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Diabetologia

Erschienen in:

01.09.2003 | Article

Haeme-oxygenase 1 expression in rat pancreatic beta cells is stimulated by supraphysiological glucose concentrations and by cyclic AMP

verfasst von: J. C. Jonas, MD PhD, Y. Guiot, J. Rahier, J. C. Henquin

Erschienen in: Diabetologia | Ausgabe 9/2003

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Abstract

Aim/hypothesis

Increased expression of haeme-oxygenase 1 (HO1) and other antioxidant enzymes could improve pancreatic beta-cell survival under stressful conditions, including hyperglycaemia. However, how hyperglycaemia increases islet HO1 expression is not known.

Methods

Rat islets were pre-cultured for 1 week in RPMI medium containing 10 mmol·l⁻¹ glucose (G10), and further cultured overnight in G5-G30 plus various test substances. Islet HO1 mRNA and protein expression was measured by semiquantitative RT-PCR, western blot, and immunohistochemistry.

Results

Islet HO1 mRNA expression was minimal after overnight culture in G10, slightly increased in G5, and increased by five- to ten-fold in G30 in parallel with a heterogeneous increase in beta-cell HO1 protein expression. The effect of G30 was fully inhibited by agents decreasing cytosolic Ca²⁺ (diazoxide, nimodipine), but was only slightly reproduced by agents raising Ca²⁺ (tolbutamide, 30 mmol·l⁻¹ potassium). It was also suppressed by the α₂-adrenoceptor agonist clonidine, whereas dibutyryl-cyclic-AMP largely increased beta-cell HO1 expression. The induction of HO1 mRNA expression by G30 was independent from changes in medium insulin concentration, but was completely inhibited by a cocktail of antioxidants. In contrast to HO1, islet mRNA expression of glutathione peroxidase and constitutive haeme-oxygenase 2 were not affected by G30, nor by dibutyryl-cyclic-AMP.

Conclusion/interpretation

High glucose and dibutyryl-cyclic-AMP stimulate expression of HO1 in rat pancreatic beta cells. The inhibition of HO1 expression in G30 by nimodipine, clonidine, and antioxidants, suggests that Ca²⁺ influx and cyclic-AMP are necessary for the generation of oxidative stress by G30, or for the stimulation of beta-cell HO1 expression by increased oxidative stress.

Tokuyama Y, Sturis J, DePaoli AM et al. (1995) Evolution of β-cell dysfunction in the male Zucker diabetic fatty rat. Diabetes 44:1447–1457PubMed

Weir GC, Sharma A, Zangen DH, Bonner-Weir S (1997) Transcription factor abnormalities as a cause of β cell dysfunction in diabetes: a hypothesis. Acta Diabetol 34:177–184CrossRefPubMed

Jonas JC, Sharma A, Hasenkamp W et al. (1999) Chronic hyperglycemia triggers loss of pancreatic β cell differentiation in an animal model of diabetes. J Biol Chem 274:14112–14121PubMed

Laybutt DR, Sharma A, Sgroi DC, Gaudet J, Bonner-Weir S, Weir GC (2002) Genetic regulation of metabolic pathways in β-cells disrupted by hyperglycemia. J Biol Chem 277:10912–10921CrossRefPubMed

Jonas JC, Laybutt DR, Steil GM et al. (2001) High glucose stimulates early response gene c-Myc expression in rat pancreatic β cells. J Biol Chem 276:35375–35381CrossRefPubMed

Laybutt DR, Weir GC, Kaneto H et al. (2002) Overexpression of c-Myc in β-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes. Diabetes 51:1793–1804PubMed

Pelengaris S, Khan M, Evan GI (2002) Suppression of Myc-induced apoptosis in β cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109:321–334PubMed

Laybutt DR, Kaneto H, Hasenkamp W et al. (2002) Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to β-cell survival during chronic hyperglycemia. Diabetes 51:413–423PubMed

Otterbein LE, Choi AM (2000) Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol 279:L1029–L1037PubMed

10.

Immenschuh S, Ramadori G (2000) Gene regulation of heme oxygenase-1 as a therapeutic target. Biochem Pharmacol 60:1121–1128CrossRefPubMed

11.

Welsh N, Sandler S (1994) Protective action by hemin against interleukin-1β induced inhibition of rat pancreatic islet function. Mol Cell Endocrinol 103:109–114CrossRefPubMed

12.

Tiedge M, Lortz S, Drinkgern J, Lenzen S (1997) Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes 46:1733–1742PubMed

13.

Ye J, Laychock SG (1998) A protective role for heme oxygenase expression in pancreatic islets exposed to interleukin-1β. Endocrinology 139:4155–4163PubMed

14.

Pileggi A, Molano RD, Berney T et al. (2001) Heme oxygenase-1 induction in islet cells results in protection from apoptosis and improved in vivo function after transplantation. Diabetes 50:1983–1991PubMed

15.

Tobiasch E, Gunther L, Bach FH (2001) Heme oxygenase-1 protects pancreatic β cells from apoptosis caused by various stimuli. J Investig Med 49:566–571PubMed

16.

Henningsson R, Alm P, Lundquist I (2001) Evaluation of islet heme oxygenase-CO and nitric oxide synthase-NO pathways during acute endotoxemia. Am J Physiol Cell Physiol 280:C1242–C1254PubMed

17.

Tanaka Y, Tran PO, Harmon J, Robertson RP (2002) A role for glutathione peroxidase in protecting pancreatic β cells against oxidative stress in a model of glucose toxicity. Proc Natl Acad Sci USA 99:12363–12368CrossRefPubMed

18.

Lortz S, Tiedge M (2003) Sequential inactivation of reactive oxygen species by combined overexpression of SOD isoforms and catalase in insulin-producing cells. Free Radic Biol Med 34:683–688CrossRefPubMed

19.

Pertusa JA, Nesher R, Kaiser N, Cerasi E, Henquin JC, Jonas JC (2002) Increased glucose sensitivity of stimulus-secretion coupling in islets from Psammomys obesus after diet induction of diabetes. Diabetes 51:2552–2560PubMed

20.

Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca²⁺ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450PubMed

21.

Clark JE, Foresti R, Green CJ, Motterlini R (2000) Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress. Biochem J 348 Pt 3:615–619

22.

Henningsson R, Alm P, Ekstrom P, Lundquist I (1999) Heme oxygenase and carbon monoxide: regulatory roles in islet hormone release: a biochemical, immunohistochemical, and confocal microscopic study. Diabetes 48:66–76PubMed

23.

Alm P, Ekstrom P, Henningsson R, Lundquist I (1999) Morphological evidence for the existence of nitric oxide and carbon monoxide pathways in the rat islets of Langerhans: an immunocytochemical and confocal microscopical study. Diabetologia 42:978–986CrossRefPubMed

24.

Sato H, Siow RC, Bartlett S et al. (1997) Expression of stress proteins heme oxygenase-1 and -2 in acute pancreatitis and pancreatic islet βTC3 and acinar AR42J cells. FEBS Lett 405:219–223CrossRefPubMed

25.

Strandell E, Buschard K, Saldeen J, Welsh N (1995) Interleukin-1β induces the expression of hsp70, heme oxygenase and Mn-SOD in FACS-purified rat islet β-cells, but not in α-cells. Immunol Lett 48:145–148CrossRefPubMed

26.

Gunther L, Berberat PO, Haga M et al. (2002) Carbon monoxide protects pancreatic β-cells from apoptosis and improves islet function/survival after transplantation. Diabetes 51:994–999PubMed

27.

Ceriello A, Dello RP, Amstad P, Cerutti P (1996) High glucose induces antioxidant enzymes in human endothelial cells in culture. Evidence linking hyperglycemia and oxidative stress. Diabetes 45:471–477PubMed

28.

Mendola JF, Goity C, Fernandez-Alvarez J et al. (1994) Immunocytochemical study of pancreatic islet revascularization in islet isograft. Effect of hyperglycemia of the recipient and of in vitro culture of islets. Transplantation 57:725–730PubMed

29.

Xu G, Stoffers DA, Habener JF, Bonner-Weir S (1999) Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats. Diabetes 48:2270–2276PubMed

30.

Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ (2003) Glucagon-like peptide-1 receptor signaling modulates β cell apoptosis. J Biol Chem 278:471–478CrossRefPubMed

31.

Hui H, Nourparvar A, Zhao X, Perfetti R (2003) Glucagon-like peptide-1 inhibits apoptosis of insulin-secreting cells via a cyclic 5′-adenosine monophosphate-dependent protein kinase A and a phosphatidylinositol 3-kinase-dependent pathway. Endocrinology 144:1444–1455CrossRefPubMed

32.

Henquin JC (2000) Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49:1751–1760PubMed

33.

Gilon P, Henquin JC (1992) Influence of membrane potential changes on cytoplasmic Ca²⁺ concentration in an electrically excitable cell, the insulin-secreting pancreatic B-cell. J Biol Chem 267:20713–20720PubMed

34.

Antunes CM, Salgado AP, Rosario LM, Santos RM (2000) Differential patterns of glucose-induced electrical activity and intracellular calcium responses in single mouse and rat pancreatic islets. Diabetes 49:2028–2038PubMed

35.

Nilsson T, Arkhammar P, Rorsman P, Berggren PO (1988) Inhibition of glucose-stimulated insulin release by α₂- adrenoceptor activation is parallelled by both a repolarization and a reduction in cytoplasmic free Ca²⁺ concentration. J Biol Chem 263:1855–1860PubMed

36.

Gilon P, Shepherd RM, Henquin JC (1993) Oscillations of secretion driven by oscillations of cytoplasmic Ca²⁺ as evidenced in single pancreatic islets. J Biol Chem 268:22265–22268PubMed

37.

