Bioactivity and mechanisms of flavonoids in decreasing insulin resistance

Figures & data

Figure 1. Chemical structures of different subclasses of flavonoids.

Figure 2. Various pathways involved in dysregulation of insulin signalling³. Activation of ir by their ligands initiates a cascade of phosphorylation events. And irs1 activates the PI3K-Akt pathway by recruiting and activating PI3K, which phosphorylates the serine/threonine residue of protein kinase B (Akt). Akt regulates the translocation of GLUT4 to the cell surface through AS160. Binding of AGE to its receptor RAGE impairs insulin signal by triggering a range of signalling pathways, including JNK, NF-κB, and activation of PKC. Red indicates inhibitory effects and green indicates positive effects.

Figure 3. Sites of flavonoid action on insulin resistance (IR). Flavonoids induce insulin receptor and IRS phosphorylation and activate PI3K/Akt pathway and AMPK, promoting GLUT4 translocation. The PI3K/Akt pathway activated by flavonoids decreases PEPCK and G6P expression, suppressing gluconeogenesis and promoting glycogen synthesis. Flavonoids reduce the levels of FFAs and inflammatory factors, reducing the negative effect on insulin signal transduction by JNK, NF-κB and PKC. Red indicates inhibitory effects and green indicates positive effects.

Table 1. Effects of flavonoids on decreasing IR in in vitro experiments.

Flavonoids	Quantity	In vitro Model	Activity	Effect	References
Luteolin	20 μM	3T3-L1 adipocytes and primary adipose cells	↓TNF-α, IL-6, MCP-1 ↑PPAR-γ, GLUT4, p-Akt2	Increase adiponectin and leptin, increase the response of glucose uptake	^39
	20 μM	a coculture system of adipocytes and macrophages cells	↓JNK, TNF-α, MCP-1, NO	Suppress the production of inflammatory mediators, attenuate IR	^40
Apigenin	25 μM	HepG2 Cells	↓SREBP-1C, SREBP-2, ER stress	Inhibit ER stress and decrease blood lipid and IR	^11
Nobiletin	10 μM	C3A liver cells	↑IRS1, PI3k, GLUT2 ↑AMPK	Alleviate dyslipidaemia and IR	^41
Chrysin	10–15 μM	HepG2 Cells	↑AMPK ↑PI3K, p-IRS1, p-Akt	Decrease IR, oxidative stress, inflammation and liver injury	^42
Quercetin	10 μM	HepG2 Cells	↓TNF-α, IL-8 ↑SOD, CAT, GSH-Px	Decrease triacyl glycerol accumulation, IR, inflammatory cytokine secretion increase cellular antioxidants	^43
Kaempferol	10–50 μM	HepG2 Cells	↑Akt, hexokinase ↓PC	Suppress glucose production, improve insulin sensitivity	^44
Rutin	100 μM	Myotubes cells	↑IRk, GLUT4	Increase glucose uptake, decrease IR	^45
Daidzein	25 μM	Adipocyte and Macrophage Co-Cultures	↑PPAR-α, PPAR-γ ↓NF-κB, JNK	Decrease chronic inflammation, alleviate IR	^46
	100 μM	L6 myocytes	↑GLUT4, AMPK	Promote glucose uptake, suppress serum total cholesterol levels	^47
Naringin	5 μM	HepG2 cells	↓RAGE, AGEs, NF-κB, ROS	Mitigate inflammation, oxidative stress and mitochondrial apoptosis	^48
Hesperidin	10 μM	L6 myotubes	↓ROS, AGEs, PI3K ↑GLUT4, IRS, Akt	Improve insulin sensitivity, reduce oxidative stress response	^49^,^50
	25 μM	HepG2 cells	↑IRS1, GLUT2 ↓TLR4, NF – κB	Increase glucose uptake, decrease IR	^51
EGCG	10–100 μM	HepG2 cells, 3T3-L1 adipocytes	↑GLUT2, PGC-1b ↓SREBP-1c, FAS ↓NF-κB, TNF-α, IL-6, ROS, MDA, p53, TNF-α	Increase glucose uptake, decrease IR	^52–54
	50 μM	HepG2 cells	↓PTP1B ↑IRS1, Akt, GLUT2	Accelerate the glucose uptake, ameliorate metabolic misalignment	^55
Anthocyanins	10–20 ug/mL	3T3‐L1 adipocytes	↓NF – κB ↑PI3K, p-Akt, GLUT1	Decrease adipocyte inflammation, IR	^56
	50 μM	3T3‐L1 adipocytes	↑p-Akt, p-IKK, p-MEK ↑GLUT4	Reduce hyperglycaemia, ameliorate inflammation and IR	^57

Table 2. Effects of flavonoids on decreasing IR in in vivo experiments.

Flavonoids	Quantity/Day	Animal Models/Length of Study	Activity	Effect	References
Luteolin	20–100 mg/kg	High-fat fed rats/12 weeks	↓IL-6, TNF-α, MCP-1 ↓PKC	Decrease glucose intolerance and insulin sensitivity reduce body weight gain, fat deposition, and adipocyte hypertrophy	^58
	50–100 mg/kg	High-fat fed rats/16 weeks	↓SREBP1, FFA ↑IRS2, PPAR-γ	Reduce hepatic lipid load, improve chronic low-grade inflammation, increase insulin levels, alleviate IR	^59–61
	100 mg/kg	High-fat fed rats/20 weeks	↑AMPKα ↑M1 polarisation	Inhibit inflammatory polarisation, enhance insulin signals	^62
Apigenin	200 mg/kg	High-fat fed mice/12 weeks	↑p-AMPK, p-ACC ↑UCP-1, PGC-1α ↓NF-кB, MAPK ↓FFAs	Ameliorate body weight gain, glucose intolerance and IR enhance lipid catabolism, thermogenesis and browning	^63
	10 mg/kg	High-fat fed rats/12 weeks	↓SREBP-1C, SREBP-2, ER stress	Inhibit ER stress and decrease blood lipid and IR	^11
	10–50 mg/kg	High-fat fed mice/16 weeks	↑PPAR-γ	Improve glucose resistance, reduce liver and muscular steatosis	^64
	50 mg/kg	High-fructose fed mice/4 weeks	↑HO-1, NQO1	Decrease IR, dyslipidemia and liver injury	^65
Nobiletin	10–100 mg/kg	High-fat fed rats/8 weeks	↑PPAR-γ, PAR-α, SREBP-1C ↓TNF-α, MCP-1 ↑GLUT4, p-Akt	Improve plasma adiponectin levels and glucose tolerance, improve dyslipidemia, decrease hyperglycaemia and IR	^66^,^67
Scutellarein	50 mg/kg	High-fat fed rats/16 weeks	↑AMPK ↑p-IRS1, p-Akt	Weight loss, improve glycometabolism, against oxidative stress	^68
Chrysin	30 mg/kg	High-fat fed mice /STZ-induced Mice/5 weeks	↑AMPK ↑PI3K, p-IRS1, p-Akt	Decrease IR, oxidative stress, inflammation and liver injury	^42
Quercetin	30 mg/kg	High-fat fed rats/6 weeks	↓NF-κB, TNF-α, IL-6, TLR-4 ↓SREBP-1c, FOXA1	Reduce HOMA-IR, inhibit inflammasome response and net stress, reduce hepatic lipid accumulation	^69^,^70
	50 mg/kg	High-fat fed mice/6 weeks	↑p-Akt, IRS1, GLUT4 ↓NLRP3	Reduce inflammation, IR and HOMA-IR, improve insulin sensitivity	^28^,^71
Kaempferol	50–150 mg/kg	High-fat fed rats/10 weeks	↓NF-κB, TNF-α, IL-6, IKK	Inhibit inflammatory response, ameliorate IR	^72^,^73
	100 mg/kg	High-fat fed Mice/20 weeks	↑GLUT4, AMPK	Improve hyperglycaemia, hyperinsulinemia, and circulating lipid profile. Preserved Pancreatic β-Cell Mass	^74
Fisetin	200 mg/kg	High-fat fed rats/16 weeks	↓GKPEPCK, G6Pase ↑IRS2	Prevent adiposity, ameliorate IR, normalise pancreatic islet dysfunction, decline hepatic gluconeogenesis and proinflammatory responses	^75
Daidzein	100 mg/kg	db/db mice/5 weeks	↑GLUT4, AMPK	Promote glucose uptake, suppress serum total cholesterol levels	^47
	50 mg/kg	ovariectomized rats/12 weeks	↓TNF-α, IL-6	Decrease weight gain, visceral fat and HOMA-IR	^76
Genistein	10–20 mg/kg	Diabetic rats/4 weeks	↓LDL, VLDL, TC, TG	Decrease HOMA-IR, enhance beta cell function and decrease IR	^77
	20–40 mg/kg	High-fat diet/streptozotocin induced mice/8 weeks	↓LPS, TNF-α, IL-1β, IL-6, NLRP3	Decrease HOMA-IR, ameliorates inflammation and IR	^78
Naringin	100 mg/kg	High-fat fed rats/12 weeks	↓RAGE, AGEs, NF-κB, ROS	Mitigate inflammation, oxidative stress and mitochondrial apoptosis	^48
	200 mg/kg	High-fat fed rats/20 weeks	↑AMPK, p-IRS1, MAPKs ↓p-JNK, p-NF-κB	Reduce oxidative damage, reduce chronic inflammation and IR	^79
Hesperidin	100 mg/kg	High-fat fed rats/20 weeks	↑p-insulin receptor, p-PDK1	Improve insulin sensitivity, regulate glycolysis and gluconeogenesis, increase glucose uptake	^80
EGCG	50 mg/kg	High-fat fed rats/12 weeks	↑Akt, GLUT4, AMPKα, sirtuin1 ↓mTOR, SREBP-1c ↑IRS1, AS160	Increase glucose uptake, decrease IR	^81
	50 mg/kg	High-fat fed mice/16 weeks	↓PTP1B ↑IRS1, Akt, GLUT2	Accelerate the glucose uptake, ameliorate metabolic misalignment	^55
Anthocyanins	50–200 mg/day	High-fat fed rats/12 weeks	↓TLR4, NF-κB, JNK ↑Nrf2, HO-1, NQO1 ↑IRS1, Akt	Decrease inflammation and oxidative stress, alleviate IR	^82

Figure 4. Structures of flavones.

Figure 5. Structures of flavonols.

Figure 6. Structures of isoflavones.

Figure 7. Structures of flavanones.

Figure 8. Structures of flavanones.

Table 3. Current clinical trials on flavonoids as potential therapy against IR.

Clinical Trial Identifier No.	Objective	Voluntary and Dose	Status
NCT04306406	Molecular Mechanisms of Raspberries Effect on IR and Inflammation (RASPBERRY)	9 male and female of 18–70 age were given single serving smoothies drink made with red raspberries to be consumed daily for two weeks	Completed
NCT01350843	The Effects of Orange Juice on Plasma Lipids	36 males of 40–60 age were given 250 mL of orange juice or a sugar matched orange drink daily	Completed
NCT02728570	Effect of Dietary Flavonoids on Intestinal Microbiota, Intestinal Inflammation and Metabolic Syndrome	30 male and female of 18–70 age were given a prepared diet with Low Dietary Flavonoids (10 mg of flavonoids/1000 Kcals) for six weeks. After a minimum washout period of 2 weeks, participants receive a prepared diet with High Dietary Flavonoids (340 mg of flavonoids/1000 Kcals) for six weeks.	Completed
NCT05158673	Effect of Cocoa Polyphenols Supplementation on Cardiovascular Risk of Postmenopausal Women	30 females of 50–60 age with an early post menopause diagnosis were given two capsules of 500 mg of the flavonoid supplementorally every 12 hours for 12 weeks.	Not yet recruiting
NCT01944579	Blackberry Flavonoid Absorption and Effects on Intestinal Bacteria	46 male and female of 25–75 age were given a controlled diet with the control food (jello) first and then cross over to the controlled diet with blackberries.	Completed
NCT02006810	Development of Endothelial Biomarkers (NUTREND)	50 males of 40–65 age were given a single dose of lipids or a single dose of flavonoids	Completed
NCT04616404	The Metabolic Effects of Cynara Supplementation in Overweight and Obese Class I Subjects with Newly Detected Impaired Fasting Glycaemia.	44 male and female were given tablets containing 500 mg of artichoke extract	Completed
NCT05243238	Hesperidin and Diosmin Effect on Metabolic Syndrome	129 male and female of 18–70 age were given either hesperidin, diosmin, or combination of both	Completed
NCT02610491	The Effect of Hesperidin on Glucose / Insulin Metabolism	53 male and female of 18–65 age were given Hesperidin Citrus peel extract	Completed
NCT02035592	The Health Effects of Blueberry Anthocyanins in Metabolic Syndrome (the CIRCLES-study) (CIRCLES)	144 male and female patients of 50–74 age with metabolic syndrome were given 26 g of freeze-dried blueberry powder per day (6 mouths)	Completed
NCT04731987	Orange Juice, Hesperidin and Their Role in Vascular Health Benefit (HESPER-HEALTH)	42 subjects between 40 and 65 years old with predisposition to cardiovascular disease will consume daily 330 mL of orange juice naturally rich in hesperidin (drink A) during 6 weeks	Recruiting
NCT01617603	A Comparison Chocolate with and Without High Cocoa Solids in Patients with Type 2 Diabetes in a Randomised Clinical Trial	62 male and female patients of 45–75 age with type 2 diabetes were given high polyphenol milk chocolate containing approximately 1 mg/g of epicatechin	Completed
NCT04053569	Grape Polyphenols and Metabolic Syndrome (PolyGrape)	40 obese male and female of 30–65 age were given grape (5 g/kg) administered for four weeks	Active, not recruiting

NCT numbers refer to the source of www.clinicalTrails.gov.

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