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daf-16/FOXO and glod-4/glyoxalase-1 are required for the life-prolonging effect of human insulin under high glucose conditions in Caenorhabditis elegans

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Abstract

Aims/hypothesis

The aim of this study was to determine the protective effects of human insulin and its analogues, B28Asp human insulin (insulin aspart) and B29Lys(ε-tetradecanoyl),desB30 human insulin (insulin detemir), against glucose-induced lifespan reduction and neuronal damage in the model organism Caenorhabditis elegans and to elucidate the underlying mechanisms.

Methods

Nematodes were cultivated under high glucose (HG) conditions comparable with the situation in diabetic patients and treated with human insulin and its analogues. Lifespan was assessed and neuronal damage was evaluated with regard to structural and functional impairment. Additionally, the activity of glyoxalase-1 and superoxide dismutase (SOD) and the formation of reactive oxygen species (ROS) and AGEs were determined.

Results

Insulin and its analogues reversed the life-shortening effect of HG conditions and prevented the glucose-induced neuronal impairment. Insulin treatment under HG conditions was associated with reduced concentration of glucose, as well as a reduced formation of ROS and AGEs, and increased SOD activity. These effects were dependent on the Forkhead box O (FOXO) homologue abnormal dauer formation (DAF)-16. Furthermore, glyoxalase-1 activity, which was impaired under HG conditions, was restored by human insulin. This was essential for the insulin-induced lifespan extension under HG conditions, as no change in lifespan was observed following either suppression or overexpression of glyoxalase-1.

Conclusions/interpretation

Human insulin and its analogues prevent the reduction in lifespan and neuronal damage caused by HG conditions. The effect of human insulin is mediated by a daf-2/insulin receptor and daf-16/FOXO-dependent pathway and is mediated by upregulation of detoxifying mechanisms.

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Abbreviations

DAF:

Abnormal dauer formation

FOXO:

Forkhead box O

GFP:

Green fluorescent protein

HG:

High glucose

MG:

Methylglyoxal

RNAi:

RNA interference

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

References

  1. Holzenberger M (2009) IGF-1 receptors in the brain control longevity in mice. Med Sci (Paris) 25:371–376 [article in French]

    Article  Google Scholar 

  2. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366:461–464

    Article  CAS  PubMed  Google Scholar 

  3. Narayanan RP, Siddals KW, Heald AH, Gibson JM (2013) Interactions of the IGF system with diabetes and its vascular complications. Exp Clin Endocrinol Diabetes 121:255–261

    Article  CAS  PubMed  Google Scholar 

  4. Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292:107–110

    Article  CAS  PubMed  Google Scholar 

  5. Nawroth PP, Rudofsky G, Humpert P (2010) Have we understood diabetes? New tasks for diagnosis and therapy. Exp Clin Endocrinol Diabetes 118:1–3

    Article  CAS  PubMed  Google Scholar 

  6. Lee SJ, Murphy CT, Kenyon C (2009) Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression. Cell Metab 10:379–391

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Mendler M, Schlotterer A, Morcos M, Nawroth PP (2012) Understanding diabetic polyneuropathy and longevity: what can we learn from the nematode Caenorhabditis elegans? Exp Clin Endocrinol Diabetes 120:182–183

    Article  CAS  PubMed  Google Scholar 

  8. Schlotterer A, Kukudov G, Bozorgmehr F et al (2009) C. elegans as model for the study of high glucose-mediated life span reduction. Diabetes 58:2450–2456

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (2007) Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 6:280–293

    Article  CAS  PubMed  Google Scholar 

  10. Thornalley PJ (2003) Glyoxalase I–structure, function and a critical role in the enzymatic defence against glycation. Biochem Soc Trans 31:1343–1348

    Article  CAS  PubMed  Google Scholar 

  11. Bierhaus A, Fleming T, Stoyanov S et al (2012) Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 18:926–933

    Article  CAS  PubMed  Google Scholar 

  12. Fleming T, Cuny J, Nawroth G et al (2012) Is diabetes an acquired disorder of reactive glucose metabolites and their intermediates? Diabetologia 55:1151–1155

