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 MnCl) 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.

Adiponectin, a Therapeutic Target for Obesity, Diabetes, and Endothelial Dysfunction

“…The treatment of diabetic mice with cobalt, a heme oxygenase inducer, reduces visceral and subcutaneous obesity, and increases insulin sensitivity through the upregulation of adiponectin [112]. Studies have suggested that supplementation of l -cysteine increases the adiponectin secretion in adipoctyes [113] and manganese supplementation increases adiponectin secretion in adipocytes and in Zucker type 2 diabetic rats too [114]. In addition, studies indicate that adiponectin levels increase in healthy, nondiabetic volunteers treated with PPAR α/γ agonists [115].…”

The Essential Element Manganese, Oxidative Stress, and Metabolic Diseases: Links and Interactions

“…In a study on Zucker rats, a higher mean plasma Mn level in the diabetic fatty group was related to enhanced oxidative stress in diabetes and obesity [ 46 ]. Researchers have shown that Mn treatment can increase insulin secretion to improve glucose tolerance under conditions of dietary stress [ 47 ], reduce oxidative stress (ROS) and NADPH oxidase [ 48 ], and lower the risk of endothelial dysfunction in diabetes [ 48 , 49 ]. A study on nonobese diabetic mice also found that Mn porphyrin catalytic antioxidant (MnP) treatment slightly enhanced glucose oxidation and reduced fatty acid oxidation [ 50 ].…”

“…Several studies indicated that Mn supplementation could reduce high glucose-induced monocyte adhesion to endothelial cells and endothelial dysfunction and also lower blood levels of ICAM-1 and cholesterol [ 48 , 49 ], elicit anti-inflammatory effects in endothelial cells [ 100 ], and potentially prevent or delay the progression of atherosclerosis. Little is known about the Mn concentration in atherosclerosis patient samples.…”

Adjuvant Therapies in Diabetic Retinopathy as an Early Approach to Delay Its Progression: The Importance of Oxidative Stress and Inflammation

“…In fact, the dietary intake of this micronutrient was inversely associated with the incidence of T2DM and was partially associated with lower OS measured by 8-hydroxydeoxyguanosine [128]; nevertheless, in preclinical studies, both deficient or excessive intake of Mn aggravated apoptosis by upregulating capase-3, caspase-8, and caspase-9 and inhibited Nrf2 signaling, while optimal intake protected against ROS, MDA, and protein carbonyl [129]. Mn may have a protective role against endothelial dysfunction by upregulating disulfide bond A-like protein (DsbA-L) and thus increasing adiponectin, which ultimately downregulate ICAM-1, a biomarker of endothelial dysfunction; nonetheless, its evaluation in retinal tissues is necessary [130]. Toxicity is caused mainly because of an excessive dose, primarily from supplementation or nondietary intake; and it has been identified through behavioral abnormalities such as hyperactivity, inferior intellectual function, impaired motor skills, and reduced olfactory function in children [125] and in association with the increase of inflammatory cytokines IL-1β, IL-6, and IL-8 and higher methylation of NF-κβ member activator NKAP [131].…”