Yamazaki S, Katada T, Ui M (1982) Alpha 2-adrenergic inhibition of insulin secretion via interference with cyclic AMP generation in rat pancreatic islets. Mol Pharmacol 21:648–653PubMed

38.

Hugues SJ, Ashcroft SJH (1992) Cyclic AMP, protein phosphorylation and insulin secretion. In: Flatt PR (ed.) Nutrient regulation of insulin secretion. Portland Press, London, pp 271–288

39.

Ling Z, Van de Casteele M, Eizirik DL, Pipeleers DG (2000) Interleukin-1β-induced alteration in a β-cell phenotype can reduce cellular sensitivity to conditions that cause necrosis but not to cytokine-induced apoptosis. Diabetes 49:340–345PubMed

40.

Kaneto H, Fujii J, Myint T et al. (1996) Reducing sugars trigger oxidative modification and apoptosis in pancreatic beta-cells by provoking oxidative stress through the glycation reaction. Biochem J 320:855–863PubMed

41.

Kaneto H, Kajimoto Y, Miyagawa J et al. (1999) Beneficial effects of antioxidants in diabetes: possible protection of pancreatic β-cells against glucose toxicity. Diabetes 48:2398–2406PubMed

42.

Matsuoka T, Kajimoto Y, Watada H et al. (1997) Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest 99:144–150PubMed

43.

Tanaka Y, Gleason CE, Tran PO, Harmon JS, Robertson RP (1999) Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad Sci USA 96:10857–10862CrossRefPubMed

44.

Elbirt KK, Bonkovsky HL (1999) Heme oxygenase: recent advances in understanding its regulation and role. Proc Assoc Am Physicians 111:438–447PubMed

45.

Kaneto H, Xu G, Song KH et al. (2001) Activation of the hexosamine pathway leads to deterioration of pancreatic β-cell function through the induction of oxidative stress. J Biol Chem 276:31099–31104CrossRefPubMed

46.

Kaneto H, Xu G, Fujii N, Kim S, Bonner-Weir S, Weir GC (2002) Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. J Biol Chem 277:30010–30018CrossRefPubMed

47.

Tacchini L, Fusar-Poli D, Bernelli-Zazzera A (2002) Activation of transcription factors by drugs inducing oxidative stress in rat liver. Biochem Pharmacol 63:139–148CrossRefPubMed

48.

Spitaler MM, Graier WF (2002) Vascular targets of redox signalling in diabetes mellitus. Diabetologia 45:476–494CrossRef

49.

Cardozo AK, Heimberg H, Heremans Y et al. (2001) A comprehensive analysis of cytokine-induced and nuclear factor-κB-dependent genes in primary rat pancreatic β-cells. J Biol Chem 276:48879–48886CrossRefPubMed

50.

Maedler K, Sergeev P, Ris F et al. (2002) Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets. J Clin Invest 110:851–860CrossRefPubMed

51.

Hoorens A, Van de Casteele M, Klöppel G, Pipeleers DG (1996) Glucose promotes survival of rat pancreatic β cells by activating synthesis of proteins which suppress a constitutive apoptotic program. J Clin Invest 98:1568–1574PubMed

52.

Efanova IB, Zaitsev SV, Zhivotovsky B et al. (1998) Glucose and tolbutamide induce apoptosis in pancreatic β-cells—a process dependent on intracellular Ca²⁺ concentration. J Biol Chem 273:33501–33507PubMed

53.

Jonas JC, Laybutt R, Steil GM, Trivedi N, Weir GC, Henquin JC (2001) Potential role of the early response gene c-myc in β-cell adaptation to changes in glucose concentration. Diabetes 50 (Suppl 1):S137PubMed

54.

Chang SH, Barbosa-Tessmann I, Chen C, Kilberg MS, Agarwal A (2002) Glucose deprivation induces heme oxygenase-1 gene expression by a pathway independent of the unfolded protein response. J Biol Chem 277:1933–1940CrossRefPubMed

55.

Chang SH, Garcia J, Melendez JA, Kilberg MS, Agarwal A (2003) Haem oxygenase 1 gene induction by glucose deprivation is mediated by reactive oxygen species via the mitochondrial electron-transport chain. Biochem J 371:877–885CrossRefPubMed

56.

Jensen J, Serup P, Karlsen C, Nielsen TF, Madsen OD (1996) mRNA profiling of rat islet tumors reveals nkx 6.1 as a β-cell-specific homeodomain transcription factor. J Biol Chem 271:18749–18758CrossRefPubMed

Titel: Haeme-oxygenase 1 expression in rat pancreatic beta cells is stimulated by supraphysiological glucose concentrations and by cyclic AMP
verfasst von: J. C. Jonas, MD PhD
Y. Guiot
J. Rahier
J. C. Henquin
Publikationsdatum: 01.09.2003
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 9/2003
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-003-1174-9

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