Anthocyanins’ effects on diabetes mellitus and islet transplantation

Figures & data

Figure 1. The structure of the anthocyanin backbone and the most common anthocyanins.

Table 1. the anti-T2DM effect of anthocyanins in clinical trial.

Subject(numbers)	Study design	intervention duration	Administered Form and dosage of anthocyanins	Main results	references
Obese adults(n = 36)	Randomized crossover study	1 week	Anthocyanin-Rich Mixed-Berry; 143.5 mg/d	↓serum insulin area under the curve	(Solverson et al. 2019)
Adults with insulin resistance (n = 21)	Randomized, single-blinded controlled study	6 hours	freeze-dried whole strawberry powder	↓Postmeal insulin concentrations ↓ Oxidized low-density lipoprotein	(Park et al. 2016)
Adults with prediabetes or newly diagnosed diabetes (n = 160)	Randomized controlled study	12 weeks	Anthocyanins 320 mg/d	↑ adipsin and apoA-1 ↓ visfatin, HbA1c, and apo B	(Yang et al. 2021)
Adults with prediabetes or early untreated diabetes (n = 138)	Randomized, double-blinded controlled study	12 weeks	Purified anthocyanins 320 mg/d	↓ HbA1c, LDL-c, and apo B ↑ apoA-1	(Yang et al. 2017)
Adults with prediabetes or newly diagnosed diabetes (n = 160)	Randomized controlled study	12 weeks	Anthocyanins 320 mg/d	↑adiponectin ↓fasting glucose (in newly diagnosed diabetes)	(Yang et al. 2020)
Adults with prediabetes (n = 36)	Randomized controlled study	3 weeks	Delphinol standardized maqui berry extract 0,60 ,120, 180 mg/d	↓ basal glycemia and insulinemia	(Alvarado, Leschot, et al. 2016)
Adults with impaired glucose intolerance (n = 10)	Randomized controlled study	12 hours	Delphinol standardized maqui berry extract; 200 mg/d	↓post prandial blood glucose and insulin	(Hidalgo et al. 2014)
Adults with obese andinsulin resistant (n = 32)	Randomized, double-blinded controlled study	6 weeks	blueberry bioactives; 45g/d	↑ insulin sensitivity	(Stull et al. 2010)
Adults with diagnose, moderate glucose intolerance (n = 31)	Randomized controlled study	3 mouths	maqui berry extract Delphinol 180 mg/d	↓ HbA1c and LDL ↑ HDL	(Alvarado, Schoenlau, et al. 2016)
Healthy volunteers (n = 14) T2DM (n = 12) T2DM-at-risk (n = 14)	Case-control study	4 weeks	Bilberries and Black currants; 320 mg/d	↓plasma IL-6, IL-8, TNF-α ↑IL-10 and adiponectin ↓fasting blood glucose ↓LDL-cholesterol	(Nikbakht et al. 2021)
T2DM (n = 20)	Randomized, double-blinded controlled study	4 weeks	Bilberry extract; 1.4 g/d	No significant differences across treatments	(Chan et al. 2021)
Obese male volunteers with T2DM (n = 8)	Randomized, double-blinded controlled study	2 weeks	Bilberry extract; 50g	↓AUC for both glucose and insulin	(Hoggard et al. 2013)
Adults with T2DM (n = 37)	Randomized, double-blind controlled study	2 months	Whortleberry fruit hydroalcoholic extract; 1.05 g/d	↓blood levels of fasting glucose, 2-h postprandial glucose, and HbA1c	(Kianbakht, Abasi, and Dabaghian 2013)
Adults with T2DM (n = 58)	Randomized, double-blinded controlled study	4 weeks	Purified anthocyanin; 320 mg/d	↓LDL cholesterol, triglycerides, apolipoprotein (apo) B-48, and apo C-III ↑HDL cholesterol ↑ Antioxidant capacity ↓fasting plasma glucose and homeostasis model assessment for insulin resistance index ↑adiponectin and β-hydroxybutyrate	(Li et al. 2015)
Female with T2DM (n = 36)	Randomized, double-blind controlled study	6 weeks	Freeze-dried strawberry; 100 g/d	↓C-reactive protein levels and lipid peroxidation ↓HbA1c and total antioxidant status	(Moazen et al. 2013)
Healthy volunteers(n = 50) T2D (n = 85)	Case-control study	3 hours	Pomegranate juice; 1.5 mL / kg	↓ fasting serum glucose and insulin resistance ↑β-cell function	(Banihani et al. 2014)
Obese volunteers with T2DM (n = 16)	Randomized crossover study	3 weeks	bilberry extract; 0.47g/d	↓ OGTT venous plasma glucose AUCi	(Alnajjar et al. 2020)

Table 2. Anti-T2DM of anthocyanins in animal trial.

