Skip to main content
SpringerLink
Log in

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

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Sarwar MS, Ahmed S, Ullah MS, Kabir H, Rahman GM, Hasnat A, Islam MS (2013) Comparative study of serum zinc, copper, manganese, and iron in preeclamptic pregnant women. Biol Trace Elem Res 154:14–20

    Article  CAS  PubMed  Google Scholar 

  2. Koh ES, Kim SJ, Yoon HE, Chung JH, Chung S, Park CW, Chang YS, Shin SJ (2014) Association of blood manganese level with diabetes and renal dysfunction: a cross-sectional study of the Korean general population. BMC Endocr Disord 14:1

    Article  Google Scholar 

  3. Baly DL, Schneiderman JS, Garcia-Welsh AL (1990) Effect of manganese deficiency on insulin binding, glucose transport and metabolism in rat adipocytes. J Nutr 120:1075–1079

    CAS  PubMed  Google Scholar 

  4. Baly DL, Lönnerdal B, Keen CL (1985) Effects of high doses of manganese on carbohydrate homeostasis. Toxicol Lett 25:95–102

    Article  CAS  PubMed  Google Scholar 

  5. Bomb B, Kumawat D, Bomb P, Taly A, Bedi T, Bedi H (1988) Effect of manganese on regression of atherosclerosis in cholesterol fed rabbits. J Assoc Physicians India 36:149–150

    CAS  PubMed  Google Scholar 

  6. Kumawat D, Bomb B, Bhatnagar H (1986) Effect of manganese on prevention of atherosclerosis in cholesterol fed rabbits. J Assoc Physicians India 34:704

    CAS  PubMed  Google Scholar 

  7. Burlet E, Jain SK (2013) Manganese supplementation reduces high glucose-induced monocyte adhesion to endothelial cells and endothelial dysfunction in Zucker diabetic fatty rats. J Biol Chem 288:6409–6416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Walter RM, Uriu-Hare JY, Olin KL, Oster MH, Anawalt BD, Critchfield JW, Keen CL (1991) Copper, zinc, manganese, and magnesium status and complications of diabetes mellitus. Diabetes Care 14:1050–1056

    Article  PubMed  Google Scholar 

  9. Kazi TG, Afridi HI, Kazi N, Jamali MK, Arain MB, Jalbani N, Kandhro GA (2008) Copper, chromium, manganese, iron, nickel, and zinc levels in biological samples of diabetes mellitus patients. Biol Trace Elem Res 122:1–18

    Article  CAS  PubMed  Google Scholar 

  10. Liu M, Liu F (2014) Regulation of adiponectin multimerization, signaling and function. Best Pract Res Clin Endocrinol Metab 28(1):25–31

    Article  PubMed  Google Scholar 

  11. Jiang Y, Owei I, Wan J, Ebenibo S, Dagogo-Jack S (2016) Adiponectin levels predict prediabetes risk: the pathobiology of prediabetes in a biracial cohort (POP-ABC) study. BMJ Open Diabetes Res Care 4(1):e000194

    Article  PubMed  PubMed Central  Google Scholar 

  12. Li F, Cheng K, Lam K, Vanhoutte P, Xu A (2011) Cross-talk between adipose tissue and vasculature: role of adiponectin. Acta physiol 203:167–180

    Article  CAS  Google Scholar 

  13. Delaigle AlM, Jonas J-C, Bauche IB, Cornu O, Brichard SM (2004) Induction of adiponectin in skeletal muscle by inflammatory cytokines: in vivo and in vitro studies. Endocrinology 145:5589–5597

    Article  Google Scholar 

  14. Piñeiro R, Iglesias MJ, Gallego R, Raghay K, Eiras S, Rubio J, Diéguez C, Gualillo O, González-Juanatey JR, Lago F (2005) Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Lett 579:5163–5169.

