Top

Published in:

01-02-2008 | Article

Inhibition of c-jun N terminal kinase (JNK) improves functional beta cell mass in human islets and leads to AKT and glycogen synthase kinase-3 (GSK-3) phosphorylation

Authors: A. Fornoni, A. Pileggi, R. D. Molano, N. Y. Sanabria, T. Tejada, J. Gonzalez-Quintana, H. Ichii, L. Inverardi, C. Ricordi, R. L. Pastori

Published in: Diabetologia | Issue 2/2008

Abstract

Aims/hypothesis

Activation of c-jun N-terminal kinase (JNK) has been described in islet isolation and engraftment, making JNK a key target in islet transplantation. The objective of this study was to investigate if JNK inhibition with a cell-permeable TAT peptide inhibitor (L-JNKI) protects functional beta cell mass in human islets and affects AKT and its substrates in islet cells.

Methods

The effect of L-JNKI (10 μmol/l) on islet count, mitochondrial membrane potential, glucose-stimulated insulin release and phosphorylation of both AKT and its substrates, as well as on reversal of diabetes in immunodeficient diabetic Nu/Nu mice was studied.

Results

In vitro, L-JNKI reduced the islet loss in culture and protected from cell death caused by acute cytokine exposure. In vivo, treatment of freshly isolated human islets and diabetic Nu/Nu mice recipients of such islets resulted in improved functional beta cell mass. We showed that L-JNKI activates AKT and downregulates glycogen synthase kinase-3 beta (GSK-3B) in human islets exposed to cytokines, while other AKT substrates were unaffected, suggesting that a specific AKT/GSK-3B regulation by L-JNKI may represent one of its mechanisms of cytoprotection.

Conclusions/interpretation

In conclusion, we have demonstrated that targeting JNK in human pancreatic islets results in improved functional beta cell mass and in the regulation of AKT/GSK3B activity.

Available only for authorised users

Abdelli S, Ansite J, Roduit R et al (2004) Intracellular stress signaling pathways activated during human islet preparation and following acute cytokine exposure. Diabetes 53:2815–2823PubMedCrossRef

Ammendrup A, Maillard A, Nielsen K et al (2000) The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic beta-cells. Diabetes 49:1468–1476PubMedCrossRef

Rosenberg L, Wang R, Paraskevas S, Maysinger D (1999) Structural and functional changes resulting from islet isolation lead to islet cell death. Surgery 126:393–398PubMed

Aikin R, Maysinger D, Rosenberg L (2004) Cross-talk between phosphatidylinositol 3-kinase/AKT and c-jun NH2-terminal kinase mediates survival of isolated human islets. Endocrinology 145:4522–4531PubMedCrossRef

Noguchi H, Nakai Y, Ueda M et al (2007) Activation of c-Jun NH(2)-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor. Diabetologia 50:612–619PubMedCrossRef

Abdelli S, Abderrahmani A, Hering BJ, Beckmann JS, Bonny C (2007) The c-Jun N-terminal kinase JNK participates in cytokine- and isolation stress-induced rat pancreatic islet apoptosis. Diabetologia 50:1660–1669PubMedCrossRef

Bonny C, Oberson A, Negri S, Sauser C, Schorderet DF (2001) Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death. Diabetes 50:77–82PubMedCrossRef

Fornoni A, Cobianchi L, Sanabria NY et al (2007) The l-isoform but not d-isoforms of a JNK inhibitory peptide protects pancreatic beta-cells. Biochem Biophys Res Commun 354:227–233PubMedCrossRef

Noguchi H, Nakai Y, Matsumoto S et al (2005) Cell permeable peptide of JNK inhibitor prevents islet apoptosis immediately after isolation and improves islet graft function. Am J Transplant 5:1848–1855PubMedCrossRef

10.

Ribeiro MM, Klein D, Pileggi A et al (2003) Heme oxygenase-1 fused to a TAT peptide transduces and protects pancreatic beta-cells. Biochem Biophys Res Commun 305:876–881PubMedCrossRef

11.

Klein D, Ribeiro MM, Mendoza V et al (2004) Delivery of Bcl-XL or its BH4 domain by protein transduction inhibits apoptosis in human islets. Biochem Biophys Res Commun 323:473–478PubMedCrossRef

12.

Cardozo AK, Buchillier V, Mathieu M et al (2007) Cell-permeable peptides induce dose- and length-dependent cytotoxic effects. Biochim Biophys Acta 1768:2222–2234PubMedCrossRef

13.

