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Urine levels of 5-aminoimidazole-4-carboxamide riboside (AICAR) in patients with type 2 diabetes

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Abstract

Aims

5-Aminoimidazole-4-carboxamide riboside (AICAR) is an endogenous activator of AMPK, a central regulator of energy homeostasis. Loss and/or reduction of AMPK signaling plays an important role in the development of insulin resistance in type 2 diabetes. The loss of AMPK in diabetes could be due to a loss of AICAR. The aim of this study was to characterize urine levels of AICAR in diabetes and determine whether an association exists with respect to late complications, e.g., retinopathy, nephropathy and neuropathy.

Methods

Urine AICAR was measured by liquid chromatography tandem mass spectrometry in 223 patients consisting of 5 healthy controls, 63 patients with pre-diabetes, 29 patients with newly diagnosed type 2 diabetes and 126 patients with long-standing type 2 diabetes. For statistical analyses, nonparametric Kruskal–Wallis test, one-way ANOVA and multivariate regression analysis were performed to investigate the associations of urinary AICAR excretion within different groups and different clinical parameters.

Results

The mean urine AICAR for all 223 patients was 694.7 ± 641.1 ng/ml. There was no significant difference in urine AICAR between the control and patients with diabetes (592.3 ± 345.1 vs. 697.1 ± 646.5 ng/ml). No association between any of the biochemical and/or clinical parameters measured and urine AICAR was found, with the exception of age of patient (R = − 0.34; p < 0.01) and estimated glomerular filtration rate (R = 0.19; p = 0.039). These results were confirmed additionally by linear regression analysis.

Conclusions

Clinical diabetes is not associated with a change in endogenous AICAR levels. Loss of AICAR may therefore not be a mechanism by which AMPK signaling is reduced in diabetes.

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Abbreviations

ACR:

Albumin to creatinine ratio

AICAR:

5-Aminoimidazole-4-carboxamide riboside

AMPK:

AMP-activated protein kinase

ASA:

Acetylsalicylic acid

BMI:

Body mass index

CBS:

Cystathionine beta-synthase

CVD:

Cardiovascular disease

HCT:

Hydrochlorothiazide

NSS:

Neuropathy symptom score (NSS)

NDS:

Neuropathy disability score (NDS)

RAAS:

Renin–angiotensin–aldosterone system

References

  1. Ruderman N, Prentki M (2004) AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov 3(4):340–351. https://doi.org/10.1038/nrd1344

    Article  PubMed  CAS  Google Scholar 

  2. Ruderman NB, Carling D, Prentki M, Cacicedo JM (2013) AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest 123(7):2764–2772. https://doi.org/10.1172/JCI67227

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM (2006) Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects. Diabetes 55(8):2277–2285. https://doi.org/10.2337/db06-0062

    Article  PubMed  CAS  Google Scholar 

  4. Xu XJ, Gauthier MS, Hess DT et al (2012) Insulin sensitive and resistant obesity in humans: AMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue. J Lipid Res 53(4):792–801. https://doi.org/10.1194/jlr.P022905

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Corton JM, Gillespie JG, Hawley SA, Hardie DG (1995) 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem 229(2):558–565

    Article  PubMed  CAS  Google Scholar 

  6. Sullivan JE, Carey F, Carling D, Beri RK (1994) Characterisation of 5′-AMP-activated protein kinase in human liver using specific peptide substrates and the effects of 5′-AMP analogues on enzyme activity. Biochem Biophys Res Commun 200(3):1551–1556

    Article  PubMed  CAS  Google Scholar 

  7. Davies SP, Helps NR, Cohen PT, Hardie DG (1995) 5′-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC. FEBS Lett 377(3):421–425. https://doi.org/10.1016/0014-5793(95)01368-7

    Article  PubMed  CAS  Google Scholar 

  8. Hawley SA, Selbert MA, Goldstein EG, Edelman AM, Carling D, Hardie DG (1995) 5′-AMP activates the AMP-activated protein kinase cascade, and Ca2+/calmodulin activates the calmodulin-dependent protein kinase I cascade, via three independent mechanisms. J Biol Chem 270(45):27186–27191

    Article  PubMed  CAS  Google Scholar 

  9. Suter M, Riek U, Tuerk R, Schlattner U, Wallimann T, Neumann D (2006) Dissecting the role of 5′-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J Biol Chem 281(43):32207–32216. https://doi.org/10.1074/jbc.M606357200