    Article  PubMed  Google Scholar 

  15. Wolf AM, Wolf D, Avila MA, Moschen AR, Berasain C, Enrich B, Rumpold H, Tilg H (2006) Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice. J Hepatol 44:537–543

    Article  CAS  PubMed  Google Scholar 

  16. Komura N, Maeda N, Mori T, Kihara S, Nakatsuji H, Hirata A, Tochino Y, Funahashi T, Shimomura I (2013) Adiponectin protein exists in aortic endothelial cells. PloS ONE 8:e71271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ebner A, Poitz DM, Alexiou K, Deussen A (2013) Secretion of adiponectin from mouse aorta and its role in cold storage-induced vascular dysfunction. Basic Res Cardiol 108:1–14

    Article  Google Scholar 

  18. Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T (1999) Novel modulator for endothelial adhesion molecules adipocyte-derived plasma protein adiponectin. Circulation 100:2473–2476

    Article  CAS  PubMed  Google Scholar 

  19. Ouchi N, Ohishi M, Kihara S, Funahashi T, Nakamura T, Nagaretani H, Kumada M, Ohashi K, Okamoto Y, Nishizawa H (2003) Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension 42:231–234

    Article  CAS  PubMed  Google Scholar 

  20. Shimabukuro M, Higa N, Asahi T, Oshiro Y, Takasu N, Tagawa T, Ueda S, Shimomura I, Funahashi T, Matsuzawa Y (2003) Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab 88:3236–3240

    Article  CAS  PubMed  Google Scholar 

  21. Son E-W, Lee S-R, Choi H-S, Koo H-J, Huh J-E, Kim M-H, Pyo S (2007) Effects of supplementation with higher levels of manganese and magnesium on immune function. Arch Pharm Res 30:743–749

    Article  CAS  PubMed  Google Scholar 

  22. Bae Y-J, Choi M-K, Kim M-H (2011) Manganese supplementation reduces the blood cholesterol levels in Ca-deficient ovariectomized rats. Biol Trace Elem Res 141:224–231

    Article  CAS  PubMed  Google Scholar 

  23. Metais C, Forcheron F, Abdallah P, Basset A, Del Carmine P, Bricca G, Beylot M (2008) Adiponectin receptors: expression in Zucker diabetic rats and effects of fenofibrate and metformin. Metabolism 57:946–953

    Article  CAS  PubMed  Google Scholar 

  24. Forcheron F, Basset A, Abdallah P, Del Carmine P, Gadot N, Beylot M (2009) Diabetic cardiomyopathy: effects of fenofibrate and metformin in an experimental model–the Zucker diabetic rat. Cardiovasc Diabetol 8:1

    Article  Google Scholar 

  25. Holm A, Johansen P, Ahnfelt-Ronne I, Romer J (2004) Adipogenic and orexigenic effects of the ghrelin-receptor ligand tabimorelin are diminished in leptin-signalling-deficient ZDF rats. Eur J Endocrinol 150:893–904

    Article  CAS  PubMed  Google Scholar 

  26. Candiloros H, Muller S, Zeghari N, Donner M, Drouin P, Ziegler O (1995) Decreased erythrocyte membrane fluidity in poorly controlled IDDM: influence of ketone bodies. Diabetes Care 18(4):549–551

    Article  CAS  PubMed  Google Scholar 

  27. Malthankar GV, White BK, Bhushan A, Daniels CK, Rodnick KJ, Lai JC (2004) Differential lowering by manganese treatment of activities of glycolytic and tricarboxylic acid (TCA) cycle enzymes investigated in neuroblastoma and astrocytoma cells is associated with manganese-induced cell death. Neurochem Res 29:709–717

    Article  CAS  PubMed  Google Scholar 

  28. Isaac AO, Kawikova I, Bothwell AL, Daniels CK, Lai JC (2006) Manganese treatment modulates the expression of peroxisome proliferator-activated receptors in astrocytoma and neuroblastoma cells. Neurochem Res 31:1305–1316