Subject(numbers)	Study design	intervention duration	Administered Form and dosage of anthocyanins	Main results	Mechanism	references
T2DM mice (KK-A^y mice)	Randomized controlled study	5 weeks	Bilberry extract; 10g/kg	↓ blood glucose ↑ insulin sensitivity ↓ glucose production and lipid content in the liver	↑ activation of AMPK signaling pathway ↑the expression of PPARα and Acox	(Takikawa et al. 2010)
T2DM mice (C57BL/6J mice fed a high fat diet)	Randomized controlled study	6 hours	Delphinidin 3-sambubioside-5-glucoside of maqui berry; 50 − 500 mg/kg	↓ fasting blood glucose levels ↑ glucose tolerance	↑ the expression of CPT1A ↓ the expression of acetyl-CoA carboxylase	(Rojo et al. 2012)
T2DM mice (KK-A^y mice) (n = 18)	Controlled study	7 weeks	Blackcurrant extract; 11 g/kg	↓ blood glucose ↑ glucose tolerance	↑activation of AMPK signaling pathway ↑the expression of GLP-1 concentration ↑ PC1/3	(Iizuka et al. 2018)
Mice with metabolic syndrome (C57BL/6J mice fed a high palatable diet )	Controlled study	150 days	blueberry fruit extract; 200 mg/kg	↓ insulin resistance ↓ body weight gain ↓visceral fat, blood glucose, TC and TG	NA	(Oliveira et al. 2017)
C57BL/KsJ-db/db mice (n = 24)	Controlled study	6 weeks	Mulberry fruit extract; 0.2%, w/w	↓ blood glucose, HbA1c, and insulin levels ↓ plasma lipid concentration	↑activation of AMPK signaling pathway ↓ the expression of G6Pase and PCK in the liver	(Choi et al. 2016)
T2DM mice (C57BL/6J mice fed a high fat diet)	Controlled study	5 weeks	cyanidin 3-glucoside; 0.2% of diet	↓ blood glucose ↑ insulin sensitivity ↓TC and steatosis in liver ↓ inflammation levels	↓the cJNK/FoxO1 signaling pathway ↓ the expression of TNF-α, IL-6, and MCP-1	(Guo, Xia, et al. 2012)
T2DM mice (KK-A^y mice) (n = 16)	Controlled study	6 weeks	Black soybean seed coat extract;22 g/kg	↓ blood glucose ↑ insulin sensitivity	↑activation of AMPK signaling pathway	(Kurimoto et al. 2013)
T2DM mice (KK-A^y mice)(n = 16)	Controlled study	5 weeks	Cyanidin 3-glucoside; 0.2% of diet	↓ blood glucose ↑ insulin sensitivity	↑ the expression of GLUT4 ↓ the expression of RBP4	(Sasaki et al. 2007)
Mice fed a high-fat, high-calorie diet	Randomized controlled study	10 weeks	Juçara freeze-dried powder ; 5 g, 20 g/kg	↓ blood glucose ↓ catalase activity and IL-10 level in epididymal adipose tissue	NA	(Oyama et al. 2016)
T2DM mice(C57BL/KsJ-leprdb/leprdb)	Randomized controlled study	21 days	Buckwheat sprouts; 0%, 5%, or 10% of diet	↓ TC, TG, TBARS, and lipids ↓ HbA1c and arteriosclerotic index	↑ the expressions of HMG-CoAR and CYP7A1 (CYP7A1> HMG-CoAR)	(Watanabe and Ayugase 2010)
T2DM mice (STZ- induced diabetic mice)	Randomized controlled study	4 weeks	Padus racemose.	↓ blood glucose ↓ triglyceride, cholesterol, and HDL	NA	(Liu et al. 2020)
T2DM mice (STZ- induced diabetic mice)	Randomized controlled study	4 weeks	Black soybean seed coat extract; 100, 200, 400 mg/kg/day	↓ fasting blood glucose levels ↓ insulin levels and HOMA-IR ↑ HOMA-β ↑ glycogen content in liver and muscle ↓ NEFA, TG, and TC ↑ HDL-c level ↓liver, kidney and pancreas damage	↑ the enzyme activity of SOD, CAT, GPX	(Chen et al. 2018)
T2DM mice (C57BL/6J genetic background)	Randomized controlled study	5 weeks	blueberry anthocyanin extract; 100,400 mg/kg	↓ fasting blood glucose levels ↓ TC and TG levels ↓ insulin level ↑ liver antioxidant	↑ activation of AMPK signaling pathway ↑ the expressions of Glut2 ↑the enzyme activity of SOD ↓ the expressions of PGC1α, FoxO1, PEPCK, G6Pase	(Herrera-Balandrano et al. 2021)
T2DM mice (KK-A^y mice) and health mice (C57BL/6JmsSlc mice)	Randomized controlled study	4 weeks	aronia juice;	↓ blood glucose ↓ body weights ↓ weights of white adipose tissues	↓ DPP IV activity ↓ α-glucosidase activity in the upper portion of the small intestine to decrease GIP level	(Yamane et al. 2016)
T2DM mice (STZ- induced diabetic mice)	Randomized controlled study	12 weeks	Purple Sweet Potato; 200, 500 mg/kg	↓ blood glucose ↑ glucose tolerance ↓ LDL-c, TG, and TC ↑ HDL-c level ↓ liver damage ↑ antioxidant capacity ↓ level of MDA	↑ protein level of INSR ↑ the enzyme activity of SOD, CAT, GPX ↑ the expressions of PK, PFK, GLUT2 ↓ G6Pase and PEPCK ↑ activation of AMPK signaling pathway	(Jiang et al. 2020)
T2DM mice (C57BL/6J genetic background)	Randomized controlled study	8 weeks	Mulberry anthocyanin extract; 50, 125 mg/kg	↓ fasting blood glucose levels ↓ the level of insulin, TC, TG, and leptin ↑ the level of adiponectin	↑activating AKT and downstream targets in liver, skeletal muscle and adipose tissues ↑ mRNA expression of PCG-1α and FoxO1 to inhibit the activities of PEPCK and G6Pase ↑ activating AKT and GSK3β to upregulate GYS2	(Yan, Dai, and Zheng 2016)
T2DM mice (C57BL/6J genetic background)	Randomized controlled study	6 weeks	Cyanidin-3-O-glucoside; 150 mg/kg	↓ fasting blood glucose levels ↓ accumulation of liver lipids ↑ glycogen synthesis	↑ GLUT-1 via the Wnt/β-catenin-WISP1 signaling pathway	(Ye et al. 2022)
T2DM mice (n = 16)	Randomized controlled study	30 days	Black soybean seed coat extract; 30 mg/kg	↓the body and white adipose tissue weight ↓the size of adipocytes	↑ gene expression of PPARγ and C/EBPα ↑ adiponectin secretion	(Matsukawa et al. 2015)
T2DM mice	Randomized controlled study	8 weeks	Cyanidin-3-O-β-glucoside; 2 g/kg	↑endothelium-dependent relaxation of the aorta	↑ adiponectin expression and secretion by promoting FoxO1expression	(Liu et al. 2014)
T2DM mice (C57BL/6J genetic background) (n = 18)	Randomized controlled study	6 weeks	Cyanidin-3-O-glucoside; 150 mg/kg	↓ fasting blood glucose levels and body weight gain ↓ pancreas damage ↓ the level of ROS	↑ activating mitophagy via the PINK1-PARKIN signaling pathway ↑the enzyme activities of SOD and CAT.	(Ye et al. 2021)

AMPK: AMP-activated protein kinase; CPT1A: carnitine palmitoyl-transferase-1A; Acox: Acyl-CoA Oxidase; GLP-1: Glucagon-like peptide-1; PC1/3: prohormone convertase 1/3; G6Pase: glucose 6-phosphatase; PCK: Phosphoenolpyruvate carboxykinase; cJNK/FoxO1: c-Jun N-terminal kinase/forkhead box O1; Glut: glucose transporter; RBP4: retinol binding protein 4; HMG-CoAR: the 3-hydroxy-3-methylglutaryl-CoA reductase; CYP7A1: cholesterol 7α-hydroxylase; SOD: Superoxide Dismutase;CAT: catalase; GPX: Glutathione peroxidase; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PEPCK: Phosphoenolpyruvate carboxykinase; INSR: Insulin Receptor; PFK: Phosphofructokinase; GSK3β: Glycogen Synthase Kinase 3β; GYS2: Glycogen Synthase 2; C/EBPα: CCAAT enhancer-binding protein; PINK1: PTEN-induced kinase 1.

Figure 2. The mechanism of health benefits of anthocyanins on diabetes mellitus and pancreatic islets.

NF-κB: nuclear factor kappa-B; cJNK: c-Jun N-terminal kinase; AMPK: AMP-activated protein kinase; GLP-1: Glucagon-like peptide-1; PC1/3: prohormone convertase 1/3; FoxO1: forkhead box O1; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; GSK3β: Glycogen Synthase Kinase 3β; GYS2: Glycogen Synthase 2; G6Pase: glucose 6-phosphatase; PEPCK: Phosphoenolpyruvate carboxykinase; ATGL: Adipose triglyceride lipase; CPT-1: Carnitine palmitoyl transferase I; PPAR: peroxisome proliferator-activated receptor; SREBP-1: sterol regulatory element binding protein; CYP7A1: Cytochrome P450 Family 7 Subfamily A Member 1; MMP: Matrix metalloproteinase; TIMP: Tissue matrix metalloproteinase; ICAM-1: leukocyte adhesion factors; VCAM-1: vascular cell adhesion molecule-1; Monocyte chemoattractant protein-1; Ngn3: neurogenin3; IRS: insulin receptor substrate; PIK3ca: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PDK1: Phosphoinositide-dependent kinase-1;

Table 3. The treatment of anthocyanins on diabetic complications in animal trial.

Subject	Organ	intervention duration	AdministeredForm and dosage of anthocyanins	Main results	Mechanism	references
STZ-induced diabetic rats	Heart	4weeks	Anthocyanin.; 250 mg/kg/day	↓ cardiac inflammation ↓ cardiac hypertrophy ↓ cardiac fibrosis ↑cardiaccontractile function	↓ TLR4/NFκB expression ↓TGF-β1 and FGF2 expression ↓ MMP-9 ↑TIMP-1	(Chen et al. 2016)
STZ-induced diabetic mice	Heart	12weeks	Anthocyanin; 250 mg/kg/day	↓ cardiac inflammation ↓cardiac fibrosis	↓ miR-214-mediated IL-17 expression ↓IL-1β, TNF-α, and IL-6 ↓collagen I and III	(Yue et al. 2020)
STZ-induced diabetic mice	Heart	4weeks	Anthocyanin; 250 mg/kg/day	↑ cardiomyocyte survival ↑ cardiac function	↓ cytochrome c and caspase ↑ IGFIR/PI3K/Akt survival pathway ↑ anti-apoptotic proteins Bcl-2	(Huang et al. 2017)
STZ-induced diabetic mice	Heart	12 weeks	Protocatechuic acid; 50,100mg/kg/day	↓ MDA levels ↓ cardiac contractile dysfunction ↑ heart rate variability	↑ anti-apoptotic proteins Bcl-2 ↓ cardiac mitochondrial dysfunction	(Semaming et al. 2014)
Db/db mice	Kidney	8 weeks	Purple corn extract; 10 mg/kg/day	↓ mesangial expansion-elicited renal injury ↓ the infiltration and accumulation of macrophages ↓ glomerulosclerosis.	↓ IL-8-Tyk2-STAT signaling ↓ ICAM-1 and CD11b expression	(Kang et al. 2012)
Db/db mice	Kidney	8 weeks	Purple corn extract; 10 mg/kg/day	↓ glomerular fibrosis ↓ renal filtration dysfunction ↓ glomerulosclerosis ↑ nephrin and podocin proteins	↓ IL-8-Tyk2-STAT signaling ↓ collagen IV expression ↓ renal TGF-β and CTGF expression ↑ MMP and ↓ TIMP-2	(Li, Kang et al. 2012)
STZ-induced diabetic mice	Kidney	8 weeks	M.cauliflora extracts; 0.1%, 0.5%,1% of diet	↓ renal injury ↓ the ratio of urine albumin/urine creatinine ↓extracellular matrix accumulation of glomeruli	↓Ras/PI3K/Akt signaling pathway	(Wu, Hung, et al. 2016)
STZ-induced diabetic mice	Kidney	8 weeks	M. cauliflora extracts; 0.1%, 0.5%,1% of diet	↓oxidant and inflammatory damage in the kidney ↓ renal fibrosis	↑ GSH, CAT, SOD, GST, GPx levels ↓ ICAM-1, VCAM-1, MCP-1, CSF-1, TNF-α, IL-1β and IL-6 expression ↓ JAK/STAT signaling pathway ↓ PKC/NF-kB signaling pathway	(Hsu et al. 2016)
STZ-induced diabetic mice	Kidney	8 weeks	Cyanidin-3-glucoside; 10, 20 mg/kg/day	↓ renal dysfuntion ↓ kidney index ↓ renal oxidative stress and inflammation ↓ renal fibrosis ↓ renal pathological change ↓ glomerulosclerosis	↓ TGF-β1/Smad2/3 signaling pathway ↓TNF-α, MCP-1, NF-kB, IL-1β and IL-6 expression ↑ GSH, CAT, SOD levels	(Zheng et al. 2020)
Db/db mice	Kidney	12 weeks	Cyanidin-3-glucoside; 20 mg/kg/day	↓ renal injury ↓ renal fibrosis ↓ renal inflammation	↑ GSH level ↓TNF-α, MCP-1 and IL-1α expression ↓ mRNA expression of collagen IV, fibronectin, TGFβ1, MMP9 and α-SMA	(Qin et al. 2018)
Db/db mice	Kidney	12 weeks	Grape seed procyanidin; 30 mg/kg/day	↓ renal cell apoptosis	↓ caspase-3, ↑ BCL-2, ↓ Bax ↓ BAX/BCL-2 ↓ p38 MAPK and ERK1/2 activity	(Wei et al. 2018)
Zucker diabetic fatty rat	Kidney	24 weeks	red orange and lemon extract; 90 mg/kg/day	↓ renal injury	↓ apoptotic protein BAX/BCL-2 ratio ↓ NADPH Oxidase 4(NOX4) expression	(Damiano et al. 2020)
Db/db mice	Kidney	14 weeks	Blueberry and sea buckthorn extract; 6 g/kg/day	↓ glomerular water permeability ↓ albuminuria ↓ glomerular fibrosis ↓ glomerular ultra-structural changes ↓ renal endothelial insult	↑anti-angiogenic VEGF-A expression ↓total VEGF-A expression ↓ NF-kB, Akt, ERK1/2 and COX-2 expression	(Stevens et al. 2019)
Db/db mice	Kidney	12 weeks	Seoritae extract; 10 mg/kg/day	↓ albuminuria ↓intra-renal lipid concentrations ↓glomerular matrix expansion and inflammation	↑ AMPK signaling pathway ↑ PPAR α and PPARγ level ↓SREBP-1 expression ↑ BCL-2, ↓BAX, ↓BAX/BCL-2	(Koh et al. 2015)
Zucker diabetic fatty rat	Kidney	24 weeks	red orange and lemon extract; 90 mg/kg/day	↓ renal oxidative stress	↑ GSH, CAT, SOD levels	(Damiano et al. 2019)
STZ-induced diabetic mice	Retina	12 weeks	Blueberry anthocyanins; 20, 40, 80 mg/kg/day	↓ oxidative stress and inflammation in the retina	↑ Nrf2/HO-1 signaling pathway ↑ GSH and GPx level	(Song, Huang, and Yu 2016)
STZ-induced diabetic mice	Retina	6 weeks	V. myrtillus extract; 100 mg/kg/day	↓ blood–retinal barrier breakdown ↑ blood–retinal barrier function	↓ VEGF protein and mRNA expression ↑ Tight junction proteins expression	(Kim, Kim et al. 2015)
STZ-induced diabetic mice	Retina	8 weeks	Cyanidin-3-o-glucosid; 20 mg/kg/day	↓ inflammation and microglial activation	↑ tight junction proteins ↓ TNF-α, IL-1β, and IL-6 expression	(Zhao et al. 2021)

TLR4: Toll-like receptors 4; NF-κB: nuclear factor kappa-B; TGF-β: transforming growth factor β1; FGF2: Fibroblast Growth Factor 2; MMP: Matrix metalloproteinase; TIMP: Tissue matrix metalloproteinase; IGFIR: insulin-like growth factor I receptor; ICAM-1: leukocyte adhesion factors; TGF-β: Transforming Growth Factor β; CTGF: Connective tissue growth factor; VCAM-1: vascular cell adhesion molecule-1; MCP-1: Monocyte chemoattractant protein-1; CSF-1: macrophage-stimulating factor; NOX4: NADPH Oxidase 4; AMPK: AMP-activated protein kinase;SREBP-1: sterol regulatory element binding protein; PPAR: peroxisome proliferator-activated receptor; Nrf2: NF-E2–related factor 2.

AOPPs: Advanced Oxidation Protein Products; OMPs: Ozone Mapping and Profiler Suite; AGEs: advanced glycation end products; MDA: Malondialdehyde.

Figure 3. The mechanism of anthocyanins on islets function and transplantation in the cellular level.

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