Hirosumi J, Tuncman G, Chang L et al (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336PubMedCrossRef

14.

Kaneto H, Nakatani Y, Miyatsuka T et al (2004) Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide. Nat Med 10:1128–1132PubMedCrossRef

15.

Lee YH, Giraud J, Davis RJ, White MF (2003) c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem 278:2896–2902PubMedCrossRef

16.

Bernal-Mizrachi E, Wen W, Stahlhut S, Welling CM, Permutt MA (2001) Islet beta cell expression of constitutively active Akt1/PKB alpha induces striking hypertrophy, hyperplasia, and hyperinsulinemia. J Clin Invest 108:1631–1638PubMedCrossRef

17.

Tuttle RL, Gill NS, Pugh W et al (2001) Regulation of pancreatic beta-cell growth and survival by the serine/threonine protein kinase Akt1/PKBalpha. Nat Med 7:1133–1137PubMedCrossRef

18.

Aikin R, Rosenberg L, Maysinger D (2000) Phosphatidylinositol 3-kinase signaling to Akt mediates survival in isolated canine islets of Langerhans. Biochem Biophys Res Commun 277:455–461PubMedCrossRef

19.

Ricordi C, Strom TB (2004) Clinical islet transplantation: advances and immunological challenges. Nat Rev Immunol 4:259–268PubMedCrossRef

20.

Ichii H, Pileggi A, Molano RD et al (2005) Rescue purification maximizes the use of human islet preparations for transplantation. Am J Transplant 5:21–30PubMedCrossRef

21.

Latif ZA, Noel J, Alejandro R (1988) A simple method of staining fresh and cultured islets. Transplantation 45:827–830PubMedCrossRef

22.

Ricordi C, Gray DW, Hering BJ et al (1990) Islet isolation assessment in man and large animals. Acta Diabetol Lat 27:185–195PubMedCrossRef

23.

Ichii H, Inverardi L, Pileggi A et al (2005) A novel method for the assessment of cellular composition and beta-cell viability in human islet preparations. Am J Transplant 5:1635–1645PubMedCrossRef

24.

Lukowiak B, Vandewalle B, Riachy R et al (2001) Identification and purification of functional human beta-cells by a new specific zinc-fluorescent probe. J Histochem Cytochem 49:519–528PubMed

25.

Brendel MD, Kong SS, Alejandro R, Mintz DH (1994) Improved functional survival of human islets of Langerhans in three-dimensional matrix culture. Cell Transplant 3:427–435PubMed

26.

Berney T, Molano RD, Cattan P et al (2001) Endotoxin-mediated delayed islet graft function is associated with increased intra-islet cytokine production and islet cell apoptosis. Transplantation 71:125–132PubMedCrossRef

27.

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 50:1983–1991PubMedCrossRef

28.

Paraskevas S, Aikin R, Maysinger D et al (2001) Modulation of JNK and p38 stress activated protein kinases in isolated islets of Langerhans: insulin as an autocrine survival signal. Ann Surg 233:124–133PubMedCrossRef

29.

Aikin R, Hanley S, Maysinger D et al (2006) Autocrine insulin action activates Akt and increases survival of isolated human islets. Diabetologia 49:2900–2909PubMedCrossRef

30.

Lakey JR, Burridge PW, Shapiro AM (2003) Technical aspects of islet preparation and transplantation. Transpl Int 16:613–632PubMedCrossRef

31.

Toyama H, Takada M, Suzuki Y, Kuroda Y (2003) Activation of macrophage-associated molecules after brain death in islets. Cell Transplant 12:27–32PubMed

32.

Noguchi H, Matsumoto S (2006) Protein transduction technology: a novel therapeutic perspective. Acta Med Okayama 60:1–11PubMed

33.

Eckhoff DE, Smyth CA, Eckstein C et al (2003) Suppression of the c-Jun N-terminal kinase pathway by 17beta-estradiol can preserve human islet functional mass from proinflammatory cytokine-induced destruction. Surgery 134:169–179PubMedCrossRef

34.

Paraskevas S, Aikin R, Maysinger D et al (1999) Activation and expression of ERK, JNK, and p38 MAP-kinases in isolated islets of Langerhans: implications for cultured islet survival. FEBS Lett 455:203–208PubMedCrossRef

35.

