open access

Vol 6, No 3 (2017)
REVIEW ARTICLES
Published online: 2017-09-29
Get Citation

Role of purinergic signalling and proinflammatory cytokines in diabetes

Marek Cieślak, Michał Cieślak
DOI: 10.5603/DK.2017.0015
·
Clinical Diabetology 2017;6(3):90-100.

open access

Vol 6, No 3 (2017)
REVIEW ARTICLES
Published online: 2017-09-29

Abstract

 Extracellular purines activate P1 adenosine receptors and P2 nucleotide receptors. These receptors are pre­sent on the pancreatic islet cells as well as on hepato­cytes, adipocytes, pancreatic blood vessels and nerves. ATP is released together with insulin from b-cell gran­ules in response to a rapid decrease in blood glucose levels. The ATP-dependent P2X receptor activation on pancreatic b-cells results in a positive autocrine signal and subsequent insulin secretion. Adenosine, through activation of P1 receptors present on adipocytes and pancreatic islet cells, inhibits the release of insulin. Adenosine activates A2B receptors thereby stimulating production of IL-6 and other cytokines, which increases insulin resistance. Interleukin-6 also plays an important role in diabetes. In type 2 diabetes and obesity, the long-term increase of IL-6 concentration in blood above 5 pg/mL leads to the chronic and permanent increase in expression of SOCS3, contributing to the increase in insulin resistance in cells of the skeletal muscles, liver and adipose tissue. In diabetes there is an increased synthesis and release of pro-inflammatory cytokines, which cause the damage of the pancreatic islet cells, and in type 2 diabetes cause the development of insulin resistance. Ecto-enzymes metabolizing nucleotides are involved in the termination of the nucleotide signalling pathway and play the key role in regulation of extracel­lular ATP concentration. Ecto-NTPDases in cooperation with 5’-nucleotidase may significantly increase ecto-adenosine concentration. NTPDase3 activity has only been demonstrated on Langerhans cells. NTPDase3 may influence the secretion of insulin by hydrolysing adenine nucleotides. In diabetes the pro-inflammatory cytokines such as interleukin 1b (IL-1b), tumour ne­crosis factor-a (TNF-a) and interferon-g (IFN-g), as well as pancreatic derived factor PANDER are involved in the apoptosis of pancreatic b-cells. This causes distur­bance of the balance between pro-inflammatory and protective cytokines. We believe that neutralization of pro-inflammatory cytokines, especially interleukin 1b, with the IL-1 receptor antagonist (IL-1Ra) and/or IL-1b antibodies might cause the reduction of the inflamma­tory process in pancreas islets, normalize concentration of glucose in blood and decrease the insulin resistance. (Clin Diabetol 2017; 6, 3: 90–100)

Abstract

 Extracellular purines activate P1 adenosine receptors and P2 nucleotide receptors. These receptors are pre­sent on the pancreatic islet cells as well as on hepato­cytes, adipocytes, pancreatic blood vessels and nerves. ATP is released together with insulin from b-cell gran­ules in response to a rapid decrease in blood glucose levels. The ATP-dependent P2X receptor activation on pancreatic b-cells results in a positive autocrine signal and subsequent insulin secretion. Adenosine, through activation of P1 receptors present on adipocytes and pancreatic islet cells, inhibits the release of insulin. Adenosine activates A2B receptors thereby stimulating production of IL-6 and other cytokines, which increases insulin resistance. Interleukin-6 also plays an important role in diabetes. In type 2 diabetes and obesity, the long-term increase of IL-6 concentration in blood above 5 pg/mL leads to the chronic and permanent increase in expression of SOCS3, contributing to the increase in insulin resistance in cells of the skeletal muscles, liver and adipose tissue. In diabetes there is an increased synthesis and release of pro-inflammatory cytokines, which cause the damage of the pancreatic islet cells, and in type 2 diabetes cause the development of insulin resistance. Ecto-enzymes metabolizing nucleotides are involved in the termination of the nucleotide signalling pathway and play the key role in regulation of extracel­lular ATP concentration. Ecto-NTPDases in cooperation with 5’-nucleotidase may significantly increase ecto-adenosine concentration. NTPDase3 activity has only been demonstrated on Langerhans cells. NTPDase3 may influence the secretion of insulin by hydrolysing adenine nucleotides. In diabetes the pro-inflammatory cytokines such as interleukin 1b (IL-1b), tumour ne­crosis factor-a (TNF-a) and interferon-g (IFN-g), as well as pancreatic derived factor PANDER are involved in the apoptosis of pancreatic b-cells. This causes distur­bance of the balance between pro-inflammatory and protective cytokines. We believe that neutralization of pro-inflammatory cytokines, especially interleukin 1b, with the IL-1 receptor antagonist (IL-1Ra) and/or IL-1b antibodies might cause the reduction of the inflamma­tory process in pancreas islets, normalize concentration of glucose in blood and decrease the insulin resistance. (Clin Diabetol 2017; 6, 3: 90–100)

