title: Manganese supplementation increases adiponectin and lowers ICAM-1 and creatinine blood levels in Zucker type 2 diabetic rats, and downregulates ICAM-1 by upregulating adiponectin multimerization protein (DsbA-L) in endothelial cells.
abstract: Blood and tissue levels of manganese (Mn) are lower in type 2 diabetic and atherosclerosis patients compared with healthy subjects. Adiponectin has anti-diabetic and anti-atherogenic properties. Impairment in Disulfide bond A-like protein (DsbA-L) is associated with low adiponectin levels and diabetes. This study investigates the hypothesis that the beneficial effects of Mn supplementation are mediated by adiponectin and DsbA-L. At 6 weeks of age, Male Zucker diabetic fatty rats (ZDF) were randomly divided into two groups: diabetic controls and Mn-supplemented diabetic rats. Each rat was supplemented with Mn (D+Mn, 16 mg/kg BW) or water (placebo, D+P) daily for 7 weeks by oral gavage. For cell culture studies, Human Umbilical Vein Endothelial Cells (HUVEC) or 3T3L1 adipocytes were pretreated with Mn (0-10 µM MnCl2) for 24 h, followed by high glucose (HG, 25 mM) or normal glucose (5 mM) exposure for another 24 h. Mn supplementation resulted in higher adiponectin (p = 0.01), and lower ICAM-1 (p = 0.04) and lower creatinine (p = 0.04) blood levels compared to those in control ZDF rats. Mn-supplemented rats also caused reduced oxidative stress (ROS) and NADPH oxidase, and higher DsbA-L expression in the liver (p = 0.03) of ZDF rats compared to those in livers of control rats; however, Fe levels in liver were lower but not significant (p = 0.08). Similarly, treatment with high glucose (25 mM) caused a decrease in DsbA-L, which was prevented by Mn supplementation in HUVEC and adipocytes. Mechanistic studies with DsbA-L siRNA showed that the beneficial effects of Mn supplementation on ROS, NOX4, and ICAM-1 expression were abolished in DsbA-L knock-down HUVEC. These studies demonstrate that DsbA-L-linked adiponectin mediates the beneficial effects observed with Mn supplementation and provides evidence for a novel mechanism by which Mn supplementation can increase adiponectin and reduce the biomarkers of endothelial dysfunction in diabetes.
authors.affiliation: Departments of Pediatrics and Biochemistry & Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA.
authors.forename: Elodie
authors.initials: E
authors.lastname: Burlet
authors.affiliation: Departments of Pediatrics and Biochemistry & Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA. sjain@lsuhsc.edu.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Jain
mesh_terms: D041721:3T3-L1 Cells; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D003404:Creatinine / Q000097:blood*; D003921:Diabetes Mellitus, Experimental / Q000178:diet therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000178:diet therapy / Q000378:metabolism; D019587:Dietary Supplements; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D008297:Male; D008345:Manganese / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D015854:Up-Regulation
chemical_list: D052242:Adiponectin; D018799:Intercellular Adhesion Molecule-1; D008345:Manganese; D003404:Creatinine; D005982:Glutathione Transferase
keywords: Adiponectin; Diabetes; DsbA-L; ICAM-1; Manganese