RSS-Feed abonnieren
DOI: 10.1055/s-0032-1327590
Basal and T3-induced ROS Production in Lymphocyte Mitochondria is Increased in Type 2 Diabetic Patients
Publikationsverlauf
received 18. Juni 2012
accepted 06. September 2012
Publikationsdatum:
26. September 2012 (online)
Abstract
Mitochondrial function, including production of reactive oxygen species (ROS), is important in the pathogenesis of diabetes and its complications. Thyroid hormones are major regulator of these processes. Hence, the aim of this study was to examine the thyroid hormone regulation of ROS production in human lymphocytes in patients with diabetes mellitus type 2 (T2DM). Lymphocytes from 10 controls and 10 persons with T2DM were examined. Mitochondrial membrane potential (MMP) was examined by flow cytometry after staining with MitoTracker Green (MTG). Similarly ROS was measured following staining with carboxy-H2DCFDA. MMP was increased in T2DM patients and T3 stimulation increased MMP in controls [1 398 a.u. (979–4 094) vs. 2 156 a.u. (1 611–15 189), p=0.04, median and quartiles] as well as in T2DM patients [9 167 a.u. (7 387–11 746) vs. 20 274 a.u. (17 183–27 839 p=0.004, median and quartiles]. Basal ROS concentration was increased in lymphocytes from T2DM and T3 significantly stimulated ROS concentration in controls [3 691 a.u. (2 584–6 396) vs. 5 650 a.u. (3 001–7 802) p=0.013, median and quartiles] and in T2DM patients [19 271 a.u. (6 288–25 282) vs. 23 178 a.u. (10 004–28 857) p=0.013, median and quartiles]. The ratio of ROS production related to MMP was significantly higher in T2DM, unstimulated as well as T3-stimulated in T2DM. Unstimulated and T3 stimulated ROS production and MMP were higher in lymphocytes from diabetic patients. An altered balance between ROS production and MMP, favoring ROS production in T2DM patients, was found suggesting that an increased mitochondrial sensitivity for T3 may be a significant factor responsible for increased ROS activity in diabetic patients.
-
References
- 1 Sivitz W, Yorik M. Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities. Antioxid Redox Signal 2010; 12: 537-576
- 2 Venditti S, De Meo S. Thyroid hormone-induced oxidative stress. Cell Mol Life Sci 2006; 63: 414-434
- 3 Moreno M, de Lange P, Lombardi A, Silvestri E, Lanni A, Goglia F. Metabolic effects of thyroid hormone derivatives. Thyroid 2008; 18: 239-253
- 4 Weitzel J, Iwen K, Seitz H. Regulation of mitochondrial biogenesis by thyroid hormone. Exp Physiol 2003; 88: 121-128
- 5 Harper M, Seifert L. Thyroid hormone effects on mitochondrial energetics. Thyroid 2008; 18: 145-156
- 6 Kvetny J, Bomholt T, Pedersen P, Wilms L, Anthonsen S, Larsen J. Thyroid hormone effect on human mitochondria measured by flow cytometry. Scand J Clin Lab Invest 2009; 69: 772-776
- 7 Areujo A, Seibel F, Oliveira U, Fernandes T, Llesuy S, Kusharsky L, Belló-Klein A. Thyroid hormone.induced haemoglobin changes and antioxidant enzymes response in erythrocytes. Cell Biochem Funct 2011; 29: 408-413
- 8 Gnocchi D, Leoni S, Incerpi S, Bruscalupi G. 3,5,3′-Triiodothyronine (T3) stimulates cell proliferation through the activation of the P13K/Akt pathway and reactive oxygen species (ROS) production in chick embryo hepatocytes. Steroids 2012; 77: 589-595
- 9 Hirabayashi Y, Taniushi S, Kobayashi Y. A quantitative assay of oxidative metabolism by neutrophils in whole blood using flow cytometry. J Immunol Meth 1985; 82: 253-259
- 10 Robinson J, Bruner L, Bassoe CF, Hudson J, Ward P, Phan S. Measurements of intracellular fluorecense of human monocytes relative to oxidative metabolism. J Leucocyte Biol 1988; 43: 304-310
- 11 Eid H, Lyberg T, Larsen J, Arnesen H, Seljeflot I. Reactive oxygen species generation by leukocytes in populations at risk for atherosclerotic disease. Scand J Clin Lab Invest 2002; 62: 431-440
- 12 Khan S, Raghuram G, Bhargave A, Pathak N, Chandra D, Jain S, Mishra PK. Role and clinical significance of lymphocyte mitochondrial dysfunction in type 2 diabetes mellitus. Transl Res 2011; 158: 344-359
- 13 Magsino C, Hamouda V, Ghanim H, Browne R, Aljada A, Dandona P. Effect of Triiodothyronine on Reactive Oxygen Species Generation by Leukocytes, Indices of Oxidative Damage, and Antioxidant Reserve. Metabolism 2000; 49: 799-803