Get Citation

Keywords

diabetes mellitus, nucleotides, adenosine, purinergic receptors, ecto-nucleotidases, proinflammatory cytokines.

About this article
Title

Role of purinergic signalling and proinflammatory cytokines in diabetes

Journal

Clinical Diabetology

Issue

Vol 6, No 3 (2017)

Pages

90-100

Published online

2017-09-29

DOI

10.5603/DK.2017.0015

Bibliographic record

Clinical Diabetology 2017;6(3):90-100.

Keywords

diabetes mellitus
nucleotides
adenosine
purinergic receptors
ecto-nucleotidases
proinflammatory cytokines.

Authors

Marek Cieślak
Michał Cieślak

References (104)
  1. Burnstock G, Novak I. Purinergic signalling and diabetes. Purinergic Signal. 2013; 9(3): 307–324.
  2. Burnstock G. Purinergic signalling in endocrine organs. Purinergic Signal. 2013; 9(3): 307–324.
  3. Memon AA, Sundquist J, Wang X, et al. The association between cytokines and insulin sensitivity in Iraqi immigrants and native Swedes. BMJ Open. 2013; 3(11): e003473.
  4. Asakawa H, Miyagawa J, Hanafusa T, et al. High glucose and hyperosmolarity increase secretion of interleukin-1 beta in cultured human aortic endothelial cells. J Diabetes Complications. 1997; 11(3): 176–179.
  5. Harding HP, Ron D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes. 2002; 51 Suppl 3: S455–S461.
  6. Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002; 106(16): 2067–2072.
  7. Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes. 2004; 53 Suppl 3: S16–S21.
  8. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993; 259(5091): 87–91.
  9. Hotamisligil GS. Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes. Diabetes. 2005; 54 Suppl 2: S73–S78.
  10. BÖCX P. Fate of ATP in secretory granules: Phosphohydrolase studies in pancreatic vascular bed. Archives of Histology and Cytology. 1989; 52(Suppl): 85–90.
  11. Lavoie EG, Fausther M, Kauffenstein G, et al. Identification of the ectonucleotidases expressed in mouse, rat, and human Langerhans islets: potential role of NTPDase3 in insulin secretion. Am J Physiol Endocrinol Metab. 2010; 299(4): E647–E656.
  12. Burnstock G, Novak I. Purinergic signalling in the pancreas in health and disease. J Endocrinol. 2012; 213(2): 123–141.
  13. Wang C, Geng B, Cui Q, et al. Intracellular and extracellular adenosine triphosphate in regulation of insulin secretion from pancreatic β cells (β). J Diabetes. 2014; 6(2): 113–119.
  14. Chapal J, Loubatières-Mariani MM, Petit P, et al. Evidence for an A2-subtype adenosine receptor on pancreatic glucagon secreting cells. Br J Pharmacol. 1985; 86(3): 565–569.
  15. RODRIGUE-CANDELA JL, MARTIN-HERNANDEZ D, CASTILLA-CORTAZAR T. Stimulation of insulin secretion in vitro by adenosine triphosphate. Nature. 1963; 197: 1304.
  16. Squires PE, James RF, London NJ, et al. ATP-induced intracellular Ca2+ signals in isolated human insulin-secreting cells. Pflugers Arch. 1994; 427(1-2): 181–183.
  17. Petit P, Lajoix AD, Gross R. P2 purinergic signalling in the pancreatic beta-cell: control of insulin secretion and pharmacology. Eur J Pharm Sci. 2009; 37(2): 67–75.
  18. Santini E, Cuccato S, Madec S, et al. Extracellular adenosine 5'-triphosphate modulates insulin secretion via functionally active purinergic receptors of X and Y subtype. Endocrinology. 2009; 150(6): 2596–2602.
  19. Jacques-Silva MC, Cabrera O, Makeeva N, et al. Endogenously relesed ATP serves as a positive autocrine feedback loop for the human pancreatic beta cell. Purinergic Signal. 2008; 4: S49.
  20. Jacques-Silva MC, Correa-Medina M, Cabrera O, et al. ATP-gated P2X3 receptors constitute a positive autocrine signal for insulin release in the human pancreatic beta cell. Proc Natl Acad Sci U S A. 2010; 107(14): 6465–6470.