    Article  CAS  PubMed  Google Scholar 

  13. Fleming TH, Humpert PM, Nawroth PP, Bierhaus A (2011) Reactive metabolites and AGE/RAGE-mediated cellular dysfunction affect the aging process: a mini-review. Gerontology 57:435–443

    CAS  PubMed  Google Scholar 

  14. Schlotterer A, Hamann A, Kukudov G et al (2010) Apurinic/apyrimidinic endonuclease 1, p53, and thioredoxin are linked in control of aging in C. elegans. Aging Cell 9:420–432

    Article  CAS  PubMed  Google Scholar 

  15. Vander Jagt DL (2008) Methylglyoxal, diabetes mellitus and diabetic complications. Drug Metabol Drug Interact 23:93–124

    CAS  PubMed  Google Scholar 

  16. Morcos M, Du X, Pfisterer F et al (2008) Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans. Aging Cell 7:260–269

    Article  CAS  PubMed  Google Scholar 

  17. Kenyon C (2005) The plasticity of aging: insights from long-lived mutants. Cell 120:449–460

    Article  CAS  PubMed  Google Scholar 

  18. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277:942–946

    Article  CAS  PubMed  Google Scholar 

  19. Pierce SB, Costa M, Wisotzkey R et al (2001) Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev 15:672–686

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Altun-Gultekin Z, Andachi Y, Tsalik EL, Pilgrim D, Kohara Y, Hobert O (2001) A regulatory cascade of three homeobox genes, ceh-10, ttx-3 and ceh-23, controls cell fate specification of a defined interneuron class in C. elegans. Development 128:1951–1969

    CAS  PubMed  Google Scholar 

  21. McLellan AC, Thornalley PJ, Benn J, Sonksen PH (1994) Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications. Clin Sci (Lond) 87:21–29

    CAS  Google Scholar 

  22. Racker E (1951) The mechanism of action of glyoxalase. J Biol Chem 190:685–696

    CAS  PubMed  Google Scholar 

  23. Abramoff MD, Magelhaes PJ, Ram SJ (2004) Image processing with ImageJ. Biophoton Int 11:36–42

    Google Scholar 

  24. Schumacher B, Schertel C, Wittenburg N et al (2005) C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage. Cell Death Differ 12:153–161

    Article  CAS  PubMed  Google Scholar 

  25. Herrmann BL, Kasser C, Keuthage W, Huptas M, Dette H, Klute A (2013) Comparison of insulin aspart vs. regular human insulin with or without insulin detemir concerning adipozytokines and metabolic effects in patients with type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 121:210–213

    Article  CAS  PubMed  Google Scholar 

  26. Yin D (1996) Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores. Free Radic Biol Med 21:871–888

    Article  CAS  PubMed  Google Scholar 

  27. Gerstbrein B, Stamatas G, Kollias N, Driscoll M (2005) In vivo spectrofluorimetry reveals endogenous biomarkers that report healthspan and dietary restriction in Caenorhabditis elegans. Aging Cell 4:127–137

    Article  CAS  PubMed  Google Scholar 

  28. Priebe S, Menzel U, Zarse K et al (2013) Extension of life span by impaired glucose metabolism in Caenorhabditis elegans is accompanied by structural rearrangements of the transcriptomic network. PLoS One 8:e77776

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Honda Y, Honda S (1999) The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J 13:1385–1393

    CAS  PubMed  Google Scholar 

  30. Zarse K, Schmeisser S, Groth M et al (2012) Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal. Cell Metab 15:451–465

    Article  CAS  PubMed  Google Scholar 

  31. Schmoll D, Walker KS, Alessi DR et al (2000) Regulation of glucose-6-phosphatase gene expression by protein kinase Balpha and the forkhead transcription factor FKHR. Evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity. J Biol Chem 275:36324–36333

    Article  CAS  PubMed  Google Scholar 

  32. Hall RK, Yamasaki T, Kucera T, Waltner-Law M, O'Brien R, Granner DK (2000) Regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein-1 gene expression by insulin. The role of winged helix/forkhead proteins. J Biol Chem 275:30169–30175