- 14 Kvetny J. 3,5-T2 stimulates oxygen consumption, but not glucose uptake in human mononuclear blood cells. Horm Metab Res 1991; 24: 322-325
- 15 Walsh J, Brenner A, Bulsara M, O’Leary P, Leedman P, Feddema P, Michelangeli V. Subclinical Thyroid Dysfunction as a Risk Factor for Cardiovascular Disease. Arch Intern Med 2005; 165: 2467-2472
- 16 Cheng S, Leonard J, Davis P. Molecular aspects of thyroid hormone actions. Endocrine Rev 2010; 31: 139-170
- 17 Weitzel JM, Iwen KA, Seitz HJ. Regulation of mitochondrial biogenesis by thyroid hormone. Exp Physiol 2003; 88: 121-128
- 18 Wrutniak-Cabello C, Casas F, Cabello G. Thyroid hormone action in mitochondria. J Mol Endocrinol 2001; 26: 67-77
- 19 Crunkhorn S, Patti M. Links between Thyroid Hormone Action, Oxidative Metabolism, and Diabetes Risk?. Thyroid 2008; 18: 227-237
- 20 Sakar M, Varshney M, Chopra M, Sehkri T, Adhikari J, Dwarakanath B. Flow-Cytometric Analysis of Reactive Oxygen Species in Peripheral Blood Mononuclear Cells of Patients with Thyroid Dysfunction. Clin Cytom 2005; 70B: 20-23
- 21 Mezosi E, Szabo J, Nagy E, Borbely A, Varga E, Paragh E, Varga Z. Nongenomic effect of thyroid hormone on free-radical production in human polymorphonuclear leukocytes. J Endocrinol 2005; 185: 121-129
- 22 Fernandez V, Tapia G, Varela P, Romanque P, Cartier-Ugarte D, Videla L. Thyroid hormone-induced oxidative stress in rodents and humans: A comparative view and relation to redox regulation of gene expressionB. Comp Biochem Physiol 2006; (Part C 142) 231-239
- 23 Friesema E, Kuiper G, Jansen J, Visser T, Kester M. Thyroid hormone transport by the human monocarboxylate transporter 8 and its rate-limiting role in intracellular metabolism. Mol Endocrinol 2006; 20: 2761-2772
- 24 Menzies K, Robinson B, Hood D. Effect of thyroid hormones on mitochondrial properties and oxidative stress in cells from patients with mtDNA defects. Am J Physiol 2009; 296: C355-C362
- 25 Widlansky M, Wang J, Shenouda S, Hagen T, Smith A, Kizhakekuttu T, Kluge MA, Weihrauch D, Gutterman DD, Vita JA. Altered mitochondrial membrane potential, mass, and morphology in the mononuclear cells of humans with type 2 diabetes. Transl Res 2010; 156: 15-25
- 26 Kvetny J, Wilms L, Pedersen P, Larsen J. Subclinical hypothyroidism affects mitochondrial function. Horm Metab Res 2010; 42: 324-327
- 27 Nishikawa T, Edelstein D, Du X, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giradino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404: 787-790
- 28 Pitozzi V, Giovannelli L, Bardini G, Rotella CM, Dolara P. Oxidative DNA damage in peripheral blood cells in type 2 diabetes mellitus: higher vulnerability of polymorphonuclear leukocytes. Mutat Res 2003; 529: 129-133
- 29 Korshunov S, Skulachef V, Starkov A. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 1997; 416: 15-18
- 30 Pendergrass W, Wolf N, Poot M. Efficacy of MitoTracker Green™ and CMXRosamine to Measure Changes in Mitochondrial Membrane Potentials in Living Cells and Tissues. Cytometry 2004; A:162-A:169
- 31 Lopez-Torres M, Romero M, Barja G. Effect of thyroid hormones on mitochondrial oxygen free radical production and DNA oxidative damage in the rat heart. Molecular and Cellular Endocrinology 2000; 168: 127-134
- 32 Yu T, Robotham J, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci USA 2006; 103: 2653-2658
- 33 Lambadiari V, Mitrou P, Raptis A, Tountas N, Raptis S, Dimitriadis G. Thyroid hormones are positively associated with insulin resistance early in the development of type 2 diabetes. Endocrine 2011; 39: 28-32
- 34 Rezzonico J, Niepomniszcze H, Rezzonico M, Pusiol E, Alberto M, Brenta G. The association of insulin resistance with subclinical thyrotoxicosis. Thyroid 2011; 21: 945-949
- 35 Peros P, McCrimmon R, Shaw G, Frier B. Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabetic Med 1996; 12: 622-637
- 36 Kvetny J. Nuclear thyroxine and triiodothyronine receptors in human mononuclear cells in diabetes mellitus. Diabetologia 1983; 24: 428-432
- 37 Kvetny J, Matzen L. Thyroid hormone stimulated glucose uptake in human mononuclear blood cells from normal persons and from patients with non-insulin-dependent diabetes mellitus. Acta Endocrinol 1989; 120: 715-720