  21. Lugo-Garcia L, Nadal B, Gomis R, et al. Human pancreatic islets express the purinergic P2Y11 and P2Y12 receptors. Horm Metab Res. 2008; 40(11): 827–830.
  22. Tahani HM. The purinergic nerve hypothesis and insulin secretion. Z Ernahrungswiss. 1979; 18(2): 128–138.
  23. Leitner JW, Sussman KE, Vatter AE, et al. Adenine nucleotides in the secretory granule fraction of rat islets. Endocrinology. 1975; 96(3): 662–677.
  24. Loubatières-Mariani MM, Loubatières AL, Chapal J, et al. [Adenosine triphosphate (ATP) and glucose. Action on insulin and glucagon secretion]. C R Seances Soc Biol Fil. 1976; 170(4): 833–836.
  25. Karanauskaite J, Hoppa MB, Braun M, et al. Quantal ATP release in rat beta-cells by exocytosis of insulin-containing LDCVs. Pflugers Arch. 2009; 458(2): 389–401.
  26. Fernandez-Alvarez J, Hillaire-Buys D, Loubatières-Mariani MM, et al. P2 receptor agonists stimulate insulin release from human pancreatic islets. Pancreas. 2001; 22(1): 69–71.
  27. Stam NJ, Klomp J, Van de Heuvel N, et al. Molecular cloning and characterization of a novel orphan receptor (P2P) expressed in human pancreas that shows high structural homology to the P2U purinoceptor. FEBS Lett. 1996; 384(3): 260–264.
  28. Ohtani M, Suzuki JI, Jacobson KA, et al. Evidence for the possible involvement of the P2Y(6) receptor in Ca (2+) mobilization and insulin secretion in mouse pancreatic islets. Purinergic Signal. 2008; 4(4): 365–375.
  29. Parandeh F, Abaraviciene SM, Amisten S, et al. Uridine diphosphate (UDP) stimulates insulin secretion by activation of P2Y6 receptors. Biochem Biophys Res Commun. 2008; 370(3): 499–503.
  30. Amisten S, Meidute-Abaraviciene S, Tan C, et al. ADP mediates inhibition of insulin secretion by activation of P2Y13 receptors in mice. Diabetologia. 2010; 53(9): 1927–1934.
  31. Léon C, Freund M, Latchoumanin O, et al. The P2Y(1) receptor is involved in the maintenance of glucose homeostasis and in insulin secretion in mice. Purinergic Signal. 2005; 1(2): 145–151.
  32. Fredholm BB, IJzerman AP, Jacobson KA, et al. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol Rev. 2011; 63(1): 1–34.
  33. Rüsing D, Müller CE, Verspohl EJ. The impact of adenosine and A(2B) receptors on glucose homoeostasis. J Pharm Pharmacol. 2006; 58(12): 1639–1645.
  34. Johansson SM, Salehi A, Sandström ME, et al. A1 receptor deficiency causes increased insulin and glucagon secretion in mice. Biochem Pharmacol. 2007; 74(11): 1628–1635.
  35. Tudurí E, Filiputti E, Carneiro EM, et al. Inhibition of Ca2+ signaling and glucagon secretion in mouse pancreatic alpha-cells by extracellular ATP and purinergic receptors. Am J Physiol Endocrinol Metab. 2008; 294(5): E952–E960.
  36. Salehi A, Parandeh F, Fredholm BB, et al. Absence of adenosine A1 receptors unmasks pulses of insulin release and prolongs those of glucagon and somatostatin. Life Sci. 2009; 85(11-12): 470–476.
  37. Yang GK, Fredholm BB, Kieffer TJ, et al. Improved blood glucose disposal and altered insulin secretion patterns in adenosine A(1) receptor knockout mice. Am J Physiol Endocrinol Metab. 2012; 303(2): E180–E190.
  38. WEIR G, KNOWLTON S, MARTIN D. Nucleotide and Nucleoside Stimulation of Glucagon Secretion. Endocrinology. 1975; 97(4): 932–936.
  39. Ismail NA, El Denshary EE, Montague W. Adenosine and the regulation of insulin secretion by isolated rat islets of Langerhans. Biochem J. 1977; 164(2): 409–413.
  40. Töpfer M, Burbiel CE, Müller CE, et al. Modulation of insulin release by adenosine A1 receptor agonists and antagonists in INS-1 cells: the possible contribution of 86Rb+ efflux and 45Ca2+ uptake. Cell Biochem Funct. 2008; 26(8): 833–843.