    Article  PubMed  CAS  Google Scholar 

  10. Bergeron R, Previs SF, Cline GW et al (2001) Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes 50(5):1076–1082

    Article  PubMed  CAS  Google Scholar 

  11. Buhl ES, Jessen N, Schmitz O et al (2001) Chronic treatment with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside increases insulin-stimulated glucose uptake and GLUT4 translocation in rat skeletal muscles in a fiber type-specific manner. Diabetes 50(1):12–17

    Article  PubMed  CAS  Google Scholar 

  12. Iglesias MA, Ye JM, Frangioudakis G et al (2002) AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes 51(10):2886–2894

    Article  PubMed  CAS  Google Scholar 

  13. Song XM, Fiedler M, Galuska D et al (2002) 5-Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice. Diabetologia 45(1):56–65. https://doi.org/10.1007/s001250200006

    Article  PubMed  CAS  Google Scholar 

  14. Barre L, Richardson C, Hirshman MF et al (2007) Genetic model for the chronic activation of skeletal muscle AMP-activated protein kinase leads to glycogen accumulation. Am J Physiol Endocrinol Metab 292(3):E802–E811. https://doi.org/10.1152/ajpendo.00369.2006

    Article  PubMed  CAS  Google Scholar 

  15. Goodyear LJ (2008) The exercise pill–too good to be true? N Engl J Med 359(17):1842–1844. https://doi.org/10.1056/NEJMcibr0806723

    Article  PubMed  CAS  Google Scholar 

  16. Narkar VA, Downes M, Yu RT et al (2008) AMPK and PPARdelta agonists are exercise mimetics. Cell 134(3):405–415. https://doi.org/10.1016/j.cell.2008.06.051

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. World Anti-Doping Agency (2009) The 2009 prohibited list international standard https://www.wada-ama.org/sites/default/files/resources/files/WADA_Prohibited_List_2009_EN.pdf. Accessed 02 Feb 2018

  18. Thomas A, Beuck S, Eickhoff JC et al (2010) Quantification of urinary AICAR concentrations as a matter of doping controls. Anal Bioanal Chem 396(8):2899–2908. https://doi.org/10.1007/s00216-010-3560-8

    Article  PubMed  CAS  Google Scholar 

  19. Middleton JE, Coward RF, Smith P (1964) Urinary excretion of A.I.C. in vitamin-B12 and folic-acid deficiencies. Lancet 284(7353):258–259. https://doi.org/10.1016/S0140-6736(64)90216-8

    Article  Google Scholar 

  20. Lulenski G, Donaldson M, Newcombe D (1970) Urinary aminoimidazolecarboxamide levels in children with acute leukemia. Pediatrics 45(6):983–995

    PubMed  CAS  Google Scholar 

  21. Newcombe DS (1970) The urinary excretion of aminoimidazolecarboxamide in the Lesch–Nyhan syndrome. Pediatrics 46(4):508–512

    PubMed  CAS  Google Scholar 

  22. Sweetman L, Nyhan WL (1970) Detailed comparison of the urinary excretion of purines in a patient with the Lesch–Nyhan syndrome and a control subject. Biochem Med 4(2):121–134

    Article  PubMed  CAS  Google Scholar 

  23. Lamia KA, Sachdeva UM, DiTacchio L et al (2009) AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326(5951):437–440. https://doi.org/10.1126/science.1172156

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Pokrywka A, Cholbinski P, Kaliszewski P, Kowalczyk K, Konczak D, Zembron-Lacny A (2014) Metabolic modulators of the exercise response: doping control analysis of an agonist of the peroxisome proliferator-activated receptor delta (GW501516) and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). J Physiol Pharmacol 65(4):469–476

    PubMed  CAS  Google Scholar 

  25. Hartmann S, Okun JG, Schmidt C et al (2006) Comprehensive detection of disorders of purine and pyrimidine metabolism by HPLC with electrospray ionization tandem mass spectrometry. Clin Chem 52(6):1127–1137. https://doi.org/10.1373/clinchem.2005.058842

    Article  PubMed  CAS  Google Scholar 

  26. Thomas A, Vogel M, Piper T et al (2013) Quantification of AICAR-ribotide concentrations in red blood cells by means of LC-MS/MS. Anal Bioanal Chem 405(30):9703–9709. https://doi.org/10.1007/s00216-013-7162-0

