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Testosterone and insulin resistance in the metabolic syndrome and T2DM in men

Abstract

Obesity, type 2 diabetes mellitus and the metabolic syndrome are major risk factors for cardiovascular disease. Studies have demonstrated an association between low levels of testosterone and the above insulin-resistant states, with a prevalence of hypogonadism of up to 50% in men with type 2 diabetes mellitus. Low levels of testosterone are also associated with an increased risk of all-cause and cardiovascular mortality. Hypogonadism and obesity share a bidirectional relationship as a result of the complex interplay between adipocytokines, proinflammatory cytokines and hypothalamic hormones that control the pituitary–testicular axis. Interventional studies have shown beneficial effects of testosterone on components of the metabolic syndrome, type 2 diabetes mellitus and other cardiovascular risk factors, including insulin resistance and high levels of cholesterol. Biochemical evidence indicates that testosterone is involved in promoting glucose utilization by stimulating glucose uptake, glycolysis and mitochondrial oxidative phosphorylation. Testosterone is also involved in lipid homeostasis in major insulin-responsive target tissues, such as liver, adipose tissue and skeletal muscle.

Key Points

  • Testosterone deficiency is highly prevalent in men with the metabolic syndrome and type 2 diabetes mellitus

  • Low levels of testosterone are an independent risk factor that predicts subsequent development of the metabolic syndrome and type 2 diabetes mellitus

  • Population studies in community-dwelling men have shown that testosterone deficiency is associated with increased all-cause mortality and cardiovascular mortality

  • The hypogonadal–obesity–adipocytokine hypothesis summarises the complex interaction of the above components and their contribution to the vicious cycle of obesity causing hypogonadism and vice versa

  • Interventional studies of testosterone replacement therapy have shown improvements in insulin resistance, body composition, glycaemic control, lipid metabolism and other cardiovascular risk factors

  • The benefit of testosterone on insulin sensitivity might be attributable to a complex regulatory influence on insulin signalling and glucose homeostasis in the major insulin-responsive target tissues

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Figure 1: The hypogonadal–obesity–adipocytokine hypothesis.
Figure 2: Potential mechanism of testosterone action on cellular insulin sensitivity and glucose homeostasis.

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All authors researched data for the article, contributed to discussion of the content and wrote the article. P. M. Rao and T. H. Jones reviewed and edited the manuscript before submission.

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Correspondence to T. Hugh Jones.

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Competing interests

T. H. Jones has received research grants and support and consultancy fees from Bayer Healthcare, been a consultant for ProStrakan in regard to the TIMES2 study, and has received honoraria for educational lectures and advisory boards from Bayer Healthcare, Clarus, Ferring, Lilly, Merck and Prostrakan. P. M. Rao and D. M. Kelly declare no competing interests.

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Rao, P., Kelly, D. & Jones, T. Testosterone and insulin resistance in the metabolic syndrome and T2DM in men. Nat Rev Endocrinol 9, 479–493 (2013). https://doi.org/10.1038/nrendo.2013.122

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