Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: identification of a novel role in improving insulin sensitivity
Yiling Si, Yali Zhao, Haojie Hao, Jiejie Liu, Yelei Guo, Yiming Mu, Jing Shen, Yu Cheng, Xiaobing Fu, Weidong Han, Yiling Si, Yali Zhao, Haojie Hao, Jiejie Liu, Yelei Guo, Yiming Mu, Jing Shen, Yu Cheng, Xiaobing Fu, Weidong Han
Abstract
Infusion of mesenchymal stem cells (MSCs) has been shown to effectively lower blood glucose in diabetic individuals, but the mechanism involved could not be adequately explained by their potential role in promoting islet regeneration. We therefore hypothesized that infused MSCs might also contribute to amelioration of the insulin resistance of peripheral insulin target tissues. To test the hypothesis, we induced a diabetic rat model by high-fat diet/streptozotocin (STZ) administration, performed MSC infusion during the early phase (7 days) or late phase (21 days) after STZ injection, and then evaluated the therapeutic effects of MSC infusion and explored the possible mechanisms involved. MSC infusion ameliorated hyperglycemia in rats with type 2 diabetes (T2D). Infusion of MSCs during the early phase not only promoted β-cell function but also ameliorated insulin resistance, whereas infusion in the late phase merely ameliorated insulin resistance. Infusion of MSCs resulted in an increase of GLUT4 expression and an elevation of phosphorylated insulin receptor substrate 1 (IRS-1) and Akt (protein kinase B) in insulin target tissues. This is the first report of MSC treatment improving insulin sensitivity in T2D. These data indicate that multiple roles and mechanisms are involved in the efficacy of MSCs in ameliorating hyperglycemia in T2D.
Figures
References
- King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care 1998;21:1414–1431
- International Diabetes Federation. The Diabetes Atlas 3rd ed. Brussels, Belgium, International Diabetes Federation, 2006
- Nyenwe EA, Jerkins TW, Umpierrez GE, Kitabchi AE. Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism 2011;60:1–23
- Piya MK, Tahrani AA, Barnett AH. Emerging treatment options for type 2 diabetes. Br J Clin Pharmacol 2010;70:631–644
- Ezquer FE, Ezquer ME, Parrau DB, Carpio D, Yañez AJ, Conget PA. Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant 2008;14:631–640
- Hess D, Li L, Martin M, et al. Bone marrow-derived stem cells initiate pancreatic regeneration. Nat Biotechnol 2003;21:763–770
- Si YL, Zhao YL, Hao HJ, Fu XB, Han WD. MSCs: biological characteristics, clinical applications and their outstanding concerns. Ageing Res Rev 2011;10:93–103
- Ankrum J, Karp JM. Mesenchymal stem cell therapy: two steps forward, one step back. Trends Mol Med 2010;16:203–209
- Song H, Song BW, Cha MJ, Choi IG, Hwang KC. Modification of mesenchymal stem cells for cardiac regeneration. Expert Opin Biol Ther 2010;10:309–319
- Mizuno H. Adipose-derived stem and stromal cells for cell-based therapy: current status of preclinical studies and clinical trials. Curr Opin Mol Ther 2010;12:442–449
- Rosser AE, Zietlow R, Dunnett SB. Stem cell transplantation for neurodegenerative diseases. Curr Opin Neurol 2007;20:688–692
- Jiang R, Han Z, Zhuo G, et al. Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: a pilot study. Fr Medecine 2011;5:94–100
- Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes 2008;57:1759–1767
- Lee RH, Seo MJ, Reger RL, et al. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci USA 2006;103:17438–17443
- Ianus A, Holz GG, Theise ND, Hussain MA. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 2003;111:843–850
- Park KS, Kim YS, Kim JH, et al. Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation. Transplantation 2010;89:509–517
- Lin HV, Ren H, Samuel VT, et al. Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues. Diabetes 2011;60:700–709
- Waller AP, Burns TA, Mudge MC, Belknap JK, Lacombe VA. Insulin resistance selectively alters cell-surface glucose transporters but not their total protein expression in equine skeletal muscle. J Vet Intern Med 2011;25:315–321
- Reed MJ, Meszaros K, Entes LJ, et al. A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism 2000;49:1390–1394
- Mageed AS, Pietryga DW, DeHeer DH, West RA. Isolation of large numbers of mesenchymal stem cells from the washings of bone marrow collection bags: characterization of fresh mesenchymal stem cells. Transplantation 2007;83:1019–1026
- Bieback K, Kern S, Klüter H, Eichler H. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 2004;22:625–634
- Bonora E, Targher G, Alberiche M, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 2000;23:57–63
- Shen HQ, Zhu JS, Baron AD. Dose-response relationship of insulin to glucose fluxes in the awake and unrestrained mouse. Metabolism 1999;48:965–970
- Haluzik MM, Lacinova Z, Dolinkova M, et al. Improvement of insulin sensitivity after peroxisome proliferator-activated receptor-alpha agonist treatment is accompanied by paradoxical increase of circulating resistin levels. Endocrinology 2006;147:4517–4524
- Sahin K, Onderci M, Tuzcu M, et al. Effect of chromium on carbohydrate and lipid metabolism in a rat model of type 2 diabetes mellitus: the fat-fed, streptozotocin-treated rat. Metabolism 2007;56:1233–1240
- Ho JH, Tseng TC, et al. Multiple intravenous transplantations of mesenchymal stem cells effectively restore long-term blood glucose homeostasis by hepatic engraftment and beta cell differentiation in streptozotocin-induced diabetic mice. Cell Transplant. 14 October 2011 [Epub ahead of print]
- Ezquer F, Ezquer M, Simon V, Conget P. The antidiabetic effect of MSCs is not impaired by insulin prophylaxis and is not improved by a second dose of cells. PLoS ONE 2011;6:e16566.