  41. Dhalla AK, Chisholm JW, Reaven GM, et al. A1 adenosine receptor: role in diabetes and obesity. Handb Exp Pharmacol. 2009(193): 271–295.
  42. Fain JN, Pointer RH, Ward WF. Effects of adenosine nucleosides on adenylate cyclase, phosphodiesterase, cyclic adenosine monophosphate accumulation, and lipolysis in fat cells. J Biol Chem. 1972; 247(21): 6866–6872.
  43. DOLE VP. Effect of nucleic acid metabolites on lipolysis in adipose tissue. J Biol Chem. 1961; 236: 3125–3130.
  44. Schwabe U, Ebert R, Erbler HC. Adenosine release from isolated fat cells and its significance for the effects of hormones on cyclic 3',5'-AMP levels and lipolysis. Naunyn Schmiedebergs Arch Pharmacol. 1973; 276(2): 133–148.
  45. Schwabe U, Ebert R. Stimulation of cyclic adenosine 3',5'-monophosphate accumulation and lipolysis in fat cells by adenosine deaminase. Naunyn Schmiedebergs Arch Pharmacol. 1974; 282(1): 33–44.
  46. Cheng JT, Chi TC, Liu IM. Activation of adenosine A1 receptors by drugs to lower plasma glucose in streptozotocin-induced diabetic rats. Auton Neurosci. 2000; 83(3): 127–133.
  47. Ma LJ, Mao SL, Taylor KL, et al. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes. 2004; 53(2): 336–346.
  48. Csoka B, Koscso B, Toro G, et al. A2B Adenosine Receptors Prevent Insulin Resistance by Inhibiting Adipose Tissue Inflammation via Maintaining Alternative Macrophage Activation. Diabetes. 2013; 63(3): 850–866.
  49. Linden J. New insights into the regulation of inflammation by adenosine. J Clin Invest. 2006; 116(7): 1835–1837.
  50. Ryzhov S, Zaynagetdinov R, Goldstein AE, et al. Effect of A2B adenosine receptor gene ablation on proinflammatory adenosine signaling in mast cells. J Immunol. 2008; 180(11): 7212–7220.
  51. Nieto-Vazquez I, Fernández-Veledo S, de Alvaro C, et al. Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle. Diabetes. 2008; 57(12): 3211–3221.
  52. Sarvas JL, Khaper N, Lees SJ. The IL-6 Paradox: Context Dependent Interplay of SOCS3 and AMPK. J Diabetes Metab. 2013; Suppl 13.
  53. Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol. 2004; 24(12): 5434–5446.
  54. Sochocka M. Rozpoznawanie patogenów przez wrodzony system odporności. Postępy Hig Med Dow. 2008; 62: 676–687.
  55. Challis RA, Budohoski L, McManus B, et al. Effects of an adenosine-receptor antagonist on insulin-resistance in soleus muscle from obese Zucker rats. Biochem J. 1984; 221(3): 915–917.
  56. Budohoski L, Challiss RA, Cooney GJ, et al. Reversal of dietary-induced insulin resistance in muscle of the rat by adenosine deaminase and an adenosine-receptor antagonist. Biochem J. 1984; 224(1): 327–330.
  57. Figler RA, Wang G, Srinivasan S, et al. Links between insulin resistance, adenosine A2B receptors, and inflammatory markers in mice and humans. Diabetes. 2011; 60(2): 669–679.
  58. Han DH, Hansen PA, Nolte LA, et al. Removal of adenosine decreases the responsiveness of muscle glucose transport to insulin and contractions. Diabetes. 1998; 47(11): 1671–1675.
  59. Kuroda M, Honnor RC, Cushman SW, et al. Regulation of insulin-stimulated glucose transport in the isolated rat adipocyte. cAMP-independent effects of lipolytic and antilipolytic agents. J Biol Chem. 1987; 262(1): 245–253.
  60. Robson SC, Sévigny J, Zimmermann H. The E-NTPDase family of ectonucleotidases: Structure function relationships and pathophysiological significance. Purinergic Signal. 2006; 2(2): 409–430.
  61. Chia JSJ, McRae JL, Cowan PJ, et al. The CD39-adenosinergic axis in the pathogenesis of immune and nonimmune diabetes. J Biomed Biotechnol. 2012; 2012: 320495.
  62. Lunkes GI, Lunkes D, Stefanello F, et al. Enzymes that hydrolyze adenine nucleotides in diabetes and associated pathologies. Thromb Res. 2003; 109(4): 189–194.