    Article  CAS  PubMed  Google Scholar 

  29. Manna P, Jain SK (2011) Hydrogen sulfide and L-cysteine increase PIP3 and glucose utilization by inhibiting PTEN and activating PI3K/AKT/PKCζ/λ in 3T3L1 adipocytes. J Biol Chem 286:39848–39859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kanikarla-Marie P, Jain SK (2014) l-Cysteine supplementation reduces high-glucose and ketone-induced adhesion of monocytes to endothelial cells by inhibiting ROS. Mol Cell Biochem 391:251–256

    Article  CAS  PubMed  Google Scholar 

  31. Jain SK, Kahlon G, Morehead L, Dhawan R, Lieblong B, Stapleton T, Caldito G, Hoeldtke R, Levine SN, Bass PF (2012) Effect of chromium dinicocysteinate supplementation on circulating levels of insulin, TNFα, oxidative stress, and insulin resistance in type 2 diabetic subjects: randomized, double-blind, placebo-controlled study. Mol Nutr Food Res 56:1333–1341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Satoh N, Naruse M, Usui T, Tagami T, Suganami T, Yamada K, Kuzuya H, Shimatsu A, Ogawa Y (2004) Leptin-to-adiponectin ratio as a potential atherogenic index in obese type 2 diabetic patients. Diabetes Care 27:2488–2490

    Article  CAS  PubMed  Google Scholar 

  33. Norata GD, Raselli S, Grigore L, Garlaschelli K, Dozio E, Magni P, Catapano AL (2007) Leptin: adiponectin ratio is an independent predictor of intima media thickness of the common carotid artery. Stroke 38:2844–2846

    Article  CAS  PubMed  Google Scholar 

  34. Oda N, Imamura S, Fujita T, Uchida Y, Inagaki K, Kakizawa H, Hayakawa N, Suzuki A, Takeda J, Horikawa Y (2008) The ratio of leptin to adiponectin can be used as an index of insulin resistance. Metabolism 57:268–273

    Article  CAS  PubMed  Google Scholar 

  35. Ntaios G, Gatselis NK, Makaritsis K, Dalekos GN (2013) Adipokines as mediators of endothelial function and atherosclerosis. Atherosclerosis 227:216–221

    Article  CAS  PubMed  Google Scholar 

  36. Blankenberg S, Barbaux S, Tiret L (2003) Adhesion molecules and atherosclerosis. Atherosclerosis 170:191–203

    Article  CAS  PubMed  Google Scholar 

  37. Sedeek M, Callera G, Montezano A, Gutsol A, Heitz F, Szyndralewiez C, Page P, Kennedy CR, Burns KD, Touyz RM (2010) Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. Am J Physiol Renal Physiol 299:F1348–F1358

    Article  Google Scholar 

  38. Syed I, Kyathanahalli CN, Jayaram B, Govind S, Rhodes CJ, Kowluru RA, Kowluru A (2011) Increased Phagocyte-Like NADPH oxidase and ROS generation in Type 2 diabetic ZDF rat and human islets role of Rac1–JNK1/2 signaling pathway in mitochondrial dysregulation in the diabetic islet. Diabetes 60:2843–2852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Matsuda M, Shimomura I (2014) Roles of adiponectin and oxidative stress in obesity-associated metabolic and cardiovascular diseases. Rev Endocr Metab Disord 15(1):1–10. doi:10.1007/s11154-013-9271-7

    Article  CAS  PubMed  Google Scholar 

  40. Yuan F, Li Y-N, Liu Y-H, Yi B, Tian J-W, Liu F-Y (2012) Adiponectin inhibits the generation of reactive oxygen species induced by high glucose and promotes endothelial NO synthase formation in human mesangial cells. Mol Med Rep 6:449–453

    CAS  PubMed  Google Scholar 

  41. Achari AE, Jain SK (2016) l-Cysteine supplementation increases adiponectin synthesis and secretion, and GLUT4 and glucose utilization by upregulating disulfide bond A-like protein expression mediated by MCP-1 inhibition in 3T3-L1 adipocytes exposed to high glucose. Mol Cell Biochem 414:105–113

