Skip to main content

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 195))

Abstract

Due to its versatile nature and its corresponding anabolic and anticatabolic properties, insulin has been prohibited in sports since 1999. Numerous studies concerning its impact on glycogen formation, protein biosynthesis, and inhibition of protein breakdown have illustrated its importance for healthy humans and diabetics as well as elite athletes. Various reports described the misuse of insulin to improve performance and muscle strength, and synthetic analogs were the subject of several studies describing the beneficial effects of biotechnologically modified insulins. Rapid- or long-acting insulins were developed to enhance the injection-to-onset profile as well as the controllability of administered insulin, where the slightest alterations in primary amino acid sequences allowed the inhibition of noncovalent aggregation of insulin monomers (rapid-acting analogs) or promoted microprecipitation of insulin variants upon subcutaneous application (long-acting analogs). Information on the metabolic fate and renal elimination of insulins has been rather limited, and detection assays for doping control purposes were primarily established using the intact compounds as target analytes in plasma and urine specimens. However, recent studies revealed the presence of urinary metabolites that have been implemented in confirmation methods of sports drug testing procedures. So far, no screening tool is available providing fast and reliable information on possible insulin misuse; only sophisticated procedures including immunoaffinity purification followed by liquid chromatography and tandem mass spectrometry have enabled the unambiguous detection of synthetic insulins in doping control blood or urine samples.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abel JJ (1926) Crystalline insulin. Proc Natl Acad Sci USA 12:132–136

    Article  PubMed  CAS  Google Scholar 

  • Ashcroft FM (1988) Adenosine 5′-triphosphate-sensitive potassium channels. Annu Rev Neurosci 11:97–118

    Article  PubMed  CAS  Google Scholar 

  • Ashcroft FM, Rorsman P (1989) Electrophysiology of the pancreatic beta-cell. Prog Biophys Mol Biol 54:87–143

    Article  PubMed  CAS  Google Scholar 

  • Atkinson MA, Eisenbarth GS (2001) Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 358:221–229

    Article  PubMed  CAS  Google Scholar 

  • Barnett AH, Owens DR (1997) Insulin analogues. Lancet 349:47–51

    Article  PubMed  CAS  Google Scholar 

  • Becker RH, Frick AD, Burger F, Potgieter JH, Scholtz H (2005a) Insulin glulisine, a new rapid-acting insulin analogue, displays a rapid time-action profile in obese non-diabetic subjects. Exp Clin Endocrinol Diabetes 113:435–443

    Article  PubMed  CAS  Google Scholar 

  • Becker RH, Frick AD, Burger F, Scholtz H, Potgieter JH (2005b) A comparison of the steady-state pharmacokinetics and pharmacodynamics of a novel rapid-acting insulin analog, insulin glulisine, and regular human insulin in healthy volunteers using the euglycemic clamp technique. Exp Clin Endocrinol Diabetes 113:292–297

    Article  PubMed  CAS  Google Scholar 

  • Benzi L, Cecchetti P, Ciccarone AM, Di Cianni G, Iozzi LC, Caricato F, Navalesi R (1990) Insulin degradation in vivo: a high-performance liquid chromatographic analysis. J Chromatogr 534:37–46

    Article  PubMed  CAS  Google Scholar 

  • Biolo G, Wolfe RR (1993) Insulin action on protein metabolism. Baillieres Clin Endocrinol Metab 7:989–1005

    Article  PubMed  CAS  Google Scholar 

  • Biolo G, Declan Fleming RY, Wolfe RR (1995) Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. J Clin Invest 95:811–819

    Article  PubMed  CAS  Google Scholar 

  • Danne T, Becker RH, Heise T, Bittner C, Frick AD, Rave K (2005) Pharmacokinetics, prandial glucose control, and safety of insulin glulisine in children and adolescents with type 1 diabetes. Diabetes Care 28:2100–2105

    Article  PubMed  CAS  Google Scholar 

  • Dawson RT, Harrison MW (1997) Use of insulin as an anabolic agent. Br J Sports Med 31:259

    Article  PubMed  CAS  Google Scholar 

  • Dole M, Mack LL, Hines RL, Mobley RC, Ferguson LD, Alice MB (1968) Molecular beams of macroions. J Chem Phys 49:2240–2249

    Article  CAS  Google Scholar 

  • Duckworth WC (1988) Insulin degradation: mechanisms, products, and significance. Endocr Rev 9:319–345

    Article  PubMed  CAS  Google Scholar 

  • Duckworth WC, Kitabchi AE (1981) Insulin metabolism and degradation. Endocr Rev 2:210–233

    Article  PubMed  CAS  Google Scholar 

  • Duckworth WC, Hamel FG, Liepnieks J, Frank BH, Yagil C, Rabkin R (1988) High performance liquid chromatographic analysis of insulin degradation products from a cultured kidney cell line. Endocrinology 123:2701–2708

    Article  PubMed  CAS  Google Scholar 

  • Duckworth WC, Bennett RG, Hamel FG (1998) Insulin degradation: progress and potential. Endocr Rev 19:608–624

    Article  PubMed  CAS  Google Scholar 

  • Evans PJ, Lynch RM (2003) Insulin as a drug of abuse in body building. Br J Sports Med 37:356–357

    Article  PubMed  CAS  Google Scholar 

  • Fabris D, Fenselau C (1999) Characterization of allosteric insulin hexamers by electrospray ioniziation mass spectrometry. Anal Chem 71:384–387

    Article  PubMed  CAS  Google Scholar 

  • Fenn JB, Mann M, Meng CK, Wong SF, Whitehouse CM (1989) Electrospray ionization for mass spectrometry of large biomolecules. Science 246:64–71

    Article  PubMed  CAS  Google Scholar 

  • Fujita S, Rasmussen BB, Cadenas JG, Grady JJ, Volpi E (2006) Effect of insulin on human skeletal muscle protein synthesis is modulated by insulin-induced changes in muscle blood flow and amino acid availability. Am J Physiol Endocrinol Metab 291:E745–E754

    Article  PubMed  CAS  Google Scholar 

  • Garlick PJ, Grant I (1988) Amino acid infusion increases the sensitivity of muscle protein synthesis in vivo to insulin. Effect of branched-chain amino acids. Biochem J 254:579–584

    PubMed  CAS  Google Scholar 

  • Halse R, Bonavaud SM, Armstrong JL, McCormack JG, Yeaman SJ (2001) Control of glycogen synthesis by glucose, glycogen, and insulin in cultured human muscle cells. Diabetes 50:720–726

    Article  PubMed  CAS  Google Scholar 

  • IDF (2006) Diabetes epidemic out of control. http://www.idf.org/home/index.cfm?unode = 7F22F450-B1ED-43BB-A57C-B975D16A812D. Cited 30 April 2007

  • Iribarne JV, Thomson BA (1976) Evaporation of small ions from charged droplets. J Chem Phys 64:2287–2294

    Article  CAS  Google Scholar 

  • Kebarle P, Ho Y (1997) On the mechanism of electrospray mass spectrometry. In: Cole RB (ed) Electrospray ionization mass spectrometry – fundamentals. Instrumentation and applications. Wiley, New York, pp 3–63

    Google Scholar 

  • Levin SR, Karam JH, Hane S, Grodsky GM, Forsham PH (1971) Enhancement of arginine-induced insulin secretion in man by prior administration of glucose. Diabetes 20:171–176

    PubMed  CAS  Google Scholar 

  • Lindström T, Hedman CA, Arnqvist HJ (2002) Use of a novel double-antibody technique to describe the pharmacokinetics of rapid-acting insulin analogs. Diabetes Care 25:1049–1054

    Article  PubMed  Google Scholar 

  • Loo JA, Edmonds CG, Smith RD (1993) Tandem mass spectrometry of very large molecules. 2. Dissociation of multiply charged proline-containing proteins from electrospray ionization. Anal Chem 65:425–438

    Article  PubMed  CAS  Google Scholar 

  • Manninen AH (2006) Hyperinsulinaemia, hyperaminoacidaemia and post-exercise muscle anabolism: the search for the optimal recovery drink. Br J Sports Med 40:900–905

    Article  PubMed  CAS  Google Scholar 

  • Mark M (2002) Sulfonylharnstoffe und Glinide. Pharm Unserer Zeit 31:252–262

    Article  PubMed  Google Scholar 

  • Plum A, Agers H, Andersen L (2000) Pharmacokinetics of the rapid-acting insulin analog, insulin aspart, in rats, dogs, and pigs, and pharmacodynamics of insulin aspart in pigs. Drug Metab Dispos 28:155–160

    PubMed  CAS  Google Scholar 

  • Proks P, Lippiat JD (2006) Membrane ion channels and diabetes. Curr Pharm Des 12:485–501

    Article  PubMed  CAS  Google Scholar 

  • Rasmussen H, Zawalich KC, Ganesan S, Calle R, Zawalich WS (1990) Physiology and pathophysiology of insulin secretion. Diabetes Care 13:655–666

    Article  PubMed  CAS  Google Scholar 

  • Reichlin S (1983) Somatostatin (second of two parts). N Engl J Med 309:1556–1563

    Article  PubMed  CAS  Google Scholar 

  • Reverter JL, Tural C, Rosell A, Dominguez M, Sanmarti A (1994) Self-induced insulin hypoglycemia in a bodybuilder. Arch Intern Med 154:225–226

    Article  PubMed  CAS  Google Scholar 

  • Rich JD, Dickinson BP, Merriman NA, Thule PM (1998) Insulin use by bodybuilders. JAMA 279:1613

    Article  PubMed  CAS  Google Scholar 

  • Rooyackers OE, Nair KS (1997) Hormonal regulation of human muscle protein metabolism. Annu Rev Nutr 17:457–485

    Article  PubMed  CAS  Google Scholar 

  • Rosak C (2001) Insulinanaloga: Struktur, Eigenschaften und therapeutische Indikationen (Teil 1: Kurzwirkende Insulinanaloga). Der Internist 42:1523–1535

    Article  PubMed  CAS  Google Scholar 

  • Rosenfeld L (2002) Insulin: discovery and controversy. Clin Chem 48:2270–2288

    PubMed  CAS  Google Scholar 

  • Ryle AP, Sanger F, Smith LF, Kitai R (1955) The disulphide bonds of insulin. Biochem J 60:541–556

    PubMed  CAS  Google Scholar 

  • Sanger F (1959) Chemistry of insulin; determination of the structure of insulin opens the way to greater understanding of life processes. Science 129:1340–1344

    Article  PubMed  CAS  Google Scholar 

  • Sanger F (1988) Sequences, sequences, and sequences. Annu Rev Biochem 57:1–28

    Article  PubMed  CAS  Google Scholar 

  • Schäfer EA (1916) The endocrine organs: an introduction to the study of internal secretion. Longmans, Green, Longmans, Green

    Google Scholar 

  • Seabright PJ, Smith GD (1996) The characterization of endosomal insulin degradation intermediates and their sequence of production. Biochem J 320(Pt 3):947–956

    PubMed  CAS  Google Scholar 

  • Shapiro ET, Tillil H, Miller MA, Frank BH, Galloway JA, Rubenstein AH, Polonsky KS (1987) Insulin secretion and clearance. Comparison after oral and intravenous glucose. Diabetes 36:1365–1371

    Article  PubMed  CAS  Google Scholar 

  • Sonksen PH (2001) Hormones and sport (insulin, growth hormone and sport). J Endocrinol 170:13–25

    Article  PubMed  CAS  Google Scholar 

  • Steiner A, Wagner RA (2002) Insulin. ISP-Verlag, Arnsberg 3:4–73

    Google Scholar 

  • Tanaka K, Waki H, Ido Y, Akita S, Yoshida Y, Yohida T (1988) Protein and polymer analyses up to m/z 100, 000 by laser ionization time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 2:151–153

    Article  CAS  Google Scholar 

  • Thevis M, Schänzer W (2005a) Examples of doping control analysis by liquid chromatography-tandem mass spectrometry: ephedrines, beta-receptor blocking agents, diuretics, sympathomimetics, and cross-linked hemoglobins. J Chromatogr Sci 43:22–31

    PubMed  CAS  Google Scholar 

  • Thevis M, Schänzer W (2005b) Identification and characterization of peptides and proteins in doping control analysis. Curr Proteom 2:191–208

    Article  CAS  Google Scholar 

  • Thevis M, Schänzer W (2005c) Mass spectrometry in doping control analysis. Curr Org Chem 9:825–848

