Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging

Abstract

Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with β-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels. The effects of testosterone on physical function and outcomes important to patients have not, however, been studied. In older men, increased hematocrit and increased risk of prostate biopsy and detection of prostate events are the most frequent, testosterone-related adverse events. Concerns about long-term risks have restrained enthusiasm for testosterone use as anabolic therapy. Selective androgen-receptor modulators that are preferentially anabolic and that spare the prostate hold promise as anabolic therapies. We need more studies to determine whether testosterone or selective androgen-receptor modulators can induce meaningful improvements in physical function and patient-important outcomes in patients with physical dysfunction associated with chronic illness or aging.

Key Points

  • Meta-analyses of clinical trials provide unequivocal evidence that testosterone administration increases skeletal muscle mass, muscle strength, and leg power; these anabolic effects of testosterone are dose-related

  • The effects of testosterone supplementation on physical function and clinical outcomes in older men with physical dysfunction and in men with chronic illness are unknown

  • Testosterone induces skeletal muscle fiber hypertrophy and increases the number of satellite cells

  • Testosterone increases muscle mass and decreases fat mass by promoting the differentiation of mesenchymal multipotent cells into myogenic lineage and inhibiting their differentiation into the adipogenic lineage

  • An increase in hematocrit and increased risk of detection of prostate events are the most frequent adverse effects of testosterone administration in older men; the anabolic applications of testosterone are constrained by dose-limiting adverse events and concerns about long-term effects on the prostate and cardiovascular risk

  • Nonsteroidal selective androgen-receptor modulators that are free of adverse effects of testosterone and are preferentially anabolic hold great promise as anabolic therapies

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Figure 1: Changes in body composition in testosterone-treated HIV-infected men and women
Figure 2: Changes in body composition in testosterone-treated older men
Figure 3: Steroidal (dihydrotestosterone) and nonsteroidal (R-bicalutamide) ligand interactions with the androgen receptor ligand-binding domain binding-pocket
Figure 4: Four general classes of selective androgen receptor modulator pharmacophores
Figure 5: Structures and relative binding affinities of some selective androgen receptor modulators

References

  1. 1

    Spillman BC and Lubitz J (2000) The effect of longevity on spending for acute and long-term care. N Engl J Med 342: 1409–1415

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Bhasin S et al. (2003) Androgen effects on body composition. Growth Horm IGF Res 13 (Suppl A): S63–S71

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Katznelson L et al. (1998) Using quantitative CT to assess adipose distribution in adult men with acquired hypogonadism. AJR Am J Roentgenol 170: 423–427

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Roy TA et al. (2002) Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men. Am J Physiol Endocrinol Metab 283: E284–E294

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Baumgartner RN et al. (1999) Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 107: 123–136

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Seidell JC et al. (1990) Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels. Metabolism 39: 897–901

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Mauras N et al. (1998) Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity. J Clin Endocrinol Metab 83: 1886–1892

    CAS  PubMed  Google Scholar 

  8. 8

    Bhasin S et al. (1997) Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab 82: 407–413

    CAS  PubMed  Google Scholar 

  9. 9

    Steidle C et al. (2003) AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab 88: 2673–2681

    CAS  PubMed  Article  Google Scholar 

  10. 10

    McNicholas TA et al. (2003) A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int 91: 69–74

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Wang C et al. (1996) Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men—a clinical research center study. J Clin Endocrinol Metab 81: 3654–3662

    CAS  PubMed  Google Scholar 

  12. 12

    Wang C et al. (2000) Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Testosterone Gel Study Group. J Clin Endocrinol Metab 85: 2839–2853

    CAS  PubMed  Google Scholar 

  13. 13

    Katznelson L et al. (1996) Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 81: 4358–4365

    CAS  PubMed  Google Scholar 

  14. 14

    Brodsky IG et al. (1996) Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men—a clinical research center study. J Clin Endocrinol Metab 81: 3469–3475

    CAS  PubMed  Google Scholar 

  15. 15

    Dobs AS et al. (2001) Interrelationships among lipoprotein levels, sex hormones, anthropometric parameters, and age in hypogonadal men treated for 1 year with a permeation-enhanced testosterone transdermal system. J Clin Endocrinol Metab 86: 1026–1033