  63. Kittel A, Garrido M, Varga G. Localization of NTPDase1/CD39 in normal and transformed human pancreas. J Histochem Cytochem. 2002; 50(4): 549–556.
  64. Crack BE, Pollard CE, Beukers MW, et al. Pharmacological and biochemical analysis of FPL 67156, a novel, selective inhibitor of ecto-ATPase. Br J Pharmacol. 1995; 114(2): 475–481.
  65. Westfall TD, Kennedy C, Sneddon P. The ecto-ATPase inhibitor ARL 67156 enhances parasympathetic neurotransmission in the guinea-pig urinary bladder. Eur J Pharmacol. 1997; 329(2-3): 169–173.
  66. Lévesque SA, Lavoie EG, Lecka J, et al. Specificity of the ecto-ATPase inhibitor ARL 67156 on human and mouse ectonucleotidases. Br J Pharmacol. 2007; 152(1): 141–150.
  67. Künzli BM, Berberat PO, Giese T, et al. Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease. Am J Physiol Gastrointest Liver Physiol. 2007; 292(1): G223–G230.
  68. Munkonda MN, Pelletier J, Ivanenkov VV, et al. Characterization of a monoclonal antibody as the first specific inhibitor of human NTP diphosphohydrolase-3 : partial characterization of the inhibitory epitope and potential applications. FEBS J. 2009; 276(2): 479–496.
  69. Thompson LF, Eltzschig HK, Ibla JC, et al. Crucial role for ecto-5'-nucleotidase (CD73) in vascular leakage during hypoxia. J Exp Med. 2004; 200(11): 1395–1405.
  70. Verspohl EJ, Johannwille B, Waheed A, et al. Effect of purinergic agonists and antagonists on insulin secretion from INS-1 cells (insulinoma cell line) and rat pancreatic islets. Can J Physiol Pharmacol. 2002; 80(6): 562–568.
  71. Pickup JC, Chusney GD, Thomas SM, et al. Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sci. 2000; 67(3): 291–300.
  72. Wang C, Guan Y, Yang J. Cytokines in the Progression of Pancreatic β-Cell Dysfunction. Int J Endocrinol. 2010; 2010: 515136.
  73. Böni-Schnetzler M, Boller S, Debray S, et al. Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I. Endocrinology. 2009; 150(12): 5218–5229.
  74. Kawasaki E, Abiru N, Eguchi K. Prevention of type 1 diabetes: from the view point of beta cell damage. Diabetes Res Clin Pract. 2004; 66 Suppl 1: S27–S32.
  75. Ehses JA, Lacraz G, Giroix MH, et al. IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proc Natl Acad Sci U S A. 2009; 106(33): 13998–14003.
  76. Ahima R. Adipose Tissue as an Endocrine Organ. Obesity. 2006; 14(5): 242–249.
  77. Bassols J, Ortega FJ, Moreno-Navarrete JM, et al. Study of the proinflammatory role of human differentiated omental adipocytes. J Cell Biochem. 2009; 107(6): 1107–1117.
  78. Yang J, Gao Z, Robert CE, et al. Structure-function studies of PANDER, an islet specific cytokine inducing cell death of insulin-secreting beta cells. Biochemistry. 2005; 44(34): 11342–11352.
  79. Wang C, Burkhardt BR, Guan Y, et al. Role of pancreatic-derived factor in type 2 diabetes: evidence from pancreatic β cells and liver. Nutr Rev. 2012; 70(2): 100–106.
  80. Dinarello CA, Donath MY, Mandrup-Poulsen T. Role of IL-1beta in type 2 diabetes. Curr Opin Endocrinol Diabetes Obes. 2010; 17(4): 314–321.
  81. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006; 116(7): 1793–1801.
  82. Donath MY, Mandrup-Poulsen T. The use of interleukin-1-receptor antagonists in the treatment of diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2008; 4(5): 240–241.
  83. Donath MY, Böni-Schnetzler M, Ellingsgaard H, et al. Cytokine production by islets in health and diabetes: cellular origin, regulation and function. Trends Endocrinol Metab. 2010; 21(5): 261–267.
  84. Larsen CM, Faulenbach M, Vaag A, et al. [Interleukin-1 receptor antagonist-treatment of patients with type 2 diabetes]. Ugeskr Laeger. 2007; 169(45): 3868–3871.
