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Mohamed Mesbah M, Ahmed Rashed L, Ahmed El-Boghdady N, Mohamed Said M. Bone Marrow-Derived Mesenchymal Stem Cells and Pioglitazone or Exendin-4 Synergistically Improve Insulin Resistance via Multiple Modulatory Mechanisms in High-Fat Diet/Streptozotocin-Induced Diabetes in Rats. rbmb.net 2023; 12 (1) :42-58
URL: http://rbmb.net/article-1-1091-en.html
URL: http://rbmb.net/article-1-1091-en.html
Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt.
Abstract: (1592 Views)
Background: Diabetes mellitus (DM) is a metabolic disease, characterized by hyperglycemia resulting from defects in insulin secretion and/or insulin action. The current study was designed to assess the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) alone and in combination with pioglitazone (Pz) or exendin-4 (Ex) in high-fat diet/streptozotocin (HFD/STZ)-induced diabetes in rats.
Methods: The rats were subjected to the HFD for three weeks before being injected with a single low dosage of STZ (35 mg/kg bw). The animals were assigned to different treatment groups after type II diabetes mellitus (T2DM) induction was confirmed.
Results: Severe insulin resistance was verified in untreated HFD/STZ T2DM rats, along with the exaggeration of oxidative stress, inflammation, apoptosis, and autophagy suppression in the adipose tissues. Monotherapy of HFD/T2DM rats with BM-MSCs and Pz or Ex alleviated diabetic complications by increasing insulin sensitivity, decreasing apoptosis and inflammation as evidenced by a decrease in serum tumor necrosis factor-alpha, caspase-3, and nuclear factor-kappa B (NF-kB) genes expression and Janus kinase (JNK) protein expression, and enhancing autophagy as revealed by upregulation in beclin and LC3, as well as peroxisome proliferator-activated receptor-g coactivator-1 alpha (PGC-1α) genes expression in the adipose tissues. An augmented ameliorative efficacy was recorded in combined treatments. The biochemical and molecular results were confirmed by histological investigation of pancreatic tissues.
Conclusions: Combining Pz or Ex with BM-MSCs is a synergistic therapeutic option that reduces insulin resistance and subsequent complications in T2DM via multiple molecular mechanisms.
Methods: The rats were subjected to the HFD for three weeks before being injected with a single low dosage of STZ (35 mg/kg bw). The animals were assigned to different treatment groups after type II diabetes mellitus (T2DM) induction was confirmed.
Results: Severe insulin resistance was verified in untreated HFD/STZ T2DM rats, along with the exaggeration of oxidative stress, inflammation, apoptosis, and autophagy suppression in the adipose tissues. Monotherapy of HFD/T2DM rats with BM-MSCs and Pz or Ex alleviated diabetic complications by increasing insulin sensitivity, decreasing apoptosis and inflammation as evidenced by a decrease in serum tumor necrosis factor-alpha, caspase-3, and nuclear factor-kappa B (NF-kB) genes expression and Janus kinase (JNK) protein expression, and enhancing autophagy as revealed by upregulation in beclin and LC3, as well as peroxisome proliferator-activated receptor-g coactivator-1 alpha (PGC-1α) genes expression in the adipose tissues. An augmented ameliorative efficacy was recorded in combined treatments. The biochemical and molecular results were confirmed by histological investigation of pancreatic tissues.
Conclusions: Combining Pz or Ex with BM-MSCs is a synergistic therapeutic option that reduces insulin resistance and subsequent complications in T2DM via multiple molecular mechanisms.
Keywords: Exendin-4, High-fat diet, Mesenchymal stem cells, Pioglitazone, Streptozotocin, Type II diabetes mellitus.
Type of Article: Original Article |
Subject:
Biochemistry
Received: 2022/11/10 | Accepted: 2023/01/8 | Published: 2023/08/15
Received: 2022/11/10 | Accepted: 2023/01/8 | Published: 2023/08/15
References
1. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045. Diabetes Res Clin Pract. 2019;157:107843. [DOI:10.1016/j.diabres.2019.107843] [PMID]
2. Joudaki R, Setorki M. The protective effect of Satureja bachtiarica hydroalcoholic extract on streptozotocin-induced diabetes through modulating glucose transporter 2 and 4 expression and inhibiting oxidative stress. Pharm Biol. 2019;57(1):318-327. [DOI:10.1080/13880209.2019.1597131] [PMID] [PMCID]
3. Chen C, Cohrs CM, Stertmann J, Bozsak R, Speier S. Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis. Mol Metab. 2017;6(9):943-957. [DOI:10.1016/j.molmet.2017.06.019] [PMID] [PMCID]
4. Ota T. Chemokine systems link obesity to insulin resistance. Diabetes Metab J. 2013;37(3):165-72. [DOI:10.4093/dmj.2013.37.3.165] [PMID] [PMCID]
5. Caballero AE. Long-term studies of treatments for type 2 diabetes. Postgrad Med. 2017;129(3):352-365. [DOI:10.1080/00325481.2017.1265417] [PMID]
6. Zang L, Hao H, Liu J, Li Y, Han W, Mu Y. Mesenchymal stem cell therapy in type 2 diabetes mellitus. Diabetol Metab Syndr. 2017;9:36. [DOI:10.1186/s13098-017-0233-1] [PMID] [PMCID]
7. Yang JS, Lu CC, Kuo SC, Hsu YM, Tsai SC, Chen SY, et al. Autophagy and its link to type II diabetes mellitus. Biomedicine (Taipei). 2017;7(2):8. [DOI:10.1051/bmdcn/2017070201] [PMID] [PMCID]
8. Demirtas L, Guclu A, Erdur FM, Akbas EM, Ozcicek A, Onk D, Turkmen K. Apoptosis, autophagy & endoplasmic reticulum stress in diabetes mellitus. Indian J Med Res. 2016;144(4):515-524.