    CAS  PubMed  Google Scholar 

  16. 16

    Snyder PJ et al. (2000) Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 85: 2670–2677

    CAS  PubMed  Google Scholar 

  17. 17

    Wang C et al. (2004) Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab 89: 2085–2098

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Bhasin S et al. (1996) The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 335: 1–7

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Blackman MR et al. (2002) Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 288: 2282–2292

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Bhasin S et al. (2001) Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab 281: E1172–E1181

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Bhasin S et al. (2005) Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 90: 678–688

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Woodhouse LJ et al. (2003) Development of models to predict anabolic response to testosterone administration in healthy young men. Am J Physiol Endocrinol Metab 284: E1009–E1017

    CAS  PubMed  Article  Google Scholar 

  23. 23

    Storer TW et al. (2003) Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension. J Clin Endocrinol Metab 88: 1478–1485

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Sinha-Hikim I et al. (2002) Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. Am J Physiol Endocrinol Metab 283: E154–E164

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Sinha-Hikim I et al. (2003) Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men. Am J Physiol Endocrinol Metab 285: E197–E205

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Singh R et al. (2003) Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology 144: 5081–5088

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Bhasin S et al. (2003) The mechanisms of androgen effects on body composition: mesenchymal pluripotent cell as the target of androgen action. J Gerontol A Biol Sci Med Sci 58: M1103–M1110

    PubMed  Article  Google Scholar 

  28. 28

    Singh R et al. (2006) Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with β-catenin and TCF4 may bypass canonical Wnt signaling to downregulate adipogenic transcription factors. Endocrinology 147: 141–154

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Bartsch W et al. (1983) Regulation and compartmentalization of androgens in rat prostate and muscle. J Steroid Biochem 19: 929–937

    CAS  PubMed  Article  Google Scholar 

  30. 30

    Carani C et al. (1997) Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 337: 91–95

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31

    Jones ME et al. (2000) Aromatase deficient (ArKO) mice have phenotype of increased adiposity. Proc Natl Acad Sci USA 97: 12735–12740

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Rietschel P et al. (2000) Prevalence of hypogonadism among men with weight loss related to human immunodeficiency virus infection who were receiving highly active antiretroviral therapy. Clin Infect Dis 31: 1240–1244

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Dobs AS et al. (1996) Serum hormones in men with human immunodeficiency virus-associated wasting. J Clin Endocrinol Metab 81: 4108–4112

    CAS  PubMed  Google Scholar 

  34. 34

    Arver S et al. (1999) Serum dihydrotestosterone and testosterone concentrations in human immunodeficiency virus-infected men with and without weight loss. J Androl 20: 611–618

    CAS  PubMed  Google Scholar 

  35. 35

    Coodley GO et al. (1994) Endocrine function in the HIV wasting syndrome. J Acquir Immune Defic Syndr 7: 46–51

    CAS  PubMed  Google Scholar 

  36. 36

    Grinspoon S et al. (1996) Loss of lean body and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodeficiency syndrome and wasting. J Clin Endocrinol Metab 81: 4051–4058

    CAS  PubMed  Google Scholar 

  37. 37

    Salehian B et al. (1999) Testicular pathologic changes and the pituitary–testicular axis during human immunodeficiency virus infection. Endocr Pract 5: 1–9

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Bhasin S et al. (2000) Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels. JAMA 283: 763–770

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Bhasin S et al. (1998) Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab 83: 3155–3162

    CAS  PubMed  Google Scholar 

  40. 40

    Dobs AS et al. (1999) The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection. Am J Med 107: 126–132

    CAS  PubMed  Article  Google Scholar 

  41. 41

    Grinspoon S et al. (1998) Effects of androgen administration in men with the AIDS wasting syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 129: 18–26

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Grinspoon S et al. (2000) Effects of testosterone and progressive resistance training in eugonadal men with AIDS wasting. A randomized, controlled trial. Ann Intern Med 133: 348–355

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Storer TW et al. (2005) A randomized, placebo-controlled trial of nandrolone decanoate in HIV-infected men with mild to moderate weight loss with recombinant human growth hormone as active reference treatment. J Clin Endocrinol Metab 90: 4474–4482

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Grunfeld C et al. A 12-week randomized, placebo-controlled trial of oxandrolone in HIV-infected patients with weight loss. J Acquir Immune Defic Syndr, in press

  45. 45

    Berger JR et al. (1996) Oxandrolone in AIDS-wasting myopathy. AIDS 10: 1657–1662

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Kong A and Edmonds P (2002) Testosterone therapy in HIV wasting syndrome: systematic review and meta-analysis. Lancet Infect Dis 2: 692–699

    CAS  PubMed  Article  Google Scholar 

  47. 47

    Rabkin JG et al. (2000) A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Arch Gen Psychiatry 57: 141–147

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Grinspoon S et al. (2000) Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men. J Clin Endocrinol Metab 85: 60–65

    CAS  PubMed  Google Scholar 

  49. 49

    Rabkin JG et al. (2004) Testosterone versus fluoxetine for depression and fatigue in HIV/AIDS: a placebo-controlled trial. J Clin Psychopharmacol 24: 379–385

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Rabkin JG et al. (1999) Testosterone therapy for human immunodeficiency virus-positive men with and without hypogonadism. J Clin Psychopharmacol 19: 19–27

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Miller K et al. (1998) Transdermal testosterone administration in women with acquired immunodeficiency syndrome wasting: a pilot study. J Clin Endocrinol Metab 83: 2717–2725

    CAS  PubMed  Google Scholar 

  52. 52

    Dolan S et al. (2004) Effects of testosterone administration in human immunodeficiency virus-infected women with low weight: a randomized placebo-controlled study. Arch Intern Med 164: 897–904

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Choi HH et al. (2005) Effects of testosterone replacement in human immunodeficiency virus-infected women with weight loss. J Clin Endocrinol Metab 90: 1531–1541

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Reid IR et al. (1985) Plasma testosterone concentrations in asthmatic men treated with glucocorticoids. Br Med J (Clin Res Ed) 291: 574

  55. 55

    Reid IR et al. (1996) Testosterone therapy in glucocorticoid-treated men. Arch Intern Med 156: 1173–1177

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Crawford BA et al. (2003) Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. J Clin Endocrinol Metab 88: 3167–3176

    CAS  PubMed  Article  Google Scholar 

  57. 57

    Casaburi R et al. (2004) Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 170: 870–878

    PubMed  Article  Google Scholar 

  58. 58

    Schols AM et al. (1995) Physiologic effects of nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease. A placebo controlled randomized trial. Am J Respir Crit Care Med 152: 1268–1274

    CAS  PubMed  Article  Google Scholar 

  59. 59

    Morley JE et al. (1993) Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc 41: 149–152

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Snyder PJ et al. (1999) Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 84: 2647–2653

    CAS  PubMed  Google Scholar 

  61. 61

    Tenover JS (1992) Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 75: 1092–1098

    CAS  PubMed  Google Scholar 

  62. 62

    Page ST et al. (2005) Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 90: 1502–1510

    CAS  PubMed  Article  Google Scholar 

  63. 63

    Kenny AM et al. (2001) Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 56: M266–M272

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Sih R et al. (1997) Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 82: 1661–1667

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Ferrando AA et al. (2003) Differential anabolic effects of testosterone and amino acid feeding in older men. J Clin Endocrinol Metab 88: 358–362

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Wittert GA et al. (2003) Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci 58: 618–625

    PubMed  Article  Google Scholar 

  67. 67

    Liverman CT and Blazer DG (eds.; 2004) Testosterone and Aging: Clinical Research Directions. Washington, DC: National Academies Press

    Google Scholar 

  68. 68

    Bhasin S and Buckwalter JG (2001) Testosterone supplementation in older men: a rational idea whose time has not yet come. J Androl 22: 718–731

    CAS  PubMed  Google Scholar 

  69. 69

    Calof O et al. (2005) Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 60: 1451–1457

    PubMed  Article  Google Scholar 

  70. 70

    Kearbey JD et al. (2004) Pharmacokinetics of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide in rats, a non-steroidal selective androgen receptor modulator. Xenobiotica 34: 273–280

