Magnesium supplementation enhances insulin sensitivity and decreases insulin resistance in diabetic rats

Document Type: Original Article

Authors

1 Department of Endocrinology, First Hospital of Handan City, No. 25 Congtai Road, Handan, Hebei Province 056002, China

2 Department of Endocrinology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China

3 Healthcare Department, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China

Abstract

Objective(s): Diabetes mellitus has been suggested to be the most common metabolic disorder associated with magnesium deficiency. This study aimed to investigate the effects and mechanisms of magnesium supplementation on insulin receptor activity in elderly type 2 diabetes using a rat model and to provide experimental evidence for insulin resistance improvement by magnesium supplementation.
Materials and Methods: Rat model of type 2 diabetes was developed using a high-fat diet along with low dose streptozotocin (STZ) treatment. Magnesium supplement was given orally by mixing with the high-fat diet. Serum insulin level, insulin sensitivity, and insulin receptor affinity were assessed using radioimmunoassay (RIA). Insulin receptor, insulin receptor substrate (IRS-2), and β-Arrestin-2 gene and protein expression levels were measured using immunohistochemistry and RT-PCR. Xanthine oxidase assay, thiobarbituric acid reactive substance assay (TCA method), colorimetric assay, and ELISA were used to determine the serum SOD, MDA, T-AOC, and ox-LDL levels, respectively.
Results: Magnesium supplementation enhanced insulin sensitivity and decreased insulin resistance in diabetic rats mainly through increasing insulin receptor expression, affinity, and augmenting insulin receptor signaling. Magnesium supplementation also inhibited lipid peroxidation in diabetic rats and protected against pancreatic cell injury in diabetic rats. In addition, we found that β-Arrestin-2 gene expression was suppressed in diabetes, which was possibly attributed to gene methylation modification, as β-arrestin 2 promotor was rich in methylation-regulating sites. Magnesium supplementation could affect β-Arrestin-2 gene expression and methylation.
Conclusion: Magnesium supplementation has a positive effect on insulin receptor activity and insulin sensitivity in type 2 diabetes.

Keywords


1. Swaminathan R. Magnesium metabolism and its disorders. Clin Biochem Rev 2003;24:47-66.
2. Bergman C, Gray-Scott D, Chen JJ, Meacham S. What is next for the dietary reference intakes for bone metabolism related nutrients beyond calcium: phosphorus, magnesium, vitamin D, and fluoride? Crit Rev Food Sci Nutr. 2009;49:136-144.
3. Volpe SL. Magnesium in disease prevention and overall health. Adv Nutr 2013;4:378S-383S.
4. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33:S62-69.
5. Sen S, Chakraborty R. Treatment and diagnosis of diabetes mellitus and its complication: Advanced approaches. Mini Rev Med Chem. 2015;15:1132-1133.
6. Chutia H, Lynrah KG. Association of serum magnesium deficiency with insulin resistance in type 2 diabetes mellitus. J Lab Physicians 2015;7:75-78.
7. Morais JBS, Severo JS, de Alencar GRR, de Oliveira ARS, Cruz KJC, Marreiro DDN, et al. Effect of magnesium supplementation on insulin resistance in humans: A systematic review. Nutrition 2017;38:54-60.
8. Tapiero H, Tew KD. Trace elements in human physiology and pathology: zinc and metallothioneins. Biomed Pharmacother 2003;57:399-411.
9. Cruz KJ, de Oliveira AR, Pinto DP, Morais JB, Lima Fda S, Colli C, et al. Marreiro Ddo, Influence of magnesium on insulin resistance in obese women. Biol Trace Elem Res 2014;160:305-310.
10. Yadav C, Manjrekar PA, Agarwal A, Ahmad A, Hegde A, Srikantiah RM. Association of serum selenium, zinc and magnesium levels with glycaemic indices and insulin resistance in pre-diabetes: A cross-sectional study from south India. Biol Trace Elem Res 2017;175: 65-71.
11. Dasgupta A, Sarma D, Saikia UK. Hypomagnesemia in type 2 diabetes mellitus. Indian J Endocrinol Metab 2012;16:1000-1003.
12. Jawerbaum A, White V. Animal models in diabetes and pregnancy. Endocr Rev 2010;31:680-701.
13. Nahdi AMTA, John A, Raza H. Elucidation of molecular mechanisms of streptozotocin-induced oxidative stress, apoptosis, and mitochondrial dysfunction in Rin-5F pancreatic β-Cells. Oxid Med Cell Longev. 2017;2017:7054272.
14. Goyal SN, Reddy NM, Patil KR, Nakhate KT, Ojha S, Patil CR, et al. Challenges and issues with streptozotocin-induced diabetes - A clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics. Chem Biol Interact 2016;244:49-63.
15. Knudsen L, De Meyts P, Kiselyov VV. Insight into the molecular basis for the kinetic differences between the two insulin receptor isoforms. Biochem J 2011;440:397-403.
16. Kiselyov VV, Versteyhe S, Gauguin L, Meyts PD. Harmonic oscillator model of the insulin and IGF1 receptors’ allosteric binding and activation. Mol Syst Biol 2009;5:243.
17. Kostov K. Effects of magnesium deficiency on mechanisms of insulin resistance in type 2 diabetes: Focusing on the processes of insulin secretion and signaling. Int J Mol Sci. 2019;20:1351.
18. Whittaker L, Hao C, Fu W, Whittaker J. High-affinity insulin binding: insulin interacts with two receptor ligand binding sites. Biochemistry 2008;47:12900-12909.
19. Barbagallo M, Dominguez LJ. Magnesium and type 2 diabetes. World J Diabetes. 2015 Aug 25;6:1152-1157.
20. Mansor LS, Gonzalez ER, Cole MA, Tyler DJ, Beeson JH, Clarke K, et al. Cardiac metabolism in a new rat model of type 2 diabetes using high-fat diet with low dose streptozotocin. Cardiovasc Diabetol. 2013;12:136.
21. Lu GP, Cui P, Cheng Y, Lu ZJ, Zhang LE, Kissoon N. Insulin control of blood glucose and GLUT4 expression in the skeletal muscle of septic rats. West Indian Med J 2015;64:62-70.
22. Veronese N, Watutantrige-Fernando S, Luchini C, Solmi M, Sartore G, Sergi G, et al. Effect of magnesium supplementation on glucose metabolism in people with or at risk of diabetes: a systematic review and meta-analysis of double-blind randomized controlled trials. Eur J Clin Nutr 2016;70:1463.
23. Hennige AM, Burks DJ, Ozcan U, Kulkarni RN, Ye J, Park S, et al. Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes. J Clin Invest. 2003;112:1521-1532.
24. Yin D, Yang X, Li H, Fan H, Zhang X, Feng Y, et al. beta-arrestin 2 promotes hepatocyte apoptosis by inhibiting Akt protein. J Biol Chem 2016;291;605-612.
25. Garcia RF, Gazola VA, Barrena HC, Hartmann EM, Berti J, Toyama MH, et al. Blood amino acids concentration during insulin induced hypoglycemia in rats: the role of alanine and glutamine in glucose recovery. Amino Acids 2007;33:151-155.
26. Laviano A, Molfino A, Lacaria MT, Canelli A, De Leo S, et al. Glutamine supplementation favors weight loss in nondieting obese female patients. A pilot study. Eur J Clin Nutr 2014;68:1264-1266.
27. Wilcox G. Insulin and insulin resistance. Clin Biochem Rev 2005;26:19-39.
28. Wanant S, Quon MJ. Insulin receptor binding kinetics: modeling and simulation studies. J Theor Biol. 2000;205:355-364.
29. Berg JM, Tymoczko JL, Stryer L. Biochemistry, 5th ed., W H Freeman, New York, 2002.
30. Hirayama I, Tamemoto H, Yokota H, Kubo SK, Wang J, Kuwano H, et al. Insulin receptor-related receptor is expressed in pancreatic beta-cells and stimulates tyrosine phosphorylation of insulin receptor substrate-1 and -2. Diabetes 1999;48:1237-1244.
31. Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014;2014:360438.
32. Davì G, Falco A, Patrono C. Lipid peroxidation in diabetes mellitus. Antioxid Redox Signal 2005;7:256-268.
33. Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002;18:1427-1431.
34. Rodgers JT, Puigserver P. Insulin resistance: beta-arrestin development. Cell Res  2009;19:275-276.
35. Luan B, Zhao J, Wu H, Duan B, Shu G, Wang X, et al. Deficiency of a beta-arrestin-2 signal complex contributes to insulin resistance. Nature 2009;457:1146-1149.