  85. Kim EK, Song MY, Hwang TO, et al. Radix clematidis extract protects against cytokine- and streptozotocin-induced beta-cell damage by suppressing the NF-kappaB pathway. Int J Mol Med. 2008; 22(3): 349–356.
  86. Lv Na, Song MY, Kim EK, et al. Guggulsterone, a plant sterol, inhibits NF-kappaB activation and protects pancreatic beta cells from cytokine toxicity. Mol Cell Endocrinol. 2008; 289(1-2): 49–59.
  87. Song MY, Kim EK, Moon WS, et al. Sulforaphane protects against cytokine- and streptozotocin-induced beta-cell damage by suppressing the NF-kappaB pathway. Toxicol Appl Pharmacol. 2009; 235(1): 57–67.
  88. Eizirik DL, Miani M, Cardozo AK. Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. Diabetologia. 2013; 56(2): 234–241.
  89. Maedler K, Sergeev P, Ris F, et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002; 110(6): 851–860.
  90. Osborn O, Brownell SE, Sanchez-Alavez M, et al. Treatment with an Interleukin 1 beta antibody improves glycemic control in diet-induced obesity. Cytokine. 2008; 44(1): 141–148.
  91. Larsen L, Størling J, Darville M, et al. Extracellular signal-regulated kinase is essential for interleukin-1-induced and nuclear factor kappaB-mediated gene expression in insulin-producing INS-1E cells. Diabetologia. 2005; 48(12): 2582–2590.
  92. Lacraz G, Giroix MH, Kassis N, et al. Islet endothelial activation and oxidative stress gene expression is reduced by IL-1Ra treatment in the type 2 diabetic GK rat. PLoS One. 2009; 4(9): e6963.
  93. Klueh U, Antar O, Qiao Yi, et al. Role of interleukin-1/interleukin-1 receptor antagonist family of cytokines in long-term continuous glucose monitoring in vivo. J Diabetes Sci Technol. 2013; 7(6): 1538–1546.
  94. Movahedi B, Van de Casteele M, Caluwé N, et al. Human pancreatic duct cells can produce tumour necrosis factor-alpha that damages neighbouring beta cells and activates dendritic cells. Diabetologia. 2004; 47(6): 998–1008.
  95. Chang I, Cho N, Kim S, et al. Role of calcium in pancreatic islet cell death by IFN-gamma/TNF-alpha. J Immunol. 2004; 172(11): 7008–7014.
  96. Chen H, Ren An, Hu S, et al. The significance of tumor necrosis factor-alpha in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Res Clin Pract. 2007; 75(3): 327–332.
  97. Steinberg GR, Michell BJ, van Denderen BJW, et al. Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab. 2006; 4(6): 465–474.
  98. Xu W, Gao Z, Wu J, et al. Interferon-gamma-induced regulation of the pancreatic derived cytokine FAM3B in islets and insulin-secreting betaTC3 cells. Mol Cell Endocrinol. 2005; 240(1-2): 74–81.
  99. Kado S, Nagase T, Nagata N. Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. Acta Diabetol. 1999; 36(1-2): 67–72.
  100. Mirza S, Hossain M, Mathews C, et al. Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: a cross-sectional study. Cytokine. 2012; 57(1): 136–142.
  101. Fain JN, Madan AK, Hiler ML, et al. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology. 2004; 145(5): 2273–2282.
  102. Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010; 40(7): 1830–1835.
  103. Ryba-Stanisławowska M, Skrzypkowska M, Myśliwska J, et al. The serum IL-6 profile and Treg/Th17 peripheral cell populations in patients with type 1 diabetes. Mediators Inflamm. 2013; 2013: 205284.
  104. Xiang JN, Chen DL, Yang LY. Effect of PANDER in βTC6-cell lipoapoptosis and the protective role of exendin-4. Biochem Biophys Res Commun. 2012; 421(4): 701–706.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

Czasopismo Diabetologia Kliniczna dostęne jest również w Ikamed - księgarnia medyczna

Wydawcą serwisu jest  "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl