Citrus polyphenols and risk of type 2 diabetes: Evidence from mechanistic studies

Figures & data

Figure 1. Chemical structures of commonly found (poly)phenols in citrus fruits.

Table 1. (Poly)phenol composition of citrus juices.

	Citrus sinensis	Citrus paradisi	Citrus limon
Flavanones
Hesperidin 1	3.51–55.2	0.25–1.79	3.84–41
Narirutin 5	0.55–14.2	2.5–17.0	–
Naringin 6	–	4.5–60.2	–
Neohesperidin 4	–	0.67–1.58	–
Didymin 7	0.8–3.10	0.27–0.33	–
Eriocitrin 10	0.11–0.67	0.27–0.54	1.67–39.1
Neoeriocitrin	0.59	0.30–0.33	–
Poncirin	0.49–1.59	0.85–1.58	–
Flavones and flavonols
6,8-di-C-Glu-apigenin 11	4.15–8	–	1.0–1.45
6,8-di-C-Glu-diosmetin	0.25–0.45	–	4.05–5.8
Rhoifolin	0.05	0.28	–
Isorhoifolin	0.07	–	–
Diosmin	0.09	–	0.51–5.1
Neodiosmin	0.08	–	–
Rutin	–	3.26	–
Luteolin-7-O-rutinoside	–	–	1.5–6.5
Polymethoxyflavones
Heptamethoxyflavone	0.04–0.12	0.01–0.11	–
Nobiletin 13	0.19–0.46	0.12–0.17	–
Sinensetin	0.37	–	–
Tangeretin 12	0.01–0.07	0.12	–
Aglycones
Taxifolin	0.03	0.16	–
Acacetin	0.03	–	–
Hesperetin 8	–	0.74	–
Naringenin 9	–	0.98–8.0	–
Quercetin	–	0.17–0.21	–
Luteolin	–	–	0.08

Data represent values extracted from different studies for the juices (Gattuso et al. 2007). All values are expressed as mg (poly)phenol/100 mL juice.

Figure 2. Potential inhibitory mechanisms of citrus (poly)phenols on starch digestion and absorption within the gut. SGLT1 (Sodium-dependent glucose cotransporter 1), GLUT2 (Glucose transporter 1), and GLUT5 (Glucose transporter 5) are sugar transporters located in the brush border membrane.

Table 2. In vitro studies on citrus compounds and the markers of type 2 diabetes.