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71

    Gao W et al. (2004) Comparison of the pharmacological effects of a novel selective androgen receptor modulator, the 5α-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats: new approach for benign prostate hyperplasia. Endocrinology 145: 5420–5428

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    Yin D et al. (2003) Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor. Mol Pharmacol 63: 211–223

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Gao W et al. (2005) Selective androgen receptor modulator (SARM) treatment improves muscle strength and body composition, and prevents bone loss in orchidectomized rats. Endocrinology 146: 4887–4897

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Salvati ME et al. (2004) Design, structural analysis, and biological profile of a novel series of AR antagonists. In American Association for Cancer Research Annual Meeting: 1996 March 27–31; Orlando, FL, abstract 1948

    Google Scholar 

  75. 75

    Bohl CE et al. (2005) Structural basis for antagonism and resistance of bicalutamide in prostate cancer. Proc Natl Acad Sci USA 102: 6201–6206

    CAS  PubMed  Article  Google Scholar 

  76. 76

    Hanada K et al. (2003) Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis. Biol Pharm Bull 26: 1563–1569

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Gronemeyer H et al. (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3: 950–964

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Katzenellenbogen BS and Katzenellenbogen JA (2002) Biomedicine. Defining the “S” in SERMs. Science 295: 2380–2381

    CAS  PubMed  Article  Google Scholar 

  79. 79

    Kemppainen JA et al. (1999) Distinguishing androgen receptor agonists and antagonists: distinct mechanisms of activation by medroxyprogesterone acetate and dihydrotestosterone. Mol Endocrinol 13: 440–454

    CAS  PubMed  Article  Google Scholar 

  80. 80

    He B and Wilson EM (2003) Electrostatic modulation in steroid receptor recruitment of LXXLL and FXXLF motifs. Mol Cell Biol 23: 2135–2150

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81

    Chang CY and McDonnell DP (2002) Evaluation of ligand-dependent changes in AR structure using peptide probes. Mol Endocrinol 16: 647–660

    CAS  PubMed  Article  Google Scholar 

  82. 82

    Sathya G et al. (2003) Pharmacological uncoupling of androgen receptor-mediated prostate cancer cell proliferation and prostate-specific antigen secretion. Cancer Res 63: 8029–8036

    CAS  PubMed  Google Scholar 

  83. 83

    Heinlein CA and Chang C (2002) Androgen receptor (AR) coregulators: an overview. Endocr Rev 23: 175–200

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Kelce WR et al. (1994) Environmental hormone disruptors: evidence that vinclozolin developmental toxicity is mediated by antiandrogenic metabolites. Toxicol Appl Pharmacol 126: 276–285

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Waller CL et al. (1996) Three-dimensional quantitative structure–activity relationships for androgen receptor ligands. Toxicol Appl Pharmacol 137: 219–227

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Christiansen RG et al. (1990) Antiandrogenic steroidal sulfonylpyrazoles. J Med Chem 33: 2094–2100

    CAS  PubMed  Article  Google Scholar 

  87. 87

    Hamann LG (2004) Discovery and preclinical profile of a highly potent and muscle selective androgen receptor modulator (SARM). In 227th National Meeting of the American Chemical Society Medicinal Chemistry Division: 2004 March 28–April 1; Anaheim, CA, MEDI-175

    Google Scholar 

  88. 88

    Miyakawa M et al. (2004) Preparation of novel tetrahydroquinoline derivatives as androgen receptor agonists. In Patent WO 2004013104 (US patent 2005277660).

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Correspondence to Shalender Bhasin.

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Competing interests

SB has received research grants from Solvay Pharmaceuticals, TAP Pharmaceuticals, and GSK and has served as a consultant for GTX, Merck, and Wyeth. OMC has received research a grant from Genentech, Inc. TWS has served as a consultant for GTX and Wyeth Pharmaceuticals. NAM was formerly an employee of Watson Pharmaceuticals. JTD is an employee of GTX, Inc. MLL, RJ, VMM and WG declared they have no competing interests.

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Bhasin, S., Calof, O., Storer, T. et al. Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Rev Endocrinol 2, 146–159 (2006). https://doi.org/10.1038/ncpendmet0120

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