9. Thulesen J, Orskov C, Holst JJ, Poulsen SS. Short-term insulin treatment prevents the diabetogenic action of streptozotocin in rats. Endocrinology. 1997;138(1):62-8. [DOI:10.1210/endo.138.1.4827] [PMID]
10. Ahire YS, Ghaisas MM, Dandawate P. Beneficial effects of co-administration of PPAR-γ agonist with melatonin on cardiovascular complications associated with diabetes. Young Sci. 2013;4(1): 59-68. [DOI:10.4103/2229-5186.108809]
11. Wang A, Li T, An P, Yan W, Zheng H, Wang B, Mu Y. Exendin-4 Upregulates Adiponectin Level in Adipocytes via Sirt1/Foxo-1 Signaling Pathway. PLoS One. 2017;12(1):e0169469. [DOI:10.1371/journal.pone.0169469] [PMID] [PMCID]
12. Ghelani H, Razmovski-Naumovski V, Nammi S. Chronic treatment of (R)-α-lipoic acid reduces blood glucose and lipid levels in high-fat diet and low-dose streptozotocin-induced metabolic syndrome and type 2 diabetes in Sprague-Dawley rats. Pharmacol Res Perspect. 2017;5(3):e00306. [DOI:10.1002/prp2.306] [PMID] [PMCID]
13. Duan B, Zhao Z, Lin L, Jin J, Zhang L, et al. Antidiabetic effect of Tibetan medicine tang-kang-fu-san on high-fat diet and streptozotocin-induced type 2 diabetic rats. Evid Based Complement Alternat Med. 2017;2017:7302965. [DOI:10.1155/2017/7302965] [PMID] [PMCID]
14. Alhadlaq A, Mao JJ. Mesenchymal stem cells: isolation and therapeutics. Stem Cells Dev. 2004;13(4):436-48. [DOI:10.1089/scd.2004.13.436] [PMID]
15. Abdel Aziz MT, Wassef MA, Ahmed HH, Rashed L, Mahfouz S, et al. The role of bone marrow derived-mesenchymal stem cells in attenuation of kidney function in rats with diabetic nephropathy. Diabetol Metab Syndr. 2014;6(1):34. [DOI:10.1186/1758-5996-6-34] [PMID] [PMCID]
16. Trinder P. Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J Clin Pathol. 1969;22(2):158-61. [DOI:10.1136/jcp.22.2.158] [PMID] [PMCID]
17. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide. 2001;5(1):62-71. [DOI:10.1006/niox.2000.0319] [PMID]
18. Yoshioka T, Kawada K, Shimada T, Mori M. Lipid peroxidation in maternal and cord blood and protective mechanism against activated-oxygen toxicity in the blood. Am J Obstet Gynecol. 1979;135(3):372-6. [DOI:10.1016/0002-9378(79)90708-7] [PMID]
19. Koracevic D, Koracevic G, Djordjevic V, Andrejevic S, Cosic V. Method for the measurement of antioxidant activity in human fluids. J Clin Pathol. 2001;54(5):356-61. [DOI:10.1136/jcp.54.5.356] [PMID] [PMCID]
20. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-54. [DOI:10.1016/0003-2697(76)90527-3] [PMID]
21. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-8. [DOI:10.1006/meth.2001.1262] [PMID]
22. Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979;76(9):4350-4. [DOI:10.1073/pnas.76.9.4350] [PMID] [PMCID]
23. Mercuri F, Quagliaro L, Ceriello A. Oxidative stress evaluation in diabetes. Diabetes Technol Ther. 2000;2(4):589-600. [DOI:10.1089/15209150050502014] [PMID]
24. Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes. 2015;6(3):456-80. [DOI:10.4239/wjd.v6.i3.456] [PMID] [PMCID]
25. Lee YS, Park MS, Choung JS, Kim SS, Oh HH, Choi CS, et al. Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes. Diabetologia. 2012;55(9):2456-68. [DOI:10.1007/s00125-012-2592-3] [PMID]
26. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280(5):E745-51. [DOI:10.1152/ajpendo.2001.280.5.E745] [PMID]
27. Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature. 2002;420(6913):333-6. [DOI:10.1038/nature01137] [PMID]
28. Tuzcu M, Sahin N, Orhan C, Agca CA, Akdemir F, Tuzcu Z, et al. Impact of chromium histidinate on high fat diet induced obesity in rats. Nutr Metab (Lond). 2011;8:28. [DOI:10.1186/1743-7075-8-28] [PMID] [PMCID]
29. Rodríguez-Calvo R, Serrano L, Coll T, Moullan N, Sánchez RM, Merlos M, et al. Activation of peroxisome proliferator-activated receptor beta/delta inhibits lipopolysaccharide-induced cytokine production in adipocytes by lowering nuclear factor-kappaB activity via extracellular signal-related kinase 1/2. Diabetes. 2008;57(8):2149-57. [DOI:10.2337/db08-0176] [PMID] [PMCID]
30. Solinas G, Becattini B. JNK at the crossroad of obesity, insulin resistance, and cell stress response. Mol Metab. 2016;6(2):174-184. [DOI:10.1016/j.molmet.2016.12.001] [PMID] [PMCID]
31. Jansen HJ, van Essen P, Koenen T, Joosten LA, Netea MG, Tack CJ, Stienstra R. Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. Endocrinology. 2012;153(12):5866-74. [DOI:10.1210/en.2012-1625] [PMID]
32. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011;469(7330):323-35. [DOI:10.1038/nature09782] [PMID] [PMCID]
33. Wang Y, Li YB, Yin JJ, Wang Y, Zhu LB, Xie GY, Pan SH. Autophagy regulates inflammation following oxidative injury in diabetes. Autophagy. 2013;9(3):272-7. [DOI:10.4161/auto.23628] [PMID] [PMCID]
34. Si Y, Zhao Y, Hao H, Liu J, Guo Y, Mu Y, et al. Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: identification of a novel role in improving insulin sensitivity. Diabetes. 2012;61(6):1616-25. [DOI:10.2337/db11-1141] [PMID] [PMCID]
35. Hughey CC, Ma L, James FD, Bracy DP, Wang Z, Wasserman DH, et al. Mesenchymal stem cell transplantation for the infarcted heart: therapeutic potential for insulin resistance beyond the heart. Cardiovasc Diabetol. 2013;12:128. [DOI:10.1186/1475-2840-12-128] [PMID] [PMCID]
36. Zhao K, Hao H, Liu J, Tong C, Cheng Y, Xie Z, et al. Bone marrow-derived mesenchymal stem cells ameliorate chronic high glucose-induced β-cell injury through modulation of autophagy. Cell Death Dis. 2015;6(9):e1885. [DOI:10.1038/cddis.2015.230] [PMID] [PMCID]
37. Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 2008;77:289-312. [DOI:10.1146/annurev.biochem.77.061307.091829] [PMID]
38. Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004;351(11):1106-18. [DOI:10.1056/NEJMra041001] [PMID]
39. Mahmoudi A, Ghatreh Samani K, Amini SA, Heidarian E. Effects of Pioglitazone on the Lipid Profile, Serum Antioxidant Capacity, and UCP1 Gene Expression in Mouse Brown Adipose Tissue. Rep Biochem Mol Biol. 2019;8(1):15-20.
40. Smith U, Gogg S, Johansson A, Olausson T, Rotter V, Svalstedt B. Thiazolidinediones (PPARgamma agonists) but not PPARalpha agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes. FASEB J. 2001;15(1):215-220. [DOI:10.1096/fj.00-0020com] [PMID]
41. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359(9309):824-30. [DOI:10.1016/S0140-6736(02)07952-7] [PMID]
42. Kim Chung le T, Hosaka T, Yoshida M, Harada N, Sakaue H, Sakai T, Nakaya Y. Exendin-4, a GLP-1 receptor agonist, directly induces adiponectin expression through protein kinase A pathway and prevents inflammatory adipokine expression. Biochem Biophys Res Commun. 2009;390(3):613-8. [DOI:10.1016/j.bbrc.2009.10.015] [PMID]
43. Liu HY, Han J, Cao SY, Hong T, Zhuo D, Shi J, et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J Biol Chem. 2009;284(45):31484-92. [DOI:10.1074/jbc.M109.033936] [PMID] [PMCID]
44. Sharma S, Mells JE, Fu PP, Saxena NK, Anania FA. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS One. 2011;6(9):e25269. [DOI:10.1371/journal.pone.0025269] [PMID] [PMCID]
45. Mostafa Tork O, Ahmed Rashed L, Bakr Sadek N, Abdel-Tawab MS. Targeting Altered Mitochondrial Biogenesis in the Brain of Diabetic Rats: Potential Effect of Pioglitazone and Exendin-4. Rep Biochem Mol Biol. 2019;8(3):287-300.
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