Abstract
The effects of long-term oral administration of magnesium sulfate and insulin on hyperglycemia were investigated using Akt2 and IRS1 gene expression methods in streptozotocin-induced diabetic rats. Fifty rats were randomly divided into five experimental groups: 1, non-diabetic control (NDC); 2, Mg2+-treated non-diabetic control (Mg-NDC); 3, chronic diabetic (CD); 4, Mg2+-treated chronic diabetic (Mg-CD); and 5, insulin-treated chronic diabetic (Ins-CD). Streptozotocin was used to induce diabetes. The Mg-CD and Mg-NDC groups received 10 g/l of MgSO4 added to drinking water. The Ins-CD group received 2.5 U/kg of insulin twice a day. Blood glucose level and body weight were measured every week. The intraperitoneal glucose tolerance test (IPGTT) was performed after 16 weeks. MgSO4 administration improved the blood glucose level and IPGTT. It also increased Akt2 and IRS1 genes as well as protein expression. Insulin lowered the blood glucose level and increased IRS1 gene and protein expression, but did not affect Akt2 gene and protein expression. Glucose reduction after Mg therapy may be mediated, at least partially, via IRS1 and Akt2 genes and protein stimulation. In insulin-treated rats, insulin resistance was not significant due to the absence of Akt2 gene expression.
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Soltani N, Keshavarz M, Minaii B, Mirershadi F, Asl SZ, Dehpour AR (2005) Effects of administration of oral magnesium on plasma glucose and pathological changes in the aorta and pancreas of diabetic rats. Clin Exp Pharmacol Physiol 32(8):604–610
Soltani N, Keshavarz M, Dehpour AR (2007) Effect of oral magnesium sulfate administration on blood pressure and lipid profile in streptozocin diabetic rat. Eur J Pharmacol 560(2–3):201–205
Gueux E, Rayssiguier Y (1983) The effect of magnesium deficiency on glucose stimulated insulin secretion in rats. Horm Metab Res 15(12):594–597
Sales CH, Pedrosa LFC (2006) Magnesium and diabetes mellitus: their relation. Clin Nutr 25(4):554–562
Barbagallo M, Dominguez LJ (2007) Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance. Arch Biochem Biophys 458(1):40–47
De Valk H, Verkaaik R, Van Rijn H, Geerdink R, Struyvenberg A (1998) Oral magnesium supplementation in insulin-requiring Type 2 diabetic patients. Diabet Med 15(6):503–507
RODRiguez-MORan M, Guerrero-Romero F (2003) Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care 26(4):1147–1152
Solaimani H, Soltani N, MaleKzadeh K, Sohrabipour S, Zhang N, Nasri S, Wang Q (2014) Modulation of GLUT4 expression by oral administration of Mg2+ to control sugar levels in STZ-induced diabetic rats. Can J Physiol Pharmacol 92(6):438–444
Paolisso G, Scheen A, d’Onofrio F, Lefebvre P (1990) Magnesium and glucose homeostasis. Diabetologia 33(9):511–514
Takaya J, Higashino H, Kobayashi Y (2004) Intracellular magnesium and insulin resistance. Magnes Res 17(2):126–136
Rodríguez-Morán M, Guerrero-Romero F (2011) Insulin secretion is decreased in non-diabetic individuals with hypomagnesaemia. Diabetes Metab Res Rev 27(6):590–596
Balkwill FR (2000) The cytokine network: frontiers in molecular biology. Oxford University Press, London
Kim Y-B, Nikoulina SE, Ciaraldi TP, Henry RR, Kahn BB (1999) Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J Clin Invest 104(6):733–741
Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414(6865):799–806
Choi K, Kim Y-B (2010) Molecular mechanism of insulin resistance in obesity and type 2 diabetes. Korean J Intern Med 25(2):119–129
Saad M, Folli F, Kahn JA, Kahn CR (1993) Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. J Clin Invest 92(4):2065–2072
Whiteman EL, Cho H, Birnbaum MJ (2002) Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metab 13(10):444–451
Olfert E, Cross B, McWilliam A (1993) Canadian Council on Animal Care—guide to the care and use of experimental animals, vol. 1. Brada Printing Services, Ottawa, ON
Sohrabipour S, Sharifi MR, Sharifi M, Talebi A, Soltani N (2018) Effect of magnesium sulfate administration to improve insulin resistance in type 2 diabetes animal model: using the hyperinsulinemic-euglycemic clamp technique. Fundam Clin Pharmacol 32(6):603–616
