 190 |
| Apigenin-6-C-β-L-fucopyranoside | GLUT-2 | MAPK-PP1 and PI3K-GSK3 pathways, Insulin secretion | In vivo and in vitro | rat soleus muscle, hyperglycemic rats serum, | Stimulated insulin secretion and glycogen synthesis, reduce blood glucose level and insulin mimetic effects. | 158 |
| luteolin-7-O-glucoside | GlUT-4 | Glucose uptake, suppressed gluconeogenic enzymes | STZ-induced diabetic rats | Rat skeletal muscle | Protected pancreatic β-cells, stimulated glucose uptake, increased GLUT-4 expression and translocation, suppressed G6Pase. | 191 |
| Tangeritin | GLUT-4 | AMPK, glucose uptake | In vitro and HFD mice | C2C12 myotubes, muscle tissue | Phosphorylated AMPK and AS160, glucose uptake, Glut4 translocation. | 192 |
| Tangeritin | GLUT-4 | PI3K/Akt1/2, glucose uptake | In vitro | 3T3-F442A adipocytes | Increased in glucose uptake. | 193 |
| Flavonols | ||||||
| Fisetin | GlUT-4 | AMPK | STZ-induced diabetic rats | Liver | Decreased the expression levels of gluconeogenic genes, such as PEPCKand G6Pase. | 194 |
| Kaempferitrin | GlUT-4 | glucose uptake, insulin receptor, PI3K, atypical PKC activity | In vitro | Rat soleus muscle | Stimulated glucose uptake, involved in translocation of GLUT-4, glucose homeostasis, insulin-mimetic role. | 83 |
| Kaempferol | GlUT-4 | Glucose uptake, PPARγ | In vitro | 3T3-L1 adipocytes | Improved glucose uptake, ameliorated hyperglycemia, PPARγ agonist activity. | 195 |
| Kaempferol 3-neohesperidoside | GLUT-4 | PI3K - GSK-3 pathway and MAPK - PP1 pathway, glycogen synthesis | In vitro | Rat soleus muscle | Stimulated glycogen synthesis. | 196 |
| Morin | GlUT-4 | Insulin receptor, IRS, PI3K/Akt, FOXO1 | In vitro | HepG2 | Insulin-mimetic effect, increases the phosphorylation of the insulin receptor and Akt, FOXO1 phosphorylation, inhibits gluconeogenesis and enhances glycogen synthesis. | 197 |
| Myricetin | GLUT-4 | IRS1, PI3k/AKT, p85 | fructose chow-fed rats | Soleus muscles, plasma | Improved insulin sensitivity through the enhancement of insulin action on IRS-1-associated PI3K and GLUT 4 activity. | 145, 146 |
| Myricetin | GLUT-2 and GLUT-4 | insulin signaling pathway | STZ-Cd induced diabetic nephrotoxic rats |
Plasma, Liver, pancreas and skeletal muscle | Increased glycogen phosphorylase, glycogen synthase and G6pase, increased insulin and insulin signaling molecule expression like GLUT-2, GLUT-4, IRS-1, IRS-2 and PKB. | 198 |
| Pentamethylquercetin | GLUT-4 | GLUT 4, PPAR | In vitro | 3T3-L1 cell | Increased mRNA levels of GLUT-4, and PPAR. | 129 |
| Quercetin | GlUT-4 | Glucose uptake, PPARγ | In vitro | 3T3-L1 adipocytes | Improved glucose uptake, ameliorated hyperglycemia, PPARγ agonist activity. | 195 |
| Rutin | GLUT-4 | PI3K, atypical PkC and MAPK pathways | Wistar rats | Isolated soleus muscles from rats | Insulin-mimetic role, stimulated glucose uptake via the PI3K, atypical PKC, CaMKII and MAPK pathways, increased GLUT-4 translocation, stimulated calcium uptake. | 143, 144 |
| Tetramethylkaempferol | GLUT-4 | GLUT-4, PPAR | In vitro | 3T3-L1 cell | Increased mRNA levels of GLUT-4, and PPAR. | 129 |
| Isoflavones | ||||||
| Genistein | GLUT-2 | CaMK II and Ca2+ signaling, insulin secretion | In vitro | INS-1 rat insulinoma cells | Stimulated insulin secretion via activation of Ca2+/CaMK II. | 100 |