    Article  CAS  Google Scholar 

  • Thevis M, Schänzer W (2007a) Current role of LC-MS(/MS) in doping control. Anal Bioanal Chem 388:1351–1358

    Article  PubMed  CAS  Google Scholar 

  • Thevis M, Schänzer W (2007b) Mass spectrometric identification of peptide hormones in doping control analysis. Analyst 132:287–291

    Article  PubMed  CAS  Google Scholar 

  • Thevis M, Schänzer W (2007c) Mass spectrometry in sports drug testing: Structure characterization and analytical assays. Mass Spectrom Rev 26:79–107

    Article  PubMed  CAS  Google Scholar 

  • Thevis M, Thomas A, Delahaut P, Bosseloir A, Schänzer W (2005) Qualitative determination of synthetic analogues of insulin in human plasma by immunoaffinity purification and liquid chromatography-tandem mass spectrometry for doping control purposes. Anal Chem 77:3579–3585

    Article  PubMed  CAS  Google Scholar 

  • Thevis M, Thomas A, Delahaut P, Bosseloir A, Schanzer W (2006) Doping control analysis of intact rapid-acting insulin analogues in human urine by liquid chromatography-tandem mass spectrometry. Anal Chem 78:1897–1903

    Article  PubMed  CAS  Google Scholar 

  • Thevis M, Loo JA, Loo RR, Schänzer W (2007) Recommended criteria for the mass spectrometric identification of target peptides and proteins (<8 kDa) in sports drug testing. Rapid Commun Mass Spectrom 21:297–304

    Article  PubMed  CAS  Google Scholar 

  • Thomas A, Thevis M, Delahaut P, Bosseloir A, Schanzer W (2007) Mass spectrometric identification of degradation products of insulin and its long-acting analogues in human urine for doping control purposes. Anal Chem 79:2518–2524

    Article  PubMed  CAS  Google Scholar 

  • Tillil H, Shapiro ET, Miller MA, Karrison T, Frank BH, Galloway JA, Rubenstein AH, Polonsky KS (1988) Dose-dependent effects of oral and intravenous glucose on insulin secretion and clearance in normal humans. Am J Physiol 254:E349–E357

    PubMed  CAS  Google Scholar 

  • Tipton KD, Wolfe RR (2001) Exercise, protein metabolism, and muscle growth. Int J Sport Nutr Exerc Metab 11:109–132

    PubMed  CAS  Google Scholar 

  • von Mering J, Minkowski O (1889) Diabetes mellitus nach Pankreasextirpation. Centralblatt für klinische Medicin 10:393–394

    Google Scholar 

  • WADA (2007) The 2007 Prohibited List. http://www.wada-ama.org/rtecontent/document/2007_List_En.pdf. Cited 30 January 2007

  • Wolfe RR (2000) Effects of insulin on muscle tissue. Curr Opin Clin Nutr Metab Care 3:67–71

    Article  PubMed  CAS  Google Scholar 

  • Wolfe RR (2005) Regulation of skeletal muscle protein metabolism in catabolic states. Curr Opin Clin Nutr Metab Care 8:61–65

    Article  PubMed  CAS  Google Scholar 

  • Yeaman SJ, Armstrong JL, Bonavaud SM, Poinasamy D, Pickersgill L, Halse R (2001) Regulation of glycogen synthesis in human muscle cells. Biochem Soc Trans 29:537–541

    Article  PubMed  CAS  Google Scholar 

  • Young J, Anwar A (2007) Strong diabetes. Br J Sports Med 41:335–336; discussion 336

    Google Scholar 

  • Zhang XJ, Chinkes DL, Wolf SE, Wolfe RR (1999) Insulin but not growth hormone stimulates protein anabolism in skin wound and muscle. Am J Physiol 276:E712–E720

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank the Manfred-Donike Institute for Doping Analysis for supporting the presented work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mario Thevis .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Thevis, M., Thomas, A., Schänzer, W. (2010). Insulin. In: Thieme, D., Hemmersbach, P. (eds) Doping in Sports: Biochemical Principles, Effects and Analysis. Handbook of Experimental Pharmacology, vol 195. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-79088-4_10

Download citation

Publish with us

Policies and ethics