Andrikopoulos S, Blair AR, Deluca N, Fam BC, Proietto J (2008) Evaluating the glucose tolerance test in mice. Am J Physiol Endocrinol Metab 295(6):E1323–E1332
Wang ZJ (2004) The role of drag in insect hovering. J Exp Biol 207(23):4147–4155
Cheng L, Song J, Li G, Liu Y, Wang Y, Meng X, Sun G, Sun X (2017) Effects of the Tangningtongluo formula as an alternative strategy for diabetics via upregulation of insulin receptor substrate-1. Mol Med Rep 16(1):703–709
Rude RK (1998) Magnesium deficiency: a cause of heterogenous disease in humans. J Bone Miner Res 13(4):749–758
Bertinato J, Xiao CW, Ratnayake WN, Fernandez L, Lavergne C, Wood C, Swist E (2015) Lower serum magnesium concentration is associated with diabetes, insulin resistance, and obesity in South Asian and white Canadian women but not men. Food Nutr Res 59(1):25974
Guerrero-Romero F, Rodríguez-Morán M (2011) Magnesium improves the beta-cell function to compensate variation of insulin sensitivity: double-blind, randomized clinical trial. Eur J Clin Investig 41(4):405–410
Suarez A, Pulido N, Casla A, Casanova B, Arrieta F, Romero R, Rovira A (1993) Decreased insulin sensitivity in skeletal muscle of hypomagnesemic rats. Springer Verlag, NEW YORK, NY 10010, pp A123–A123
Chutia H, Lynrah KG (2015) Association of serum magnesium deficiency with insulin resistance in type 2 diabetes mellitus. J Lab Phys 7(2):75–78
Abel ED, Peroni O, Kim JK, Kim Y-B, Boss O, Hadro E, Minnemann T, Shulman GI, Kahn BB (2001) Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409(6821):729–733
Gandhi GR, Jothi G, Antony PJ, Balakrishna K, Paulraj MG, Ignacimuthu S, Stalin A, Al-Dhabi NA (2014) Gallic acid attenuates high-fat diet fed-streptozotocin-induced insulin resistance via partial agonism of PPARγ in experimental type 2 diabetic rats and enhances glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway. Eur J Pharmacol 745:201–216
Hajduch E, Litherland GJ, Hundal HS (2001) Protein kinase B (PKB/Akt)–a key regulator of glucose transport? FEBS Lett 492(3):199–203
Lee C-H, Shieh Y-S, Hsiao F-C, Kuo F-C, Lin C-Y, Hsieh C-H, Hung Y-J (2014) High glucose induces human endothelial dysfunction through an Axl-dependent mechanism. Cardiovasc Diabetol 13(1):53
Wang Y, Fofana B, Roy M, Ghose K, Yao X-H, Nixon M-S, Nair S, Nyomba GB (2015) Flaxseed lignan secoisolariciresinol diglucoside improves insulin sensitivity through upregulation of GLUT4 expression in diet-induced obese mice. J Funct Foods 18:1–9
Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, Coskran T, Black SC, Brees DJ, Wicks JR (2003) Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBβ. J Clin Invest 112(2):197–208
Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ). Science 292(5522):1728–1731
Wang J, Ma X-Y, Feng Y-F, Ma Z-S, Ma T-C, Zhang Y, Li X, Wang L, Lei W (2017) Magnesium ions promote the biological behaviour of rat calvarial osteoblasts by activating the PI3K/Akt signalling pathway. Biol Trace Elem Res 179(2):284–293
Maria Z, Campolo AR, Lacombe VA (2015) Diabetes alters the expression and translocation of the insulin-sensitive glucose transporters 4 and 8 in the atria. PLoS One 10(12):e0146033
Sylow L, Kleinert M, Pehmøller C, Prats C, Chiu TT, Klip A, Richter EA, Jensen TE (2014) Akt and Rac1 signaling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance. Cell Signal 26(2):323–331
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This study was supported by the Hormozgan University of Medical Science under grant number 9471.
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The animals were managed in agreement with the criteria defined in the NIH publication no. 85-23, revised in 1985, and the experimental protocol was approved by the Ethics Committee HUMS REC.1394.112 for Animal Care of Hormozgan University of Medical Sciences.
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Kamran, M., Kharazmi, F., Malekzadeh, K. et al. Effect of Long-term Administration of Oral Magnesium Sulfate and Insulin to Reduce Streptozotocin-Induced Hyperglycemia in Rats: the Role of Akt2 and IRS1 Gene Expressions. Biol Trace Elem Res 190, 396–404 (2019). https://doi.org/10.1007/s12011-018-1555-z
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DOI: https://doi.org/10.1007/s12011-018-1555-z