Kutlu B, Cardozo AK, Darville MI et al (2003) Discovery of gene networks regulating cytokine-induced dysfunction and apoptosis in insulin-producing INS-1 cells. Diabetes 52:2701–2719PubMedCrossRef

36.

Scarim AL, Heitmeier MR, Corbett JA (1997) Irreversible inhibition of metabolic function and islet destruction after a 36-hour exposure to interleukin-1beta. Endocrinology 138:5301–5307PubMedCrossRef

37.

Eizirik DL, Mandrup-Poulsen T (2001) A choice of death—the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia 44:2115–2133PubMedCrossRef

38.

Montolio M, Biarnes M, Tellez N, Escoriza J, Soler J, Montanya E (2007) Interleukin-1beta and inducible form of nitric oxide synthase expression in early syngeneic islet transplantation. J Endocrinol 192:169–177PubMedCrossRef

39.

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

40.

Sarti P, Arese M, Bacchi A et al (2003) Nitric oxide and mitochondrial complex IV. IUBMB Life 55:605–611PubMedCrossRef

41.

Storling J, Binzer J, Andersson AK et al (2005) Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt. Diabetologia 48:2039–2050PubMedCrossRef

42.

Muller D, Huang GC, Amiel S, Jones PM, Persaud SJ (2006) Identification of insulin signaling elements in human β-cells: autocrine regulation of insulin gene expression. Diabetes 55:2835–2842PubMedCrossRef

43.

Leibiger IB, Leibiger B, Berggren PO (2002) Insulin feedback action on pancreatic beta-cell function. FEBS Lett 532:1–6PubMedCrossRef

44.

Mussmann R, Geese M, Harder F et al (2007) Inhibition of GSK3 promotes replication and survival of pancreatic beta cells. J Biol Chem 282:12030–12037PubMedCrossRef

45.

Amaral ME, Cunha DA, Anhe GF et al (2004) Participation of prolactin receptors and phosphatidylinositol 3-kinase and MAP kinase pathways in the increase in pancreatic islet mass and sensitivity to glucose during pregnancy. J Endocrinol 183:469–476PubMedCrossRef

46.

Nascimento EB, Fodor M, van der Zon GC et al (2006) Insulin-mediated phosphorylation of the proline-rich Akt substrate PRAS40 is impaired in insulin target tissues of high-fat diet-fed rats. Diabetes 55:3221–3228PubMedCrossRef

47.

Saito A, Narasimhan P, Hayashi T, Okuno S, Ferrand-Drake M, Chan PH (2004) Neuroprotective role of a proline-rich Akt substrate in apoptotic neuronal cell death after stroke: relationships with nerve growth factor. J Neurosci 24:1584–1593PubMedCrossRef

48.

Vilimek D, Duronio V (2006) Cytokine-stimulated phosphorylation of GSK-3 is primarily dependent upon PKCs, not PKB. Biochem Cell Biol 84:20–29PubMedCrossRef

49.

He J, Usui I, Ishizuka K et al (2006) Interleukin-1alpha inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes. Mol Endocrinol 20:114–124PubMedCrossRef

50.

Fahmy RG, Waldman A, Zhang G et al (2006) Suppression of vascular permeability and inflammation by targeting of the transcription factor c-Jun. Nat Biotechnol 24:856–863PubMedCrossRef

Title: Inhibition of c-jun N terminal kinase (JNK) improves functional beta cell mass in human islets and leads to AKT and glycogen synthase kinase-3 (GSK-3) phosphorylation
Authors: A. Fornoni
A. Pileggi
R. D. Molano
N. Y. Sanabria
T. Tejada
J. Gonzalez-Quintana
H. Ichii
L. Inverardi
C. Ricordi
R. L. Pastori
Publication date: 01-02-2008
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 2/2008
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-007-0889-4

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Please log in to get access to this content

Other articles of this Issue 2/2008

Effect of beta-adrenergic stimulation on whole-body and abdominal subcutaneous adipose tissue lipolysis in lean and obese men

Serum procalcitonin and C-reactive protein concentrations to distinguish mildly infected from non-infected diabetic foot ulcers: a pilot study

Inhibition or deletion of the lipopolysaccharide receptor Toll-like receptor-4 confers partial protection against lipid-induced insulin resistance in rodent skeletal muscle

Duration of breast-feeding and the incidence of type 2 diabetes mellitus in the Shanghai Women’s Health Study

The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes

Continuous Glucose Monitoring System in children with type 1 diabetes mellitus: a systematic review and meta-analysis

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials