Islet transplantation and antioxidant management: A comprehensive review

Table 1 In-vitro effects of antioxidants on pancreatic islets

Authors	Substance/Dose	Sample	Study design	Duration	Assessments
Campbell et al[21], 2008	Sodium selenite (30 nmol/L)	Rat	Islets were incubated with/without Na2SeO3	72 h	Insulin content ↑ Insulin secretion ↑ Glucose-stimulated insulin secretion1
Kanitkar et al[22], 2008	Curcumin (10 μmol/L)	Rat	Cryopreservation of islets with/without curcumin Assessments were performed after 24 h culture post-thawing	Cryopreserved	Intact islets ↑ ROS ↓ Insulin Secretion ↑ Expression of Hsp70 and HO-1 ↑
Thomas et al[23], 2007	Peptide SS-31 (1 nmol/L)	Mice	SS-31 was added to all reagents which were used for islet isolation	Isolation procedure	Islet apoptosis ↓ Islet yield ↑
		Human	Islets were incubated in culture medium with without SS-31	72 h	Islet apoptosis ↓
Hara et al[24], 2007	Epigallocatechin-3-gallate (EGCG) (36, 72, 360 μmol/L)	Rat	Islets cultured under normal or H/R condition with/ without EGCG	48 h	Islet apoptosis ↓ LDH ↓ Insulin secretion ↑
Xiong et al[25], 2006	Puerarin (10, 50, 100 μmol/L)	Rat	Islets cultured under normal or H2O2 stress conditions with/without Puerarin	24 h	Islet apoptosis ↓, Islet viability ↑ CAT & SOD activity ↑, ROS ↓ Insulin secretion ↑
Marzorati et al[26], 2006	Glutathione (1, 5, 10 mmol/L) Vitamin E (2 × 10-5 mmol/L) Ascorbic acid (0.3 mmol/L)	Human	Antioxidant agents were added to culture medium individually	48 h	Glutathione : CCL2/MCP-1 release ↓ Insulin secretion1 Vitamin E: CCL2/MCP-1 release1 Ascorbic acid: CCL2/MCP-1 release1
Amoli et al[27], 2006	Curcumin (10, 20 μmol/L)	Rat	Curcumin was added to culture medium	18 h + 24 h	MCP-1 release ↓
Rao et al[28], 2005	MCI – 186	Rat	Islets were treated with H2O2 in the presence or absence of MCI-186	18 h	Cell death ↓
Avila et al[29], 2005	L-glutamine (5 mmol/L)	Human	Pancreas were manually perfused through the main pancreatic duct with either the standard HBSS or with HBSS + L-glutamine	0 → 24 h	Islet yield ↑ Lipid peroxidation (MDA) ↓ Glutathione (GSH) ↑ Viability1 Insulin secretion1
Brandhorst et al[30], 2005	Free L-glutamine (2.5 & 5 mmol/L/L) Stable L-glutamine [ NALG] (2.5 & 5 mmol/L)	Pig	Islets pretreated with free L-glutamine or NALG for 24 h and then stressed with H2O2, ETA or cytokine mix	24 h	Viability: L-glutamine ↑ NALG1
Giovagnoli et al[31], 2005	Encapsulated enzymes (100 mg/35 mL)	NPCCs	NPCCs were co-cultured with/without entrapped enzymes	9 d	Viability ↑, Insulin secretion ↑ Insulin/DNA ratio ↑ mRNA expression of insulin and Glut-2 ↑
Bottino et al[32], 2004	MnTDE (34 μmol/L)	Human	MnTDE was added as a supplement to culture or isolation medium	60 h	Islet yield ↑, Insulin secretion ↑ NF-κB DNA-binding ↓ IL6 & MCP-1 ↓, IL81 PARP activation ↑
Arata et al[33], 2004	Ascorbic Acid-2 Glucoside (AA2G) (100 μg/mL)	Human	Cryopreservation of islets with UW solution or AA2G + UW solution	Cryopreserved	Viability ↑ Insulin secretion ↑ Insulin gene expression ↑
Luca et al[34], 2003	Free vitamin D3 (2 μmol/L) Encapsulated vitamin D3 (20 μmol/L)	Rat	Islets were treated with/ without vitamin D3	9 d	Insulin secretion ↑
Hardikar et al[35], 2001	Taurine (0.3 & 3 mmol/L)	Rat	Cryopreservation of islets with/without taurine	Cryopreserved	Viability ↑ Lipid peroxidation ↓
Luca et al[36], 2000	Vitamin D3 Vitamin E	NPCCs	NPCC cells were treated with/without VitD3 & VitE during their maturation and differentiation process	16 d	Large & intact islets ↑ Insulin secretion ↑
Tajiri et al[37], 1999	Vitamin E (50 μg/mL)	Rat	Islets were co-cultured with/ without vitamin E	1 d	Insulin secretion ↑
Shewade et al[38], 1999	Riboflavin	Rat	Inclusion of riboflavin in the cryopreserved medium	Cryopreserved	Viability ↑ Lipid peroxidation ↓ GSH ↑, Insulin secretion ↑
Jindal et al[39], 1996	Zinc (20 μmol/L)	Rat	Preservation of islets in UW and Hanks solution with/without Zinc	1, 3, 6 d	Viability1

↑: Significant increase compared with non-treated group; ↓: Significant decrease compared with non-treated group;

¹No significance difference between groups. Hsp70: Heat shock protein 70; HO-1: Heme oxygenase-1; H/R: Hypoxia/Reoxygenation; LDH: Lactate dehydrogenase; CCL2/MCP-1: Monocyte chemoattractant protein 1; HBSS: Hanks balanced salt solution; NALG: N-acetyl-L-alanyl-L-glutamine; MDA: Malondialdehyde; MnTDE: Manganese (III) 5,10,15,20-tetrakis (1,3-diethyl-2imidazoyl) porphyrin; NF-κB: Nuclear factor-κB; PARP: Poly (ADP-ribose) Polymerase indicative of ongoing cell damage and death; UW: University of Wisconsin; NPCCs: Neonatal pancreatic porcine cell clusters.

Table 2 In-vivo effects of antioxidants on pancreatic islets

Author	Substance/Dose	Sample	Procedure	Output
Thomas et al[23], 2007	Peptide SS-31 (3 mg/kg)	Mice → Mice	Injection of SS-31 to donor mouse + adding SS-31 during islet isolation	Better glucose control after transplant
Avila et al[29], 2005	L-glutamine (5 mmol/L)	Human → Rat	Transplantation of human islets which were treated before with/without intraductal L-glutamine to nude rats	Normoglycemia percentage ↑ (83% vs 26%) Time to reach normoglycemia ↓ (1.83 d vs 7.6 d)
Brown et al[40], 2005	Pyruvate Vitamin E Vitamin C	Rat → Rat	Oral administration of pyruvate, vitamin E and vitamin C during perioperative period	Pyruvate enhanced engraftment & functionality of suboptimal islet mass Vitamin E and vitamin C failed to enhance
Olcott et al[41], 2004	Salen-manganese [EUK-8] (100 mg/kg)	Mice → Mice	Daily treatment with/without EUK-8 (IP injection) to recipient NOD mice	Better glucose control until 20 d after transplant
Winter et al[42], 2002	Vitamin A (500 μg) Ascorbic Acid (40 mg) Vitamin E (10.6 mg) Selenium (2 μg)	Rat → Rat	Oral antioxidants, 24 h prior to transplantation	Slight better glucose control
Bottino et al[43], 2002	SOD mimetic compound (34 μmol/L)	Human → Mice	Culture of isolated islet in the presence of SOD mimetic for at least 2 h before transplantation	Better glucose control
Hardikar et al[35], 2001	Taurine (0.3 & 3 mmol/L)	Rat → Mice	Transplantation of islets which were previously cryopreserved with/without taurine	No significant difference was observed
Tajiri et al[37], 1999	Vitamin E (40 mg/kg)	Rat → Rat	Every other day IP injection of vitamin E to transplanted rats	Treatment for 2 not for 6 wk enhanced basal insulin release and arginine induced insulin release
Vajkoczy et al[44], 1997	Vitamin E (150, 8000 mg/kg)	Rat → Rat	Oral vitamin E after xenograft	Reduction of xenograft leukocyte- endothelium interaction at day 6 Adequate development of functional capillary density
Gembal et al[45], 1993	Allopurinol Vitamin E Chlorpromazine	Rat → Rat	Transplantation of islets which were pretreated with/without combination of allopurinol, alpha-tocopherol and chlorpromazine.	Better glucose control after 3 d

↑: Significant increase compared with non-treated group; ↓: Significant decrease compared with non-treated group.