    Article  PubMed  CAS  Google Scholar 

  27. Levey AS, Stevens LA, Schmid CH et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612

    Article  PubMed  PubMed Central  Google Scholar 

  28. Dyck PJ (1988) Detection, characterization, and staging of polyneuropathy: assessed in diabetics. Muscle Nerve 11(1):21–32. https://doi.org/10.1002/mus.880110106

    Article  PubMed  CAS  Google Scholar 

  29. Dyck PJ, Sherman WR, Hallcher LM et al (1980) Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry. Ann Neurol 8(6):590–596. https://doi.org/10.1002/ana.410080608

    Article  PubMed  CAS  Google Scholar 

  30. Quattrini C, Tavakoli M, Jeziorska M et al (2007) Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes 56(8):2148–2154. https://doi.org/10.2337/db07-0285

    Article  PubMed  CAS  Google Scholar 

  31. Henry RJ (1964) Non-protein nitrogenous constituents. In: Henry RJ (ed) Clinical chemistry, principles and techniques. Harper & Row, New York, pp 292–299

    Google Scholar 

  32. Radcliffe NJ, Seah JM, Clarke M, MacIsaac RJ, Jerums G, Ekinci EI (2017) Clinical predictive factors in diabetic kidney disease progression. J Diabetes Investig 8(1):6–18. https://doi.org/10.1111/jdi.12533

    Article  PubMed  CAS  Google Scholar 

  33. Allen SV, Hopkins WG (2015) Age of peak competitive performance of elite athletes: a Systematic review. Sports Med 45(10):1431–1441. https://doi.org/10.1007/s40279-015-0354-3

    Article  PubMed  Google Scholar 

  34. Fogarty S, Hardie DG (1804) Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer. Biochim Biophys Acta 3:581–591. https://doi.org/10.1016/j.bbapap.2009.09.012

    Article  CAS  Google Scholar 

  35. Vincent MF, Marangos PJ, Gruber HE, Van den Berghe G (1991) Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes 40(10):1259–1266

    Article  PubMed  CAS  Google Scholar 

  36. Longnus SL, Wambolt RB, Parsons HL, Brownsey RW, Allard MF (2003) 5-Aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms. Am J Physiol Regul Integr Comp Physiol 284(4):R936–R944. https://doi.org/10.1152/ajpregu.00319.2002

    Article  PubMed  CAS  Google Scholar 

  37. Coughlan KA, Valentine RJ, Ruderman NB, Saha AK (2014) AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes 7:241–253. https://doi.org/10.2147/DMSO.S43731

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors would like thank Kathrin Schmidt for her excellent technical assistance.

Authors’ contributions

MM and PPN designed the study, interpreted data and drafted the manuscript. JBG contributed substantially in the acquisition of data and revised the manuscript critically for important intellectual content. SK contributed substantially in the analysis and interpretation of data and preparing the tables and figures. CR revised the manuscript critically for important intellectual content. THF contributed substantially to the interpretation of data and revised the manuscript elaborately. JGO established the AICAR measurement, interpreted the data and revised the manuscript for important intellectual content. All authors read and approved the final manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding

This study was supported by the DFG (CRC1118 to MM, CR, THF & PPN).

Author information

Author notes

  1. Peter P. Nawroth and Jürgen G. Okun have contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410, Heidelberg, Germany

    Michael Mendler, Stefan Kopf, Jan B. Groener, Christin Riedinger, Thomas H. Fleming & Peter P. Nawroth

  2. German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany

    Stefan Kopf, Jan B. Groener, Thomas H. Fleming & Peter P. Nawroth

  3. Institute for Diabetes and Cancer, IDC Helmholtz Center Munich, Germany & Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany

    Peter P. Nawroth

  4. Dietmar-Hopp Metabolic Center, Center for Child and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany

    Jürgen G. Okun

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  1. Michael Mendler
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Corresponding author

Correspondence to Michael Mendler.

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Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical standards

Urine samples were obtained from three studies that have been approved by the Ethics Committee Heidelberg (S-245/2013, S-232-2013, S-383/2016) that have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

All patients gave their written consent prior to their inclusion in the studies.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Managed by Antonio Secchi.

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Cite this article

Mendler, M., Kopf, S., Groener, J.B. et al. Urine levels of 5-aminoimidazole-4-carboxamide riboside (AICAR) in patients with type 2 diabetes. Acta Diabetol 55, 585–592 (2018). https://doi.org/10.1007/s00592-018-1130-2

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  • DOI: https://doi.org/10.1007/s00592-018-1130-2

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