Table 1.

The anti-diabetic properties and the underlying mechanisms of dietary flavonoids

Flavonoid	Function	In vitro or in vivo model	Mode of action	Ref.
1. Flavon-3-ols
EGCG	↑ Viability	β-cells	↑ IRS2 ↑ Akt ↑ FoXO1 ↑ PDX-1	[11]
EGCG	↓ Apoptosis ↑ Glucose uptake	β-cells	↑ Bcl-2 ↓ Mitochondrial translocation of Bax	[24]
EGCG	Protect muscle cells against FFA induced insulin resistanc	C2C12 muscle cells	↑ AMPK activation ↓ PKC activation ↓ IRS1 serine phosphorylation ↑ ERK1/2 activation ↑ p38 MAPK activation ↓ ACC signaling pathway	[27]
EGCG	Delay the onset of T1D	NOD mice	↑ IL-10	[13]
EGCG	Preserve islet morphology	db/db mice	↓ Ddit3 ↓ Ppp1r15a ↓ Cdkn1a	[45]
EGCG	↑ Mitochondrial function ↓ Excessive muscle autophagy	T2D mice	Down-regulation of ROS-ERK/JNK-p53 pathway	[48]
2. Flavanones
Naringin or hesperidin	↓ Hyperglycemia	STZ-induced diabetic mice		[56]
Naringin	↓ Hyperglycemia ↑ Plasma insulin ↑ Leptin	db/db mice	↓ PEPCK and G6Pase expression	[57]
Hesperidin or Naringin	↑ GLUT2 (liver) ↓ GLUT4 (WAT)	db/db mice	↑ PPARγ	[18]
Naringin	↓ Hyperglycemia ↑ β cell function	T2D mice	↑ PPARγ ↑ HSP-72 ↑ HSP-26 Maintain adequate pool of insulin secretory granules	[61]
3. Anthocyanidins
Bilberry anthocyanins	↓ Hyperglycemia ↑ insulin sensitivity ↑ GLUT4 (WAT and muscle)	T2D mice	↑ Total AMPK ↑ AMPK phosphorylation ↓ PEPCK and G6Pase expression ↓ Acetyl Co-A carboxylase ↓ PPARα ↑ Acyl-CoA oxidase ↑ CPT-1A ↓ RBP4	[17]
Black soybean anthocyanins	↑ GLUT4 (muscle) ↑ β cell viability ↓ β cell apoptosis	STZ-induced diabetic rats	↑ IR phosphorylation ↑ Bcl-2 ↓ Bax ↓ Caspase-3	[72]
Anthocyanin mixture	↑ Plasma insulin Preserve pancreatic islets	HF induced diabetic mice		[74]
Purple corn color anthocyanidin	↓ Insulin ↓ Leptin ↓ Adipocyte hypertrophy	HF fed mice	↓ Lipogenic gene expression	[75]
Blue berry anthocyanins	↓ hyperglycemia	HF fed mice		[76]
Bayberry fruit anthocyanins	↑ β cell viability ↓ β cell apoptosis ↑ GSIS	INS-1 cells	↑ PDX-1 ↑ Insulin like growth factor II	[80]
Delphinidin-3-glucoside	↑ GSIS	INS-1 cells		[83]
Cyanidin-3-glucoside and its metabolite Protocatechuic acid	↑ Glucose uptake ↑ GLU4 expression ↑ Adiponectin	Human and murine adipocytes	↑ PPARγ	[85]
Pelargonidin	↑ Glucose tolerance ↑ Serum insulin ↑ Antioxidant enzymes	STZ-induced diabetic rats		[81]
Cyanidin-3-glucoside	↓ Fasting glucose ↑ Insulin sensitivity ↓ Inflammatory cytokines	db/db mice and HF-fed obese mice	↑ Phosphorylation of Akt, FoXO1 ↓ Nuclear translocation of FoXO1 ↓ JNK activation	[86]
4. Flavonols
Fistein	↓ Hyperglycemia ↓ Glycosylated Hb	STZ-induced diabetic rat	↓ PEPCK and G6Pase	[94]
Kaempferol	↑ Secretion of insulin ↓ β cell apoptosis	INS-1E cells and pancreatic human islets	↑ Akt ↑ Bcl-2 ↑ cAMP signaling ↑ PKA activation ↑ CREB phosphorylation ↑ PDX-1 ↓ Caspase-3	[14]
Quercetin rich extract Quercetin-3-Oglucoside, Q-3-O-galactoside	↑ Glucose uptake	C2C12 muscle cells	↑ AMPK	[16]
Quercetin	↓ Hyperglycemia ↑ Insulin Cell proliferation in liver and pancreas	STZ-induced diabetic mice	↓ Cdkn1a	[102]
Quercetin	↓ Hyperglycemia Improve insulin resistance	db/db mice		[105]
Quercetin	↑ GSIS	INS-1 cells	ERK1/2 pathway	[106]
Quercetin and its glucoside quercitrin	↑ GSIS ↑ Cell viability	Rat insulinoma cells	↓ iNOS ↓ Nuclear translocation of NFκB ↓ Cytochrome C release from mitochondria	[107]
Quercetin, isoquercetin, rutin	Inhibit α-glucosidase	Cell free system		[108]
5. Flavones
Apigenin	↓ Hyperglycemia ↑ Hepatic antioxidant enzymes	Alloxan - diabetic mice		[115]
Apigenin	↓ Hyperglycemia	STZ- induced diabetic mice		[116]
Apigenin	↓ Apoptosis	HIT-T15 clonal β-cells		[117]
Apigenin, luteolin	↓ Apoptosis	Rat insulinoma cells	↓ iNOS ↓ NFκB activation	[118]
Apigenin	↑ GLUT4	HepG2 hepatocytes	↑ AMPK phosphorylation	[119]
6. Isoflavones
Genistein and daidzein	Improve glucose homeostasis	NOD mice	↓ PEPCK and G6Pase	[130]
Genistein	↓ Hyperglycemia ↑ β-cell mass	T2D mice		[131]
Genistein	Insulinotropic effect	INS-1 MIN-6 Human islet β-cells	Activation of cAMP/PKA-dependent ERK1/2 signaling pathway ↑ Cyclin D1	[12]
Genistein	↓ Hyperglycemia ↑ Glucose tolerance ↑ Insulin ↑ β-cell proliferation, survival and mass	STZ-induced diabetic mice	Activation of cAMP/PKA-dependent ERK1/2 signaling pathway	[12]
Genistein	↑ Insulin secretion	INS-1 cells	CaMK II and Ca2+ signaling	[147]
Genistein	↑ β-cell function	RINm5F (RIN) cells	↓ NFκB, ERK1/2 and JAK/STAT pathway	[148]