Mechanism	Reference	Test model/ Source	Test sample	Test concen-tration	Positive control	Outcome	Physiological relevance		Comments
							Test sample	Test/ active dose
Inhibition of starch digesting enzymes	(Casacchia et al. 2019)	Human pancreatic α-amylase	Clementine; Tarocco tetraploids; cross-bred hybrid Tacle	0.05–400 μg/mL	Acarbose	IC50 ranged from 44.3 ± 0.7 to 99.66 ± 0.36 µg/mL. Acarbose IC50 = 36.5 ± 0.3 μg/mL.	√	√	–
	(Uddin et al. 2014)	α-amylase (unknown source)	Citrus macroptera Montr. fruit extract	500–2000 μg/mL	Acarbose	Citrus extract inhibited α-amylase (IC50 = 3.64 mg/mL); acarbose (IC50 = 0.91 mg/mL).	√	√	Enzyme source not known.
	(Oboh and Ademosun 2011)	Porcine pancreatic α-amylase and yeast α-glucosidase	Shaddock (Citrus maxima) peel extract	80–320 µg/mL	–	Moderate α-amylase and strong α-glucosidase inhibition.	√	√	α-glucosidase from yeast not relevant to human enzyme; porcine α-amylase somewhat relevant.
	(Alu’datt et al. 2017)	α-amylase (unknown source) and yeast α-glucosidase	Shamouti and red blood orange; white grapefruit; lemon; white pummelo; clementine	–	–	Exhibited poor/no α-amylase and strong α-glucosidase inhibitory activity.	√	–	α-glucosidase from yeast not relevant to human enzyme.
	(Kim, Shin, and Jang 2009)	Rat intestinal α-glucosidase and porcine pancreatic α-amylase	Citrus grandis Osbeck (CGO) extract; CGO aglycones; Aspergillus saitoi-treated CGO extract	–	–	CGO extract showed poor α-glucosidase inhibition and no α-amylase inhibition. A. saitoi-treated CGO extract inhibited the enzymes >50%; aglycones showed moderate inhibition.	√	–	Enzymes from non-human sources have only partial relevance to human enzymes.
	(Menichini et al. 2011)	Porcine pancreatic α-amylase and yeast α-glucosidase	Citrus medica L. extract	5–1000 μg/mL	Acarbose	Weak inhibition: α-amylase and α-glucosidase (∼8.5- and ∼16-fold lower than acarbose, respectively).	√	√	α-glucosidase from yeast not relevant to human enzyme; porcine α-amylase somewhat relevant.
	(de la Garza et al. 2013)	Porcine pancreatic α-amylase and yeast α-glucosidase	Grapefruit extract	20–1500 μg/mL	Acarbose	Poor inhibition of α-amylase and α-glucosidase (IC50 = 420 and 410 µg/mL, respectively). Acarbose (IC50 = 4.1 and 6.9 µg/mL)	√	√	α-glucosidase from yeast not relevant to human enzyme; porcine α-amylase somewhat relevant.
	(Gong et al. 2017)	Yeast α-glucosidase	Hesperetin 8	0–2500 μM	–	Inhibited yeast α-glucosidase with IC50 value = 380 µM.	√	X	α-glucosidase from yeast not relevant to human enzyme. Hesperetin 8 used at much higher concentration than physiological.
	(Kerimi, Gauer, et al. 2019)	Rat intestinal sucrase	Hesperidin 1	0–1000 μM	Acarbose	No inhibition.	√	√	Rat enzyme only somewhat relevant to human.
	(Zheng, Lu, and Xing 2021)	Yeast α-glucosidase	Hesperidin 1; hesperidin hydrolysates (acid hydrolysis); hesperetin 8	60–10000 μg/mL	–	Hesperidin hydrolysates exhibited strong α-glucosidase inhibition (IC50 = 83 μg/mL); hesperetin 8 moderate effect. Hesperidin 1 very weak (<15% at 10 mg/mL).	√	√	α-glucosidase from yeast not relevant to human enzyme. Only trace levels of the aglycones are present naturally in the fruit; only a very small amount is produced after deglycosylation in the small intestine.
	(Shen, Xu, and Lu 2012)	Porcine pancreatic α-amylase and yeast α-glucosidase	Hesperidin 1; naringin 6; neo-hesperidin 4; nobiletin 13	12.5–160 μM	Acarbose	Weak inhibition	√	√	α-glucosidase from yeast not relevant to human enzyme; porcine α-amylase somewhat relevant.
	(Priscilla et al. 2014)	Yeast and rat intestinal α-glucosidase	Naringenin 9	3.15–794 μM	Acarbose	Naringenin 9 inhibited yeast and rat intestinal α-glucosidase with an IC50 value of 6.51 and 384 µM, respectively (Acarbose 49.7 and 2.45 µM, respectively).	√	√	α-glucosidase from yeast not relevant to human enzyme; rat α-glucosidase somewhat relevant. Only trace levels of the aglycones are present naturally in the fruit; only a very small amount is produced after deglycosylation in the small intestine.
	(Ali et al. 2019)	Yeast α-glucosidase	Didymin 7	0–250 µM	Acarbose	Didymin 7 (IC50 = 48.8 ± 1.0 μM) was 2.6 times higher than acarbose (IC50 = 129.9 ± 0.8 μM).	√	√	α-glucosidase from yeast not relevant to human enzyme.
Glucose transporters	(de la Garza et al. 2013)	Caco-2 cells	Grapefruit extract	480 µg/mL	Phloridzin (500 µM)	Grapefruit extract inhibited SGLT1-mediated methyl glucoside uptake by 29% (Phloridzin − 56%).	√	√	–
	(Kerimi, Gauer, et al. 2019)	Caco-2/TC7 cell and Xenopus laevis oocytes expressing human GLUT2 or GLUT5	Hesperidin 1; hesperetin 8; orange juice	80–1600 μM	–	Hesperidin 1 and orange juice moderately inhibited the glucose transporters in Caco-2/TC7 cells.	√	√	–
	(J. M. Li et al. 2006)	Rat everted intestinal sleeves	Naringenin 9	10–500 µM	Phloridzin	Naringenin 9 strongly inhibited glucose uptake (IC50 = 2.4 µM); phloridzin (IC50 = 1.9 µM).	√	√	–
	(Johnston et al. 2005)	Caco-2/TC7 cells	Naringin 6; neohesperidin dihydrochalcone	100 μM	–	Neohesperidin dihydrochalcone inhibited glucose absorption (∼50%) by inhibiting SGLT1. Naringin was weaker (<20%).	√	x (neo-hesper-idin)	The active neohesperidin 4 concentration is far higher than found by ingesting citrus fruits (<26 μM).
	(Kwon et al. 2007)	Xenopus laevis oocytes expressing GLUT2 or GLUT5	Hesperetin 8; naringenin 9; naringin 6	0–300 μM	–	Hesperetin 8 inhibited deoxy-D-glucose and fructose absorption with IC50 = 48.6 and 66.5 μM, respectively. Naringenin 9 poor inhibition (IC50 = >300 μM); naringin 6, no inhibition	√	√	Only trace levels of the aglycones are present naturally in the fruit; only a very small amount is produced after deglycosylation in the small intestine.
Insulin sensitivity	(Horiba et al. 2010)	3T3-L1 adipocytes	Chronic naringenin chalcone treatment (8 days)	25–100 μM	–	Naringenin chalcone (≥25 μM) ↑ adiponectin mRNA and protein secretion via PPAR-γ.	√	x	Active dose is far above the level of naringenin metabolites (21–26) in plasma after consuming citrus fruits (<6 μM).
	(Rebello et al. 2019)	Human white adipocyte (hADSC) and abdominal subcutaneous adipose tissue (pWAT)	Chronic naringenin 9 treatment hADSC − 3 or 7 days pWAT − 7 or 14 days	8 µM	–	In both cell lines, ↑ mRNA expression of GLUT4, adiponectin, and ChREBP.	√	√	–
	(Murugesan et al. 2020)	Human subcutaneous adipocyte	Chronic naringenin 9 treatment for 2 days	8 µM	–	No effect on GLUT4 mRNA expression.	√	√	–
	(Zhao et al., 2020)	HTR-8/SVneo and HUVEC cells	Chronic naringenin 9 treatment for 2 days	50 µM	–	Naringenin 9 ↑ insulin-stimulated glucose uptake by reducing miR-140 expression and ↑ insulin signaling pathway.	√	x	Active dose is far above the level of naringenin metabolites (21–26) found in plasma after consuming citrus fruits (<6 μM).
	(Richard et al. 2013)	3T3-L1 adipocytes and sub-cutaneous human adipocytes	Naringenin 9	44–184 µM	–	↓ differentiation of preadipocytes and ↑ insulin resistance by ↓ IRS-1 tyrosine phosphorylation in 3T3-L1 adipocytes. ↓ adiponectin expression in both human (92 µM) and murine mature adipocytes (184 µM).	√	x	Active doses are far above the level of naringenin metabolites (21–26) found in plasma after consuming citrus fruits (<6 μM).
	(Harmon and Patel 2003)	3T3-L1 adipocytes	Naringenin 9	25–100 μM	–	Naringenin 9 (≥25 μM) inhibited insulin-stimulated glucose uptake by inhibiting PI3K.	√	x	Active doses are far above the physiological plasma concentration of naringenin metabolites (21–26) (<6 μM).
	(Yoshida et al. 2013)	3T3-L1 adipocytes	Naringenin 9	1–100 µM		Naringenin 9 > 10 µM ↓ TLR2 mRNA and protein expression during adipocyte differentiation, with no effect in pre- and matured adipocytes.	√	√	–
	(Yang et al. 2013)	MDA-MB-231 breast cancer cells	Hesperetin 8	5–100 µM	–	Hesperetin 8 ↓ basal (≥50 µM) and insulin-stimulated glucose uptake (≥100 µM), down-regulated GLUT1, ↓ insulin-induced translocation of GLUT4, suppressed phosphorylation of insulin receptor-β subunit and Akt.	√	x	Active doses are far above the reported physiological plasma concentrations of hesperetin metabolites (14–20) (<2.2 μM).
	(Claussnitzer et al. 2011)	3T3-L1 adipocytes and mature human adipocytes	Hesperidin 1; naringin 6; naringenin 9	20 µM	–	Naringenin 9 ↓ basal (no insulin) and insulin-induced glucose uptake in both cells. Hesperidin 1 ↓ insulin-induced glucose absorption in 3T3-L1 adipocytes; naringin 6, no effect.	x (hesperidin 1, naringin 6)	x	Hesperidin 1 and naringin 6 do not reach circulation in their original forms so physiologically not relevant. Active dose of naringenin 9 is far above plasma concentrations of naringenin metabolites (21–26) (<6 μM).
Mechanism	Reference	Test model/ Source	Test sample	Test concen-tration	Positive control	Outcome	Physiological relevance		Comments
							Test sample	Test/ active dose
	(Liu et al. 2008)	3T3-L1 adipocytes	Hesperetin 8; naringenin 9	20 − 160 µM	Rosiglitazone (10 μM)	↑ adiponectin transcription (80 µM) and PPAR-γ controlled luciferase expression (≥20 µM) in a dose-dependent manner.	√	x	Active doses are far above the reported plasma concentrations of flavanone metabolites (14–26) (<2.2 and 6 μM for hesperetin 8 and naringenin 9, respectively).
	(Park 1999)	Myelocytic U937 cells	Hesperetin 8; naringenin 9; naringin 6	0–100 μM	–	Hesperetin 8 and naringenin 9 significantly inhibited glucose uptake (IC50 = ∼50 µM) in U937 cells in a dose-dependent manner, while naringin 6 did not affect uptake.	x (naringin)	x	Naringin 6 does not reach circulation in its original forms so physiologically not relevant. The active concentrations of the aglycones are higher than the reported physiological plasma concentration of the respective metabolites (14–26) (<2.2 and 6 μM for hesperetin 8 and naringenin 9, respectively).
	(Nomura et al. 2008)	MC3T3-G2/PA6 adipocytes	Hesperetin 8; naringenin 9; hesperidin 1	10 μM	–	No effect on deoxy-D-glucose uptake	x (hesperidin 1)	√	Hesperidin 1 is not absorbed in its original form.
	(Onda et al. 2013)	3T3-F442A adipocytes	Tangeretin 12; nobiletin 13	5–50 µM	–	Tangeretin 12 and nobiletin 13 (≥5 µM) ↑ the uptake of deoxy-D-[1-^3H]- glucose dose-dependently by modulating the PI3K/protein kinase A pathways.	√	√	–
	(Kim et al. 2012)	C2C12 myotubes	Tangeretin 12	0–200 μM	–	Tangeretin 12 (>100 μM) significantly ↑ glucose uptake and phosphorylation of AMPK.	√	x	The active concentration is not achieved under normal physiological conditions (tangeretin 12 content in the edible portion of citrus fruit <5 μM).
	(Miyata et al. 2011)	3T3-L1 adipocytes	Tangeretin 12; nobiletin 13	16–128 µM	Pioglitazone (for adiponectin test)	Both flavonoids ↑ secretion of adiponectin (16–64 µM), and ↓ secretion of MCP-1 (128 µM). Nobiletin 13 at 128 µM ↓ secretion of resistin.	√	x	The active concentrations are not achieved under normal physiological conditions (tangeretin 12 and nobiletin 13 content in edible portion of citrus fruit <11 μM).
	(Saito, Abe, and Sekiya 2007)	3T3-L1 adipocytes	Nobiletin 13	60 μM	–	Nobiletin 13 enhanced differentiation, upregulated adiponectin mRNA levels, and ↑ lipolysis.	√	x	The active concentration is not achievable under normal physiological conditions (nobiletin 13 content in the edible portion of citrus fruit <11 μM).
	(Kanda et al. 2012)	3T3-L1 adipocytes and mouse embryonic fibroblasts	Nobiletin 13	1–100 µM	–	Suppressed adipocyte differentiation (≥1 µM) in 3T3-L1 preadipocytes and mouse embryonic fibroblasts.	√	√	–
	(Kunimasa et al. 2009)	ST-13 adipocytes	Nobiletin 13	10 μM	Troglitazone	Nobiletin 13 induced differentiation of preadipocytes into mature adipocytes; ↑ adiponectin (3.4-fold).	√	√	–
	(Ali et al. 2019)	Insulin-resistant HepG2 cells	Didymin 7	10–30 µM	Metformin	Didymin 7 (≥10 µM) improved insulin-dependent glucose uptake by down- regulating PTP1B, leading to ↑ phosphorylation of IRS-1, PI3K, Akt, and GSK-3. ↓ PEPCK and G6Pase expression.	x	√	Didymin 7 is not absorbed in its original form and so will not reach the liver in this form.
	(Gamo et al. 2014)	3T3-L1 adipocytes	Hesperetin-7- glucuronide 14; hesperetin-3′- glucuronide 16	250 µM	Troglitazone (10 µM)	Enhanced adipocyte differentiation by activating PPAR-γ; comparable to troglitazone.	√	x	The active concentration is not achieved under normal physiological conditions (maximum reported 2.2 μM).
	(Nguyen‐Ngo, Willcox, and Lappas 2019)	TNF-α-stimulated human skeletal muscle tissue explant	Naringenin 9	400 μM	–	Naringenin 9 ↑ insulin-stimulated glucose uptake in TNF-α stimulated gestational diabetes model skeletal muscle cells.	√	x	The active concentration is not achieved under normal physiological conditions (maximum reported 6 μM).
	(Li et al. 2019)	TNF-α-stimulated C2Cl2 myoblasts	Naringenin 9	184 µM	–	Naringenin 9 significantly ↑ GLUT4 translocation and glucose uptake in TNF-stimulated insulin-resistant muscle cells.	√	x	The active concentration is not achieved under normal physiological conditions (maximum reported 6 μM).
Insulin secretion	(Gupta et al. 2018)	Human recombinant DPP-4	Rutin; eriocitrin 10; eriodictyol; naringenin 9; naringin 6; hesperidin 1; hesperetin 8	–	Sitagliptin; saxagliptin; vildagliptin	Poor DPP-4 inhibition (IC50 = 485 to 5700 µM); commercial drugs (IC50 values sitagliptin − 0.684 µM, saxagliptin − 0.707 µM, and vildagliptin − 2.286 µM).	x (naringin 6, hesperidin 1, rutin, eriocitrin 10)	x	Naringin 6, hesperidin 1, eriocitrin 10 and rutin are not absorbed in their original form. The active concentrations are not achieved under normal physiological conditions.
	(Fan et al. 2013)	Porcine kidney DPP-4	Hesperetin 8; naringenin 9; eriocitrin 10	–	Diprotin A	Hesperetin 8 and naringenin 9 showed potential DPP-4 inhibition (IC50 = 0.28 and 0.24 µM, respectively) compared to positive control (IC50 = 4.21 µM).	x (eriocitrin 10)	√	Study used enzyme from non-human sources. Eriocitrin 10 is not absorbed in its original form.
	(Parmar et al. 2012)	DPP-4 (unknown source)	Naringin 6	9 µM	Sitagliptin (9 µM)	Naringin exhibited potent DPP-4 inhibitory activity (∼69%), comparable to sitagliptin (∼60%).	x	x	Naringin is not absorbed in its original form.
	(Xing, Yang, and Wu 2016)	Human embryonic stem cells-derived pancreatic endoderm	Naringenin 9	367 µM	–	Naringenin 9 ↑ glucose-stimulated insulin secretion.	√	x	The active concentration is not achieved under normal physiological conditions (maximum reported 6 μM).
	(Bhattacharya et al. 2014)	INS-1E cells	Naringenin 9	10^−10, 10^−8, 10^−6 M	–	Chronic and acute naringenin 9 exposure ↑ glucose-stimulated insulin secretion in a dose-dependent manner. Naringenin 9 ↑ GLUT2, GK, Ins1, Ins2, Akt1, and Akt2 mRNA expression.	√	√	–
Insulin mimetic activity	(Borradaile, de Dreu, and Huff 2003)	HepG2 cells	Naringenin 9	200 μM	Insulin (100 nM)	Naringenin 9 ↑ LDL receptor and SREBP-1 expression and ↓ apoB secretion via activating PI3K independent of insulin.	√	x	The active concentration is not achieved under normal physiological conditions (maximum reported 6 μM).
	(Allister et al. 2005)	HepG2 cells	Naringenin 9	100 μM	Insulin (100 nM)	Naringenin 9 ↓ MTP expression, resulting in inhibition of apoB100 secretion.	√	x	The active concentration is not achieved under normal physiological conditions (maximum reported 6 μM).
	(Lim, Soh, and Kuppusamy 2008)	Rat adipocyte primary cells	Naringenin 9	0.01–100 nM	Insulin (1 and 100 µM)	Naringenin 9 (≥0.01 µM) inhibited epinephrine-induced lipolysis by ∼50%, boosted (1 µM) antilipolytic effect of insulin, ↑ glucose uptake in a dose-dependent manner.	√	√	–
	(Zygmunt et al. 2010)	L6 myotubes	Naringenin 9	10–150 μM	Insulin (100 nM)	Naringenin 9 at >50 μM ↑ glucose uptake, independent of insulin via AMPK pathway.	√	x	The active concentration is not achieved under normal physiological conditions (maximum reported 6 μM).
Hepatic glucose homeostasis	(do Nascimento et al. 2018)	Isolated perfused rat liver	Naringenin 9; hesperetin 8; hesperidin 1	100–300 μM	–	All (300 μM) stimulated glycogenolysis and glycolysis. Naringenin 9 and hesperetin 8 inhibited G6P (≥100 µM) and GK (≥50 µM), and mitochondrial respiration linked to ADP phosphorylation. Hesperetin 8 and naringenin 9 (300 μM) inhibited glucose uptake.	x (hesperidin)	x	Hesperidin is not absorbed in its original form. The active concentrations are not achieved under normal physiological conditions (<2.2 and 6 μM for hesperetin 8 and naringenin 9, respectively).
	(Shen, Xu, and Lu 2012)	HepG2 cells	Hesperidin 1; neohesperidin 4; naringin 6; nobiletin 13	10 and 50 μM	Metformin	The flavonoids (≥10 µM) ↑ glucose consumption, glycogen level, hepatic GK activity, and ↓ G6P activity.	x (hesperidin 1, neo-hesperidin 4, naringin 6)	√	Hesperidin 1, neohesperidin 4 and naringin 6 are not absorbed in their original form.
	(Constantin et al. 2014)	Isolated perfused rat liver	Hesperidin 1; hesperetin 8; naringenin 9	25–300 μM	–	Hesperetin 8 and naringenin 9 inhibited hepatic gluconeogenesis from lactate, pyruvate, and alanine, mainly by inhibiting pyruvate carboxylase (IC50 = 134.2 and 143.5 μM, respectively).	x (hesperidin 1)	x	Hesperidin 1 is not absorbed in its original form. The active concentrations are not achieved under normal physiological conditions (< 2.2 and 6 μM for hesperetin 8 and naringenin 9, respectively).
	(Purushotham, Tian, and Belury 2009)	Fao hepatoma cells	Naringenin 9; naringin 6	6–100 µM	Metformin (1 mM)	Naringenin 9 (≥25 μM) significantly ↓ hepatic glucose production in a dose-dependent manner, but not naringin 6.	x (naringin 6)	x	Naringin 6 is not absorbed in its original form. The active concentrations not achieved under normal physiological conditions (maximum for naringenin 9 is 6 μM).