    Article  CAS  PubMed  Google Scholar 

  33. Matsumoto M, Pocai A, Rossetti L, Depinho RA, Accili D (2007) Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab 6:208–216

    Article  CAS  PubMed  Google Scholar 

  34. Skriver MV, Borch-Johnsen K, Lauritzen T, Sandbaek A (2010) HbA1c as predictor of all-cause mortality in individuals at high risk of diabetes with normal glucose tolerance, identified by screening: a follow-up study of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION), Denmark. Diabetologia 53:2328–2333

    Article  CAS  PubMed  Google Scholar 

  35. Ahmed N, Thornalley PJ, Dawczynski J et al (2003) Methylglyoxal-derived hydroimidazolone advanced glycation end-products of human lens proteins. Invest Ophthalmol Vis Sci 44:5287–5292

    Article  PubMed  Google Scholar 

  36. Genuth S, Sun W, Cleary P et al (2005) Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes 54:3103–3111

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Birkenmeier G, Stegemann C, Hoffmann R, Gunther R, Huse K, Birkemeyer C (2010) Posttranslational modification of human glyoxalase 1 indicates redox-dependent regulation. PLoS One 5:e10399

    Article  PubMed Central  PubMed  Google Scholar 

  38. Reger MA, Watson GS, Green PS et al (2008) Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis 13:323–331

    CAS  PubMed Central  PubMed  Google Scholar 

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Funding

This study was supported by the Dietmar-Hopp-Stiftung, the Deutsche Forschungsgemeinschaft (DFG), projects ‘NA-137’ and ‘Sonderforschungsbereich 1118’ and Novo Nordisk (to MMo). MMe was supported by the postdoctoral fellowship programme of the medical faculty of Heidelberg University. PPN and TF are supported by the German Center for Diabetes Research (DZD).

Duality of interest

MMo has received lecture fees and honorary as an advisory board member from Novo Nordisk. All other authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

MMe, AS, PPN, and MMo had substantial contributions to conception and design; MMe, AS, YI, GK, TF, CR contributed to the acquisition of data; all authors contributed to analysis or interpretation of data. MMe and AS drafted the article and the other authors revised it critically for important intellectual content. All authors except, tragically, AB approved the version to be published. MMe is responsible for the integrity of the work as a whole.

Author information

Authors and Affiliations

  1. Department of Medicine 1 and Clinical Chemistry, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Michael Mendler, Andreas Schlotterer, Youssef Ibrahim, Georgi Kukudov, Thomas Fleming, Angelika Bierhaus, Christin Riedinger, Vedat Schwenger, Jens Tyedmers, Peter P. Nawroth & Michael Morcos

  2. Joint Research Division Molecular Metabolic Control, German Cancer Research Centre Heidelberg, Centre for Molecular Biology, University of Heidelberg, Heidelberg, Germany

    Stephan Herzig

  3. Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany

    Markus Hecker

Authors
  1. Michael Mendler
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  2. Andreas Schlotterer
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  3. Youssef Ibrahim
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  4. Georgi Kukudov
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  5. Thomas Fleming
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  6. Angelika Bierhaus
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  7. Christin Riedinger
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  8. Vedat Schwenger
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  9. Stephan Herzig
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  10. Markus Hecker
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  11. Jens Tyedmers
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  12. Peter P. Nawroth
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  13. Michael Morcos
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Corresponding author

Correspondence to Michael Mendler.

Additional information

Michael Mendler and Andreas Schlotterer contributed equally to this work.

Angelika Bierhaus died on 15 April 2012.

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Mendler, M., Schlotterer, A., Ibrahim, Y. et al. daf-16/FOXO and glod-4/glyoxalase-1 are required for the life-prolonging effect of human insulin under high glucose conditions in Caenorhabditis elegans . Diabetologia 58, 393–401 (2015). https://doi.org/10.1007/s00125-014-3415-5

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  • DOI: https://doi.org/10.1007/s00125-014-3415-5

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