    Article  CAS  PubMed  Google Scholar 

  42. Okamoto Y, Arita Y, Nishida M, Muraguchi M, Ouchi N, Takahashi M, Igura T, Inui Y, Kihara S, Nakamura T (2000) An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls. Horm Metab Res 32:47–50

    Article  CAS  PubMed  Google Scholar 

  43. Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumada M, Hotta K, Nishida M, Takahashi M (2002) Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB–binding protein and regulates growth factor–induced common postreceptor signal in vascular smooth muscle cell. Circulation 105:2893–2898

    Article  CAS  PubMed  Google Scholar 

  44. Kumada M, Kihara S, Ouchi N, Kobayashi H, Okamoto Y, Ohashi K, Maeda K, Nagaretani H, Kishida K, Maeda N (2004) Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation 109:2046–2049

    Article  CAS  PubMed  Google Scholar 

  45. Hayashi M, Shibata R, Takahashi H, Ishii H, Aoyama T, Kasuga H, Yamada S, Ohashi K, Maruyama S, Matsuo S (2011) Association of adiponectin with carotid arteriosclerosis in predialysis chronic kidney disease. Am J Nephrol 34:249–255

    Article  CAS  PubMed  Google Scholar 

  46. Deng G, Long Y, Yu Y, Li M (2010) Adiponectin directly improves endothelial dysfunction in obese rats through the AMPK–eNOS Pathway. Int J Obes 34:165–171

    Article  CAS  Google Scholar 

  47. Hui X, Lam KS, Vanhoutte PM, Xu A (2012) Adiponectin and cardiovascular health: an update. Br J Pharmacol 165:574–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rossander-Hulten L, Brune M, Sandstrom B, Lonnerdal B, Hallberg L (1991) Competitive inhibition of iron absorption by manganese and zinc in humans. Am J Clin Nutr 54:152–156

    Google Scholar 

  49. Davis CD, Wolf TL, Greger JL (1992) Varying levels of manganese and iron affect absorption and gut endogenous losses of manganese by rats. J Nutr 122:1300–1308

    Google Scholar 

  50. Fitsanakis VA, Zhang N, Garcia S, Aschner M (2010) Manganese (Mn) and iron (Fe): interdependency of transport and regulation. Neurotox Res 18:124–131

    Google Scholar 

  51. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388:482–488

    Google Scholar 

  52. Daly MJ (2006) Modulating radiation resistance: insights based on defenses against reactive oxygen species in the radioresistant bacterium Deinococcus radiodurans. Clin Lab Med 26:491–504

    Google Scholar 

  53. Daly MJ (2009) A new perspective on radiation resistance based on Deinococcus radiodurans. Nat Rev Microbiol 7:237–245

    Google Scholar 

  54. Daly MJ, Gaidamakova EK, Matrosova VY, Vasilenko A, Zhai M, Venkateswaran A, Hess M, Omelchenko MV, Kostandarithes HM, Makarova KS, Wackett LP, Fredrickson JK, Ghosal D (2004) Accumulation of Mn(II) in Deinococcus radiodurans facilitates gamma-radiation resistance. Science 306:1025–1028

    Google Scholar 

Download references

Acknowledgements

The authors are supported by Grants from NCCIH and the Office of Dietary Supplements of the National Institutes of Health RO1 AT007442, the Malcolm Feist Endowed Chair in Diabetes, and funded by a fellowship from the Malcolm Feist Cardiovascular Research Endowment, LSU Health Shreveport. The authors thank Ms Georgia Morgan for excellent editing of this manuscript.

Author information

Authors and Affiliations

  1. Departments of Pediatrics and Biochemistry & Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA

    Elodie Burlet & Sushil K. Jain

Authors
  1. Elodie Burlet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sushil K. Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sushil K. Jain.

Ethics declarations

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Burlet, E., Jain, S.K. 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. Mol Cell Biochem 429, 1–10 (2017). https://doi.org/10.1007/s11010-016-2931-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-016-2931-7

Keywords

Search

Navigation