Physiologically relevant test compound and dose (√), and physiologically irrelevant test compound and dose (x). Compounds shown within parenthesis in the column with the (x) sign indicate the corresponding compound.

Abbreviations: ↓ – Decreased; ↑ – Increased; ADP – Adenosine diphosphate; Akt – Protein kinase B; AMPK – 5’ adenosine monophosphate-activated protein kinase; apoB – Apolipoprotein B; ChREBP – Carbohydrate response element-binding protein; DMSO – Dimethyl sulfoxide; DPP-4 – Dipeptidyl-peptidase 4; G6P – Glucose 6-phosphatase; GK – Glucokinase; GLUT1 – Glucose transporter 1; GLUT4 – Glucose transporter 4; GSK-3 – Glycogen synthase kinase-3; Ins1 – Insulin 1;Ins2 – Insulin 2; IRS-1 – Insulin receptor substrate; LDL – Low-density lipoprotein; MCP-1 – Monocyte chemoattractant protein; miR-140 – MicroRNA-140; mRNA – Messenger ribonucleic acid; MTP – Microsomal triglyceride transfer protein; PI3-K – Phosphatidylinositol 3 kinase; PPAR-γ – Peroxisome proliferator-activated receptor gamma; PTP1B – protein tyrosine phosphatase 1B; SREBP-1 – Sterol regulatory element-binding protein; TLR-2 – Toll-like receptor 2; TNF-α – Tumor necrosis factor-α.

Table 3. In vivo studies using animal models on citrus compounds and type 2 diabetes.

Model	Treatment	Challenge	Test duration and route of administration	Test sample and dose	Outcome	References
C57BL/KsJ-db/db type 2 diabetic mice	Control Vs. hesperidin 1 Vs. naringin 6	–	5 weeks, oral	200 mg hesperidin or naringin/kg diet (0.02%)	Hesperidin and naringin ↓ blood glucose, ↑ plasma insulin, C-peptide, leptin, and hepatic glycogen levels, and hepatic GK activity. Naringin also ↓ hepatic G6P and PEPCK activity.	(Jung et al. 2004)
C57BL/KsJ-db/db mice with leptin receptor mutation	Control Vs. hesperidin 1 Vs. naringin 6	–	5 weeks, oral	200 mg hesperidin or naringin/kg diet (0.02%)	Naringin and hesperidin ↑ hepatic GK mRNA, adipocyte GLUT4, hepatic and adipocyte PPARγ expression, and ↓ hepatic GLUT2 protein. Naringin also ↓ mRNA expression of PEPCK and G6P.	(Jung et al. 2006)
Goto-Kakizaki rats with type 2 diabetes	Control Vs. hesperidin 1 Vs. cyclodextrin (CD)-clathrated hesperetin	–	4 weeks, oral	10,000 mg hesperidin 1/kg diet (1%) and 46 g CD-hesperetin /kg diet (4.6%)	Hesperidin 1 and CD-hesperetin normalized blood glucose levels by modulating activities of GK (↑) and G6P (↓); changed PPARs, HMG-CoA reductase, LDL receptor mRNA.	(Akiyama et al. 2009)
STZ-induced marginal type 1 diabetic rats	Control Vs. hesperidin 1	–	4 weeks, oral	10,000 mg hesperidin/kg diet (1 %)	Hesperidin ↓ blood glucose and G6P activity, and ↑serum insulin, adiponectin, and GK activity.	(Akiyama et al. 2010)
STZ-induced diabetic rats	Grapefruit juice	Glucose (3 g/kg bw) intraperitoneal	60 days, oral	3 mL/kg bw grapefruit juice	Improved FBG and glucose intolerance. ↑ hepatic glycogen content and GK activity and ↓ G6P and PEPCK activities.	(Hayanga et al. 2016)
Sprague-Dawley female non-diabetic rats	Control (water) Vs. citrus extract (Citrus macroptera Montr) Vs. glibenclamide	Glucose (1 g/kg bw)	3 hr	500 and 1000 mg/kg bw citrus extract 5 mg /kg bw glibenclamide	Both doses significantly reduced blood glucose after 2 hr. No change was observed after 1 hr of glucose administration compared to the control.	(Uddin et al. 2014)
STZ/NA-induced type 2 diabetic rats	Control Vs. Navel orange peel hydroethanolic extract Vs. naringin 6 Vs. naringenin 9	–	4 weeks, oral	100 mg/kg bw	Improved impaired oral glucose tolerance, ↑ serum insulin and C-peptide levels, and ↓ hepatic glycogenolysis and glucose output. ↑ insulin receptor β-subunit, GLUT4, and adiponectin mRNA in adipose tissues.	(Ahmed et al. 2017)
Wistar albino male rats	Control Vs. naringin 6 Vs. sitagliptin	–	9 days, oral	40 mg/kg bw twice daily	Naringin ↓ serum DPP-4 activity (31%) and blood glucose (53%), and ↑ serum insulin (68%).	(Parmar et al. 2012)
C57BL/6J mice	Control Vs. clarified grapefruit juice Vs. naringin 6 Vs. metformin	High-fat diet	100 days, oral	Clarified grapefruit juice 25 and 50% per day mixed with drinking water Naringin (0.72 mg/day) Metformin (7.5 mg/day)	Grapefruit juice ↓ body weight, liver TG, FBG, and FBI. Naringin ↓ FBG and FBI, but not body weight.	(Chudnovskiy et al. 2014)
High-fat diet-induced obesity/diabetes mouse model	Control Vs. Citrus reticulata Blanco peel extract	High-fat diet	15 weeks, oral	2500 mg (0.25%) and 500 mg (0.5%) citrus extract/kg diet	Citrus extract improved glucose homeostasis, insulin sensitivity, and lipid metabolism.	(Guo et al. 2016)
Healthy Wistar rats	Control Vs. grapefruit extract	Starch or maltose or glucose (2 g/kg bw)	3 hr, oral gastric intubation	500 mg/kg bw grapefruit extract	Grapefruit extract did not significantly reduce postprandial hyperglycemia after maltose or glucose tolerance tests.	(de la Garza et al. 2013)
Insulin resistant Wistar rats	Control Vs. grapefruit extract	High-fat sucrose diet	5 weeks, oral	1000 mg/kg bw grapefruit extract	Grapefruit improved hyperinsulinemia (50%) and HOMA-IR (54%).	(de la Garza et al. 2013)
Fructose induced insulin-resistant rats	Control Vs. naringenin 9	High-fructose diet (60% fructose)	44 days, oral	50 mg naringenin 9/kg bw	Naringenin 9 restored fructose-induced insulin resistance. ↓ FBG, FBI, and HOMA-IR. Further ↑ hepatic and muscle glycogen level, hexokinase, pyruvate kinase activity and ↓ G6P, glycogen phosphorylase, and F16BP activity.	(Kannappan and Anuradha 2010)
C57BL/6J mice with metabolic syndrome	Control Vs. naringin 6	High-fat diet	20 weeks, oral	200 mg naringin/kg diet (0.02%)	Naringin ↓ FBG, FBI, HOMA-IR, serum leptin, TNF-α, hepatic G6P and PEPCK, and ↑ serum adiponectin.	(Pu et al. 2012)
Wistar rats	Control Vs. citrus hybrid Tacle^®	High-fat diet	12 weeks, oral	20 mg extract daily	Citrus intervention ↓ adiposity, LDL-C, TC, TG, and improved insulin sensitivity and glucose tolerance.	(Casacchia et al. 2019)
STZ-induced diabetic rats	Control Vs. tangeretin 12 Vs. glibenclamide	–	75 days, intragastric	25, 50, 100 mg tangeretin 12/kg bw 5 mg glibenclamide/kg bw	100 mg/kg bw tangeretin 12 treatment ↓ FBG, HbA1c and ↑ FBI, hepatic glycogen levels, and altered hepatic enzyme levels to normalcy, comparable to glibenclamide.	(Sundaram, Shanthi, and Sachdanandam 2014)
STZ-induced insulin-resistant diabetic rats	Control Vs. Citrus sinensis fruit peel extract Vs. metformin	High-fat diet	30 days, oral gavage	50 and 100 mg citrus extract/kg bw 100 mg metformin/kg bw	Citrus treatment (50 and 100 mg) ↓ FBG, FBI, and HOMA-IR levels and ↑ PPARγ, GLUT4, and insulin receptor mRNA and protein expression. Effects comparable to metformin.	(Sathiyabama et al. 2018)
C57BL/KsJ-db/db mice with type 2 diabetes	Control Vs. Citrus unshiu peel ethanol extract Vs. rosiglitazone	–	6 weeks, oral	20 mg citrus peel extract/g diet (2%) Rosiglitazone (0.001%)	Citrus extract ↓ weight gain, body fat mass, blood glucose level, hepatic PEPCK, MCP-1, TNF-α, and IL-6 level, and ↑ adiponectin and IL-10 levels.	(Park et al. 2013)
OFA rats with metabolic syndrome	Control Vs. hesperidin 1 and naringenin 9 supplemented biscuit	Obesogenic cafeteria diet	8 weeks, oral	40 mg hesperidin 1 and 20 mg naringenin 9/kg bw	The flavanone supplemented biscuit ↓ systolic blood pressure, serum TC and LDL-C, abdominal obesity, and improved insulin resistance.	(Mayneris-Perxachs et al. 2019)
Fructose-induced insulin resistant hamsters	Control Vs. polymethoxyflavone supplement	Fructose-rich diet (60% fructose)	4 weeks, oral	62.5 and 125 mg/kg bw polymethoxy flavone	PMF (125 mg) improved insulin resistance and glucose tolerance. ↓ expression of TNF-α, IFN-γ, IL-1β, and IL-6 and ↑ serum adiponectin, and hepatic PPARα and PPARγ protein expression.	(R. W. Li et al. 2006)
C57BL/6 J mice	Control Vs. tangeretin 12	High-fat diet	8 weeks, oral	200 mg tangerine/kg diet (0.02%)	Tangeretin 12 improved insulin resistance, ↓ leptin, resistin, adiponectin, MCP-1, and IL-6.	(Kim et al. 2012)
STZ-induced type 2 diabetic rats	Control Vs. naringenin 9 Vs. metformin	High-fat diet	6 weeks, intragastric	50 and 100 mg naringenin 9/kg bw 160 mg metformin/kg bw	Naringenin 9 ↓ FBG and improved insulin resistance. Effect comparable to metformin.	(Ren et al. 2016)
Pancreatic endoderm transplanted pregnant db/+ mice with diabetes	Control Vs. naringenin 9	–	20 days, oral	50 mg/kg bw	Naringenin 9 ↑ serum insulin levels and ↓serum glucose level in pregnant diabetic mice.	(Xing, Yang, and Wu 2016)
STZ/NA-induced diabetic rats	Control Vs. naringenin 9 Vs. glyclazide	–	21 days, oral	50 mg naringenin 9/kg bw 5 mg glyclazide/kg bw	Naringenin 9 ↓ FBG and HbA1c levels and ↑ serum insulin and antioxidant enzyme activities. Effect comparable to glyclazide.	(Annadurai et al. 2012)
LDL receptor-null (Ldlr^-/-) mice with insulin resistance	Control Vs. naringenin 9	High-fat diet	4 weeks, oral	1% and 3% wt/wt naringenin 9 in the diet	Naringenin 9 (3%) ↓insulin resistance and improved glucose tolerance.	(Mulvihill et al. 2009)
LDL receptor-null (Ldlr^-/-) mice with insulin resistance	Control Vs. nobiletin 13	High-fat diet	8 weeks, oral	0.1% and 0.3% wt/wt nobiletin 13 in the diet	Nobiletin 13 (0.3%) ↓ FBG and FBI and ↑ hepatic and peripheral insulin sensitivity.	(Mulvihill et al. 2011)
Obese diabetic ob/ob mice	Control Vs. nobiletin 13	Glucose (2 g/kg bw)	5 weeks, oral gavage	200 mg nobiletin 13/kg bw	Nobiletin 13 ↓ fasting and non-fasting plasma glucose level, HOMA-IR, and ↑ plasma adiponectin levels. ↓ mRNA of IL-6 and MCP-1 and ↑ adiponectin and PPAR-γ in adipose tissues. ↑ GLUT4 and GLUT1 in muscle and adipose.	(Lee et al. 2010)
High-fat diet-fed STZ induced type 2 diabetic rat	Control Vs. naringenin 9	Maltose or sucrose (2 g/kg bw)	2 hr, oral	25 mg naringenin 9/kg bw	Naringenin 9 reduced the total glycemic response (AUC) for both maltose and sucrose by 49%.	(Priscilla et al. 2014)
C57BL/6J mice	Control Vs. naringenin 9	High-fat diet	16 weeks, oral	1% naringenin 9 in the diet	Naringenin 9 ↓ FBG, TNF-α, MCP-1, and TLR2 in adipose tissue.	(Yoshida et al. 2013)
Wistar rats	Control Vs. grapefruit juice	3 g/kg bw of glucose	14 days, oral	3 mL/kg bw grapefruit juice	Grapefruit juice ↓ FBS, and improved glucose tolerance, with no change in insulin. Grapefruit juice did not affect intestinal glucose absorption.	(Owira and Ojewole 2009)
STZ/NA-induced type 2 diabetic rats	Control Vs. naringenin 9 Vs. glibenclamide	2 g/kg of glucose or sucrose	5 days, intragastric	50 mg naringenin 9/kg bw 5 mg glibenclamide /kg bw	Acute and chronic administration of naringenin 9 ↓ glucose intolerance compared to control.	(Ortiz-Andrade et al. 2008)
Pregnant db/+mice with gestational diabetes	Control Vs. naringenin 9	–	7 days, intraperitoneal	50 mg naringenin 9/kg bw	Naringenin 9 ↓ FBG by 15% and improved glucose intolerance by 12.5% and reduced GDM associated inflammation.	(Nguyen‐Ngo, Willcox, and Lappas 2019)
Pregnant C57BLKsJ db/+ mice with gestational diabetes	Control Vs. naringenin 9	Glucose (2 g/kg bw) and insulin (1.0 mU/kg bw)	4 weeks, oral gavage	100 mg naringenin 9/kg bw	Naringenin 9 ↓ FBS, IL-1β, IL-6, TNF-α, and MCP-1, and improved glucose and insulin tolerance.	(Li et al. 2019)
Wistar rats with cadmium-induced pancreatitis	Control Vs. hesperidin 1	–	4 weeks, oral	50 and 100 mg hesperidin/kg bw	Both hesperidin 1 doses ↑ serum insulin and pancreatic antioxidant status and reduced FBG, serum α-amylase, lipase, and inflammatory markers, IL-6, TNF-α, NF-κB, and iNOS.	(Aja et al. 2020)

Abbreviations: ↓ – Decreased; ↑ – Increased; bw – Body weight; DPP-4 – Dipeptidyl peptidase-4; F16BP – Fructose 1,6-bisphosphatase; FBG – Fasting blood glucose; FBI – Fasting blood insulin; GDM – Gestational diabetes mellitus; GK – Glucokinase; GLUT1 – Glucose transporter 1; GLUT2 – Glucose transporter 2; GLUT4 – Glucose transporter 4; HbA1c – Glycosylated hemoglobin; HMG-CoA – 3-hydroxy-3-methylglutaryl coenzyme A; HOMA-IR – Homeostatic model assessment of insulin resistance; IFN-γ – Interferon-gamma; IL-10 – Interleukin 10; IL-1β – Interleukin 1 beta; IL-6 – Interleukin 6; iNOS – Inducible nitric oxide synthase; LDL – Low-density lipoprotein; MCP-1 – Monocyte chemoattractant protein; NF-κB – Nuclear factor Kappa B; PEPCK – Phosphoenolpyruvate carboxykinase; PMF – Polymethoxyflavone; PPARα – Peroxisome proliferator-activated receptor alpha; PPARγ – Peroxisome proliferator-activated receptor gamma; STZ – Streptozotocin; STZ/NA – Streptozotocin-nicotinamide; TC – Total cholesterol; TG – Triglyceride; TLR2 – Toll-like receptor 2; TNF-α – Tumor necrosis factor-α.

Figure 3. Post-absorptive antidiabetic mechanism of citrus (poly)phenols derived from in vitro and animal models. Abbreviations: ↑ – Increase, ↓ – Decrease, PI3-K – Phosphatidylinositol 3 kinase, AMPK – Adenosine monophosphate-activated protein kinase, PPAR-γ – Peroxisome proliferator-activated receptor gamma, GLUT4 – Glucose transporter 4, GK – Glucokinase, PEPCK – Phosphoenolpyruvate carboxykinase, G6P – Glucose-6-phosphatase.

Figure 4. Structures of main hesperetin and naringenin metabolites. Compounds detected in plasma/urine after consuming orange juice, based on data of Pereira-Caro et al. (2014, 2016).

Gattuso, G., D. Barreca, C. Gargiulli, U. Leuzzi, and C. Caristi. 2007. Flavonoid composition of citrus juices. Molecules (Basel, Switzerland) 12 (8):1641–73. doi: 10.3390/12081641.

 PubMed Web of Science ®Google Scholar

Casacchia, T., M. A. Occhiuzzi, F. Grande, B. Rizzuti, M. C. Granieri, C. Rocca, A. Gattuso, A. Garofalo, T. Angelone, and G. Statti. 2019. A pilot study on the nutraceutical properties of the citrus hybrid tacle® as a dietary source of polyphenols for supplementation in metabolic disorders. Journal of Functional Foods 52:370–81. doi: 10.1016/j.jff.2018.11.030.

 Web of Science ®Google Scholar

Uddin, N., M. R. Hasan, M. M. Hossain, A. Sarker, A. H. M. N. Hasan, A. F. M. M. Islam, M. M. H. Chowdhury, M. S. Rana, A. H. M. Nazmul Hasan, A. F. M. Mahmudul Islam, et al. 2014. In vitro α–amylase inhibitory activity and in vivo hypoglycemic effect of methanol extract of Citrus macroptera Montr. fruit. Asian Pacific Journal of Tropical Biomedicine 4 (6):473–9. doi: 10.12980/APJTB.4.2014C1173.

 PubMedGoogle Scholar

Oboh, G., and A. O. Ademosun. 2011. Shaddock peels (Citrus maxima) phenolic extracts inhibit α-amylase, α-glucosidase and angiotensin i-converting enzyme activities: A nutraceutical approach to diabetes management. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 5 (3):148–52. doi: 10.1016/j.dsx.2012.02.008.

 PubMedGoogle Scholar

Alu’datt, M. H., T. Rababah, M. N. Alhamad, M. A. Al-Mahasneh, K. Ereifej, G. Al-Karaki, M. Al-Duais, J. E. Andrade, C. C. Tranchant, S. Kubow, et al. 2017. Profiles of free and bound phenolics extracted from citrus fruits and their roles in biological systems: Content, and antioxidant, anti-diabetic and anti-hypertensive properties. Food & Function 8 (9):3187–97. doi: 10.1039/C7FO00212B.

 PubMed Web of Science ®Google Scholar

Kim, G.-N., J.-G. Shin, and H.-D. Jang. 2009. Antioxidant and antidiabetic activity of dangyuja (Citrus grandis Osbeck) extract treated with aspergillus saitoi. Food Chemistry 117 (1):35–41. doi: 10.1016/j.foodchem.2009.03.072.

 Web of Science ®Google Scholar

Menichini, F., M. R. Loizzo, M. Bonesi, F. Conforti, D. De Luca, G. A. Statti, B. de Cindio, F. Menichini, and R. Tundis. 2011. Phytochemical profile, antioxidant, anti-inflammatory and hypoglycemic potential of hydroalcoholic extracts from Citrus medica l. cv diamante flowers, leaves and fruits at two maturity stages. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association 49 (7):1549–55. doi: 10.1016/j.fct.2011.03.048.

 PubMed Web of Science ®Google Scholar

de la Garza, A. L., U. Etxeberria, M. P. Lostao, B. San Román, J. Barrenetxe, J. A. Martínez, and F. I. Milagro. 2013. Helichrysum and grapefruit extracts inhibit carbohydrate digestion and absorption, improving postprandial glucose levels and hyperinsulinemia in rats. Journal of Agricultural and Food Chemistry 61 (49):12012–9. doi: 10.1021/jf4021569.

 PubMed Web of Science ®Google Scholar

Gong, Y., X.-Y. Qin, Y.-Y. Zhai, H. Hao, J. Lee, and Y.-D. Park. 2017. Inhibitory effect of hesperetin on α-glucosidase: Molecular dynamics simulation integrating inhibition kinetics. International Journal of Biological Macromolecules 101:32–9. doi: 10.1016/j.ijbiomac.2017.03.072.

 PubMed Web of Science ®Google Scholar

Kerimi, A., J. S. Gauer, S. Crabbe, J. W. Cheah, J. Lau, R. Walsh, P. F. Cancalon, and G. Williamson. 2019. Effect of the flavonoid hesperidin on glucose and fructose transport, sucrase activity and glycaemic response to orange juice in a crossover trial on healthy volunteers. The British Journal of Nutrition 121 (7):782–92. doi: 10.1017/S0007114519000084.

 PubMed Web of Science ®Google Scholar

Zheng, M., S. Lu, and J. Xing. 2021. Enhanced antioxidant, anti-inflammatory and α-glucosidase inhibitory activities of citrus hesperidin by acid-catalyzed hydrolysis. Food Chemistry 336:127539. doi: 10.1016/j.foodchem.2020.127539.

 PubMed Web of Science ®Google Scholar

Shen, W., Y. Xu, and Y.-H. Lu. 2012. Inhibitory effects of citrus flavonoids on starch digestion and antihyperglycemic effects in HepG2 cells. Journal of Agricultural and Food Chemistry 60 (38):9609–19. doi: 10.1021/jf3032556.

 PubMed Web of Science ®Google Scholar

Priscilla, D. H., D. Roy, A. Suresh, V. Kumar, and K. Thirumurugan. 2014. Naringenin inhibits α-glucosidase activity: A promising strategy for the regulation of postprandial hyperglycemia in high fat diet fed streptozotocin induced diabetic rats. Chemico-Biological Interactions 210 (1):77–85. doi: 10.1016/j.cbi.2013.12.014.

 PubMedGoogle Scholar

Ali, M. Y., S. Zaib, M. M. Rahman, S. Jannat, J. Iqbal, S. K. Park, and M. S. Chang. 2019. Didymin, a dietary citrus flavonoid exhibits anti-diabetic complications and promotes glucose uptake through the activation of pi3k/akt signaling pathway in insulin-resistant hepg2 cells. Chemico-Biological Interactions 305:180–94. doi: 10.1016/j.cbi.2019.03.018.

 PubMed Web of Science ®Google Scholar

Li, J. M., C. T. Che, C. B. S. Lau, P. S. Leung, and C. H. K. Cheng. 2006. Inhibition of intestinal and renal Na+-glucose cotransporter by naringenin. The International Journal of Biochemistry & Cell Biology 38 (5-6):985–95. doi: 10.1016/j.biocel.2005.10.002.

 PubMed Web of Science ®Google Scholar

Johnston, K., P. Sharp, M. Clifford, and L. Morgan. 2005. Dietary polyphenols decrease glucose uptake by human intestinal Caco-2 cells. FEBS Letters 579 (7):1653–7. doi: 10.1016/j.febslet.2004.12.099.

 PubMed Web of Science ®Google Scholar

Kwon, O., P. Eck, S. Chen, C. P. Corpe, J. Lee, M. Kruhlak, and M. Levine. 2007. Inhibition of the intestinal glucose transporter GLUT2 by flavonoids. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 21 (2):366–77. doi: 10.1096/fj.06-6620com.

 PubMed Web of Science ®Google Scholar

Horiba, T., I. Nishimura, Y. Nakai, K. Abe, and R. Sato. 2010. Naringenin chalcone improves adipocyte functions by enhancing adiponectin production. Molecular and Cellular Endocrinology 323 (2):208–14. doi: 10.1016/j.mce.2010.03.020.

 PubMed Web of Science ®Google Scholar

Rebello, C. J., F. L. Greenway, F. H. Lau, Y. Lin, J. M. Stephens, W. D. Johnson, and A. A. Coulter. 2019. Naringenin promotes thermogenic gene expression in human white adipose tissue. Obesity 27 (1):103–11. doi: 10.1002/oby.22352.

 PubMed Web of Science ®Google Scholar

Murugesan, N., K. Woodard, R. Ramaraju, F. L. Greenway, A. A. Coulter, and C. J. Rebello. 2020. Naringenin increases insulin sensitivity and metabolic rate: A case study. Journal of Medicinal Food 23 (3):343–8. doi: 10.1089/jmf.2019.0216.

 PubMed Web of Science ®Google Scholar

Zhao, C., C. Zhao, and H. Zhao. 2020. Defective insulin receptor signaling in patients with gestational diabetes is related to dysregulated miR-140 which can be improved by naringenin. The International Journal of Biochemistry & Cell Biology 128:105824. doi: 10.1016/j.biocel.2020.105824. PMC: 32814161.

 PubMed Web of Science ®Google Scholar

Richard, A. J., Z. Amini-Vaughan, D. M. Ribnicky, and J. M. Stephens. 2013. Naringenin inhibits adipogenesis and reduces insulin sensitivity and adiponectin expression in adipocytes. Evidence-Based Complementary and Alternative Medicine: eCAM 2013:549750–10. doi: 10.1155/2013/549750.

 PubMed Web of Science ®Google Scholar

Harmon, A. W., and Y. M. Patel. 2003. Naringenin inhibits phosphoinositide 3-kinase activity and glucose uptake in 3T3-L1 adipocytes. Biochemical and Biophysical Research Communications 305 (2):229–34. doi: 10.1016/S0006-291X(03)00720-4.

 PubMed Web of Science ®Google Scholar

Yoshida, H., W. Watanabe, H. Oomagari, E. Tsuruta, M. Shida, and M. Kurokawa. 2013. Citrus flavonoid naringenin inhibits TLR2 expression in adipocytes. The Journal of Nutritional Biochemistry 24 (7):1276–84. doi: 10.1016/j.jnutbio.2012.10.003.

 PubMed Web of Science ®Google Scholar

Yang, Y., J. Wolfram, K. Boom, X. Fang, H. Shen, and M. Ferrari. 2013. Hesperetin impairs glucose uptake and inhibits proliferation of breast cancer cells. Cell Biochemistry and Function 31 (5):374–9. doi: 10.1002/cbf.2905.

 PubMed Web of Science ®Google Scholar

Claussnitzer, M., T. Skurk, H. Hauner, H. Daniel, and M. J. Rist. 2011. Effect of flavonoids on basal and insulin-stimulated 2-deoxyglucose uptake in adipocytes. Molecular Nutrition & Food Research 55 (S1):S26–S34. doi: 10.1002/mnfr.201000372.

 PubMedGoogle Scholar

Liu, L., S. Shan, K. Zhang, Z.-Q. Ning, X.-P. Lu, and Y.-Y. Cheng. 2008. Naringenin and hesperetin, two flavonoids derived from citrus aurantium up-regulate transcription of adiponectin. Phytotherapy Research: PTR 22 (10):1400–3. doi: 10.1002/ptr.2504.

 PubMed Web of Science ®Google Scholar

Park, J. B. 1999. Flavonoids are potential inhibitors of glucose uptake in U937 cells. Biochemical and Biophysical Research Communications 260 (2):568–74. doi: 10.1006/bbrc.1999.0890.

 PubMed Web of Science ®Google Scholar

Nomura, M., T. Takahashi, N. Nagata, K. Tsutsumi, S. Kobayashi, T. Akiba, K. Yokogawa, S. Moritani, and K. Miyamoto. 2008. Inhibitory mechanisms of flavonoids on insulin-stimulated glucose uptake in MC3T3-G2/PA6 adipose cells. Biological & Pharmaceutical Bulletin 31 (7):1403–9. doi: 10.1248/bpb.31.1403.

 PubMed Web of Science ®Google Scholar

Onda, K., N. Horike, T. Suzuki, and T. Hirano. 2013. Polymethoxyflavonoids tangeretin and nobiletin increase glucose uptake in murine adipocytes. Phytotherapy Research: PTR 27 (2):312–6. doi: 10.1002/ptr.4730.

 PubMed Web of Science ®Google Scholar

Kim, M. S., H. J. Hur, D. Y. Kwon, and J.-T. Hwang. 2012. Tangeretin stimulates glucose uptake via regulation of AMPK signaling pathways in C2C12 myotubes and improves glucose tolerance in high-fat diet-induced obese mice. Molecular and Cellular Endocrinology 358 (1):127–34. doi: 10.1016/j.mce.2012.03.013.

 PubMed Web of Science ®Google Scholar

Miyata, Y., H. Tanaka, A. Shimada, T. Sato, A. Ito, T. Yamanouchi, and H. Kosano. 2011. Regulation of adipocytokine secretion and adipocyte hypertrophy by polymethoxyflavonoids, nobiletin and tangeretin. Life Sciences 88 (13-14):613–8. doi: 10.1016/j.lfs.2011.01.024.

 PubMed Web of Science ®Google Scholar

Saito, T., D. Abe, and K. Sekiya. 2007. Nobiletin enhances differentiation and lipolysis of 3T3-L1 adipocytes. Biochemical and Biophysical Research Communications 357 (2):371–6. doi: 10.1016/j.bbrc.2007.03.169.

 PubMed Web of Science ®Google Scholar

Kanda, K., K. Nishi, A. Kadota, S. Nishimoto, M. C. Liu, and T. Sugahara. 2012. Nobiletin suppresses adipocyte differentiation of 3T3-L1 cells by an insulin and ibmx mixture induction. Biochimica et Biophysica Acta 1820 (4):461–8. doi: 10.1016/j.bbagen.2011.11.015.

 PubMed Web of Science ®Google Scholar

Kunimasa, K., S. Kuranuki, N. Matsuura, N. Iwasaki, M. Ikeda, A. Ito, Y. Sashida, Y. Mimaki, M. Yano, M. Sato, et al. 2009. Identification of nobiletin, a polymethoxyflavonoid, as an enhancer of adiponectin secretion. Bioorganic & Medicinal Chemistry Letters 19 (7):2062–4. doi: 10.1016/j.bmcl.2009.02.002.

 PubMed Web of Science ®Google Scholar

Gamo, K., H. Miyachi, K. Nakamura, and N. Matsuura. 2014. Hesperetin glucuronides induce adipocyte differentiation via activation and expression of peroxisome proliferator-activated receptor-γ. Bioscience, Biotechnology, and Biochemistry 78 (6):1052–9. doi: 10.1080/09168451.2014.910097.

 PubMed Web of Science ®Google Scholar

Nguyen‐Ngo, C., J. C. Willcox, and M. Lappas. 2019. Anti-diabetic, anti-inflammatory, and anti-oxidant effects of naringenin in an in vitro human model and an in vivo murine model of gestational diabetes mellitus. Molecular Nutrition & Food Research 63 (19):e1900224. doi: 10.1002/mnfr.201900224.

 PubMed Web of Science ®Google Scholar

Li, S., Y. Zhang, Y. Sun, G. Zhang, J. Bai, J. Guo, X. Su, H. Du, X. Cao, J. Yang, et al. 2019. Naringenin improves insulin sensitivity in gestational diabetes mellitus mice through AMPK. Nutrition & Diabetes 9 (1):28. doi: 10.1038/s41387-019-0095-8.

 PubMedGoogle Scholar

Gupta, A., G. A. Jacobson, J. R. Burgess, H. F. Jelinek, D. S. Nichols, C. K. Narkowicz, and H. A. Al-Aubaidy. 2018. Citrus bioflavonoids dipeptidyl peptidase-4 inhibition compared with gliptin antidiabetic medications. Biochemical and Biophysical Research Communications 503 (1):21–5. doi: 10.1016/j.bbrc.2018.04.156.

 PubMed Web of Science ®Google Scholar

Fan, J., M. H. Johnson, M. A. Lila, G. Yousef, and E. G. de Mejia. 2013. Berry and citrus phenolic compounds inhibit dipeptidyl peptidase iv: Implications in diabetes management. Evidence-Based Complementary and Alternative Medicine: eCAM 2013:479505–13. doi: 10.1155/2013/479505.

 PubMed Web of Science ®Google Scholar

Parmar, H. S., P. Jain, D. S. Chauhan, M. K. Bhinchar, V. Munjal, M. Yusuf, K. Choube, A. Tawani, V. Tiwari, E. Manivannan, et al. 2012. DPP-iv inhibitory potential of naringin: An in silico, in vitro and in vivo study. Diabetes Research and Clinical Practice 97 (1):105–11. doi: 10.1016/j.diabres.2012.02.011.

 PubMed Web of Science ®Google Scholar

Xing, B., F. Yang, and X. Wu. 2016. Naringenin enhances the efficacy of human embryonic stem cell-derived pancreatic endoderm in treating gestational diabetes mellitus mice. Journal of Pharmacological Sciences 131 (2):93–100. doi: 10.1016/j.jphs.2016.04.014.

 PubMed Web of Science ®Google Scholar

Bhattacharya, S., N. Oksbjerg, J. F. Young, and P. B. Jeppesen. 2014. Caffeic acid, naringenin and quercetin enhance glucose-stimulated insulin secretion and glucose sensitivity in ins-1e cells. Diabetes, Obesity & Metabolism 16 (7):602–12. doi: 10.1111/dom.12236.

 PubMed Web of Science ®Google Scholar

Borradaile, N. M., L. E. de Dreu, and M. W. Huff. 2003. Inhibition of net hepg2 cell apolipoprotein b secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation. Diabetes 52 (10):2554–61. doi: 10.2337/diabetes.52.10.2554.

 PubMed Web of Science ®Google Scholar

Allister, E. M., N. M. Borradaile, J. Y. Edwards, and M. W. Huff. 2005. Inhibition of microsomal triglyceride transfer protein expression and apolipoprotein b100 secretion by the citrus flavonoid naringenin and by insulin involves activation of the mitogen-activated protein kinase pathway in hepatocytes. Diabetes 54 (6):1676–83. doi: 10.2337/diabetes.54.6.1676.

 PubMed Web of Science ®Google Scholar

Lim, S., K. Soh, and U. Kuppusamy. 2008. Effects of naringenin on lipogenesis, lipolysis and glucose uptake in rat adipocyte primary culture: A natural antidiabetic agent. The Internet Journal of Alternative Medicine 5 (2):1–5. doi: 10.5580/22f3.

 Google Scholar

Zygmunt, K., B. Faubert, J. MacNeil, and E. Tsiani. 2010. Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK. Biochemical and Biophysical Research Communications 398 (2):178–83. doi: 10.1016/j.bbrc.2010.06.048.

 PubMed Web of Science ®Google Scholar

do Nascimento, G. S., R. P. Constantin, E. H. Gilglioni, C. V. de Castro Ghizoni, A. Bracht, K. S. Utsunomiya, N. S. Yamamoto, E. L. Ishii-Iwamoto, J. Constantin, and R. P. Constantin. 2018. The acute effects of citrus flavanones on the metabolism of glycogen and monosaccharides in the isolated perfused rat liver. Toxicology Letters 291:158–72. doi: 10.1016/j.toxlet.2018.04.001.

 PubMed Web of Science ®Google Scholar

Constantin, R. P., R. P. Constantin, A. Bracht, N. S. Yamamoto, E. L. Ishii-Iwamoto, and J. Constantin. 2014. Molecular mechanisms of citrus flavanones on hepatic gluconeogenesis. Fitoterapia 92:148–62. doi: 10.1016/j.fitote.2013.11.003.

 PubMed Web of Science ®Google Scholar

Purushotham, A., M. Tian, and M. A. Belury. 2009. The citrus fruit flavonoid naringenin suppresses hepatic glucose production from fao hepatoma cells. Molecular Nutrition & Food Research 53 (2):300–7. doi: 10.1002/mnfr.200700514.

 PubMed Web of Science ®Google Scholar

Jung, U. J., M.-K. Lee, K.-S. Jeong, and M.-S. Choi. 2004. The hypoglycemic effects of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KsJ-db/db mice. The Journal of Nutrition 134 (10):2499–503. doi: 10.1093/jn/134.10.2499.

 PubMed Web of Science ®Google Scholar

Jung, U. J., M.-K. Lee, Y. B. Park, M. A. Kang, and M.-S. Choi. 2006. Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. The International Journal of Biochemistry & Cell Biology 38 (7):1134–45. doi: 10.1016/j.biocel.2005.12.002.

 PubMed Web of Science ®Google Scholar

Akiyama, S., S.-I. Katsumata, K. Suzuki, Y. Nakaya, Y. Ishimi, and M. Uehara. 2009. Hypoglycemic and hypolipidemic effects of hesperidin and cyclodextrin-clathrated hesperetin in goto-kakizaki rats with type 2 diabetes. Bioscience, Biotechnology, and Biochemistry 73 (12):2779–82. doi: 10.1271/bbb.90576.