- Fraulob JC, Ogg-Diamantino R, Fernandes-Santos C, Aguila MB, Mandarim-de-Lacerda CA. A mouse model of metabolic syndrome: insulin resistance, fatty liver and non-alcoholic fatty pancreas disease (NAFPD) in C57BL/6 mice fed a high fat diet. J Clin Biochem Nutr 2010;46:212–223
- Coronel MF, Musolino PL, Villar MJ. Selective migration and engraftment of bone marrow mesenchymal stem cells in rat lumbar dorsal root ganglia after sciatic nerve constriction. Neurosci Lett 2006;405:5–9
- Le Blanc K. Mesenchymal stromal cells: tissue repair and immune modulation. Cytotherapy 2006;8:559–561
- Leturque A, Brot-Laroche E, Le Gall M. GLUT2 mutations, translocation, and receptor function in diet sugar managing. Am J Physiol Endocrinol Metab 2009;296:E985–E992
- Rencurel F, Waeber G, Antoine B, et al. Requirement of glucose metabolism for regulation of glucose transporter type 2 (GLUT2) gene expression in liver. Biochem J 1996;314:903–909
- Gual P, Le Marchand-Brustel Y, Tanti JF. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 2005;87:99–109
- Chao KC, Chao KF, Fu YS, Liu SH. Islet-like clusters derived from mesenchymal stem cells in Wharton’s jelly of the human umbilical cord for transplantation to control type 1 diabetes. PLoS ONE 2008;3:e1451.
- Xie QP, Huang H, Xu B, et al. Human bone marrow mesenchymal stem cells differentiate into insulin-producing cells upon microenvironmental manipulation in vitro. Differentiation 2009;77:483–491
- Bell GI, Broughton HC, Levac KD, et al. Transplanted human bone marrow progenitor subtypes stimulate endogenous islet regeneration and revascularization. Stem Cells Dev. 21 Oct 2011 [Epub ahead of print]
- Park KS, Kim YS, Kim JH, et al. Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation. Transplantation 2010;89:509–517
- Anzalone R, Lo Iacono M, Loria T, et al. Wharton’s jelly mesenchymal stem cells as candidates for beta cells regeneration: extending the differentiative and immunomodulatory benefits of adult mesenchymal stem cells for the treatment of type 1 diabetes. Stem Cell Rev 2011;7:342–363
- Phinney DG, Prockop DJ. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair—current views. Stem Cells 2007;25:2896–2902
- Karp JM, Leng Teo GS. Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 2009;4:206–216
- Napoli R, Hirshman MF, Horton ES. Mechanisms and time course of impaired skeletal muscle glucose transport activity in streptozocin diabetic rats. J Clin Invest 1995;96:427–437
- Zisman A, Peroni OD, Abel ED, et al. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med 2000;6:924–928
- Hirshman MF, Goodyear LJ, Wardzala LJ, Horton ED, Horton ES. Identification of an intracellular pool of glucose transporters from basal and insulin-stimulated rat skeletal muscle. J Biol Chem 1990;265:987–991
- Funaki M, Benincasa K, Randhawa PK. Peptide rescues GLUT4 recruitment, but not GLUT4 activation, in insulin resistance. Biochem Biophys Res Commun 2007;360:891–896
Source: PubMed