 PubMed Web of Science ®Google Scholar

Akiyama, S., S. I. Katsumata, K. Suzuki, Y. Ishimi, J. Wu, and M. Uehara. 2010. Dietary hesperidin exerts hypoglycemic and hypolipidemic effects in streptozotocin-induced marginal type 1 diabetic rats. Journal of Clinical Biochemistry and Nutrition 46 (1):87–92. doi: 10.3164/jcbn.09-82.

 PubMed Web of Science ®Google Scholar

Hayanga, J. A., S. P. Ngubane, A. N. Murunga, and P. M. O. Owira. 2016. Grapefruit juice improves glucose intolerance in streptozotocin-induced diabetes by suppressing hepatic gluconeogenesis. European Journal of Nutrition 55 (2):631–8. doi: 10.1007/s00394-015-0883-4.

 PubMed Web of Science ®Google Scholar

Ahmed, O. M., M. A. Hassan, S. M. Abdel-Twab, and M. N. Abdel Azeem. 2017. Navel orange peel hydroethanolic extract, naringin and naringenin have anti-diabetic potentials in type 2 diabetic rats. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 94:197–205. doi: 10.1016/j.biopha.2017.07.094.

 PubMed Web of Science ®Google Scholar

Chudnovskiy, R., A. Thompson, K. Tharp, M. Hellerstein, J. L. Napoli, and A. Stahl. 2014. Consumption of clarified grapefruit juice ameliorates high-fat diet induced insulin resistance and weight gain in mice. Ed. Makoto Makishima. PLoS One 9 (10):e108408. doi: 10.1371/journal.pone.0108408.

 PubMed Web of Science ®Google Scholar

Guo, J., H. Tao, Y. Cao, C.-T. Ho, S. Jin, and Q. Huang. 2016. Prevention of obesity and type 2 diabetes with aged citrus peel (Chenpi) extract. Journal of Agricultural and Food Chemistry 64 (10):2053–61. doi: 10.1021/acs.jafc.5b06157.

 PubMed Web of Science ®Google Scholar

Kannappan, S., and C. V. Anuradha. 2010. Naringenin enhances insulin-stimulated tyrosine phosphorylation and improves the cellular actions of insulin in a dietary model of metabolic syndrome. European Journal of Nutrition 49 (2):101–9. doi: 10.1007/s00394-009-0054-6.

 PubMed Web of Science ®Google Scholar

Pu, P., D.-M. Gao, S. Mohamed, J. Chen, J. Zhang, X.-Y. Zhou, N.-J. Zhou, J. Xie, and H. Jiang. 2012. Naringin ameliorates metabolic syndrome by activating amp-activated protein kinase in mice fed a high-fat diet. Archives of Biochemistry and Biophysics 518 (1):61–70. doi: 10.1016/j.abb.2011.11.026.

 PubMed Web of Science ®Google Scholar

Sundaram, R., P. Shanthi, and P. Sachdanandam. 2014. Effect of tangeretin, a polymethoxylated flavone on glucose metabolism in streptozotocin-induced diabetic rats. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology 21 (6):793–9. doi: 10.1016/j.phymed.2014.01.007.

 PubMed Web of Science ®Google Scholar

Sathiyabama, R. G., G. Rajiv Gandhi, M. Denadai, G. Sridharan, G. Jothi, P. Sasikumar, J. d. S. Siqueira Quintans, N. Narain, L. E. Cuevas, et al. 2018. Evidence of insulin-dependent signalling mechanisms produced by Citrus sinensis (l.) Osbeck fruit peel in an insulin resistant diabetic animal model. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association 116 (Pt B):86–99. doi: 10.1016/j.fct.2018.03.050.

 PubMedGoogle Scholar

Park, H.-J., U. J. Jung, S.-J. Cho, H.-K. Jung, S. Shim, and M.-S. Choi. 2013. Citrus unshiu peel extract ameliorates hyperglycemia and hepatic steatosis by altering inflammation and hepatic glucose- and lipid-regulating enzymes in db/db mice. The Journal of Nutritional Biochemistry 24 (2):419–27. doi: 10.1016/j.jnutbio.2011.12.009.

 PubMed Web of Science ®Google Scholar

Mayneris-Perxachs, J., J. M. Alcaide-Hidalgo, E. de la Hera, J. M. del Bas, L. Arola, and A. Caimari. 2019. Supplementation with biscuits enriched with hesperidin and naringenin is associated with an improvement of the metabolic syndrome induced by a cafeteria diet in rats. Journal of Functional Foods 61:103504. doi: 10.1016/j.jff.2019.103504.

 Web of Science ®Google Scholar

Ren, B., W. Qin, F. Wu, S. Wang, C. Pan, L. Wang, B. Zeng, S. Ma, and J. Liang. 2016. Apigenin and naringenin regulate glucose and lipid metabolism, and ameliorate vascular dysfunction in type 2 diabetic rats. European Journal of Pharmacology 773:13–23. doi: 10.1016/j.ejphar.2016.01.002.

 PubMed Web of Science ®Google Scholar

Annadurai, T., A. R. Muralidharan, T. Joseph, M. J. Hsu, P. A. Thomas, and P. Geraldine. 2012. Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin-nicotinamide-induced experimental diabetic rats. Journal of Physiology and Biochemistry 68 (3):307–18. doi: 10.1007/s13105-011-0142-y.

 PubMed Web of Science ®Google Scholar

Mulvihill, E. E., E. M. Allister, B. G. Sutherland, D. E. Telford, C. G. Sawyez, J. Y. Edwards, J. M. Markle, R. A. Hegele, and M. W. Huff. 2009. Naringenin prevents dyslipidemia, apolipoprotein b overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes 58 (10):2198–210. doi: 10.2337/db09-0634.

 PubMed Web of Science ®Google Scholar

Mulvihill, E. E., J. M. Assini, J. K. Lee, E. M. Allister, B. G. Sutherland, J. B. Koppes, C. G. Sawyez, J. Y. Edwards, D. E. Telford, A. Charbonneau, et al. 2011. Nobiletin attenuates VLDL overproduction, dyslipidemia, and atherosclerosis in mice with diet-induced insulin resistance. Diabetes 60 (5):1446–57. doi: 10.2337/db10-0589.

 PubMed Web of Science ®Google Scholar

Lee, Y.-S., B.-Y. Cha, K. Saito, H. Yamakawa, S.-S. Choi, K. Yamaguchi, T. Yonezawa, T. Teruya, K. Nagai, and J.-T. Woo. 2010. Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice. Biochemical Pharmacology 79 (11):1674–83. doi: 10.1016/j.bcp.2010.01.034.

 PubMed Web of Science ®Google Scholar

Owira, P. M. O., and J. A. O. Ojewole. 2009. Grapefruit juice improves glycemic control but exacerbates metformin-induced lactic acidosis in non-diabetic rats. Methods and Findings in Experimental and Clinical Pharmacology 31 (9):563–70. doi: 10.1358/mf.2009.31.9.1435463.

 PubMed Web of Science ®Google Scholar

Ortiz-Andrade, R. R., J. C. Sánchez-Salgado, G. Navarrete-Vázquez, S. P. Webster, M. Binnie, S. García-Jiménez, I. León-Rivera, P. Cigarroa-Vázquez, R. Villalobos-Molina, and S. Estrada-Soto. 2008. Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulation. Diabetes, Obesity and Metabolism 10 (11):1097–104. doi: 10.1111/j.1463-1326.2008.00869.x.

 PubMed Web of Science ®Google Scholar

Aja, P. M., F. I. Izekwe, A. C. Famurewa, E. U. Ekpono, F. E. Nwite, I. O. Igwenyi, J. N. Awoke, O. G. Ani, C. Aloke, N. A. Obasi, et al. 2020. Hesperidin protects against cadmium-induced pancreatitis by modulating insulin secretion, redox imbalance and inos/nf-ĸb signaling in rats. Life Sciences 259:118268. doi: 10.1016/j.lfs.2020.118268.

 PubMed Web of Science ®Google Scholar

Pereira-Caro, G., G. Borges, J. van der Hooft, M. N. Clifford, D. Del Rio, M. E. J. Lean, S. A. Roberts, M. B. Kellerhals, and A. Crozier. 2014. Orange juice (poly)phenols are highly bioavailable in humans. The American Journal of Clinical Nutrition 100 (5):1378–84. doi: 10.3945/ajcn.114.090282.

 PubMed Web of Science ®Google Scholar

Pereira-Caro, G., I. A. Ludwig, T. Polyviou, D. Malkova, A. García, J. M. Moreno-Rojas, and A. Crozier. 2016. Identification of plasma and urinary metabolites and catabolites derived from orange juice (poly)phenols: Analysis by high-performance liquid chromatography-high-resolution mass spectrometry. Journal of Agricultural and Food Chemistry 64 (28):5724–35. doi: 10.1021/acs.jafc.6b02088.

 PubMed Web of Science ®Google Scholar