15 January 2016 Subscribe to our news feed

Testosterone Therapy Reduces Insulin Resistance and Inflammation in Men with Type 2 Diabetes

Testosterone Therapy Reduces Insulin Resistance and Inflammation in Men with Type 2 Diabetes

Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes.
Dhindsa S, Ghanim H, Batra M, et al. Diabetes Care. 2016;39(1):82-91.

Testosterone deficiency – defined as low levels of total testosterone in the presence of symptoms - is common among men with obesity and type 2 diabetes, with a reported prevalence of 58% and 45%, respectively.1,2 However, even after adjusting for age and BMI, the prevalence of subnormal free testosterone levels (<5 ng/dL or 144 pmol/L) in men with type 2 diabetes is higher than in men without (45% versus 33%).3

Here we summarize the results of a well conducted randomized, parallel, placebo controlled, double-blind, prospective trial that specifically selected men with type 2 diabetes based on low free testosterone levels (calculated free testosterone of <6.5 ng/dL on two occasions).4

The aims of the study were to investigate:4

1) The impact of testosterone deficiency (hypogonadotropic hypogonadism) on insulin resistance, inflammation, and body composition in men with type 2 diabetes.

2) The effects of intramuscular testosterone replacement on insulin sensitivity, inflammation, and body composition.

Key Points

  • Men with testosterone deficiency and type 2 diabetes had higher subcutaneous and visceral fat mass, and more severe insulin resistance, than eugonadal men.
  • Testosterone treatment for 6 months in hypogonadal men reduced insulin resistance and subcutaneous fat mass (approx. 3 kg) and increased lean mass (approx. 3 kg), without changing body weight.
  • The expression of insulin signaling genes (IR-beta, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in hypogonadal men and was upregulated after testosterone treatment.
  • Testosterone treatment also caused a significant fall in inflammatory mediators and circulating concentrations of free fatty acids, C-reactive protein, interleukin-1beta, tumor necrosis factor-alpha, and leptin.
  • Testosterone treatment additionally improved parameters of sexual function.
  • In this study PSA levels did not change, and no subject developed hemoglobin >18 g/dL, hematocrit >55%, supranormal PSA concentrations (>4 ng/mL), or a prostate nodule during the trial.

What is known

Measuring SHBG and calculating free or bioavailable testosterone is advisable in men with type 2 diabetes, in whom low levels of free testosterone are consistently more common than low total testosterone levels.2,5-7

Diabetic hypgonadal men also have significantly higher plasma levels of C-reactive protein (CRP)8 - indicating systemic inflammation - and suggestive of increased insulin resistance9 and atherogenicity.10 In line with this, men with low testosterone levels - irrespective of diabetes - have increased insulin resistance (as measured by HOMA-IR)11,12, and low testosterone levels increase risk for cardiovascular disease.13

Several lines of research show that inflammatory mediators contribute to insulin resistance by interfering with insulin signaling.9,14-19 Long-term testosterone therapy has been shown to reduce CRP levels.20-22 However, the effect of testosterone therapy in men with type 2 diabetes on insulin resistance, measured by HOMA-IR, is unclear23, with studies showing either improvement in insulin resistance24 or no effect on insulin resistance.25

HOMA-IR is a commonly used index of insulin resistance.26,27 However, when investigating the effect of testosterone therapy on insulin resistance in men with type 2 diabetes, it has to be underscored that HOMA-IR is inaccurate because inadequate insulin secretion and beta-cell loss can lead to inappropriately low insulin concentrations and a falsely low HOMA-IR.27-29 The most accurate way to assess insulin resistance is through hyperinsulinemic-euglycemic (HE) clamps.

What this study adds

The study by Dhindsa used the HE clamp to investigate the effect of testosterone deficiency and treatment in type 2 diabetic men. In addition, detailed analysis of the expression of insulin signaling genes (IR-b, IRS-1, AKT-2, and GLUT4) in adipose tissue was conducted, as well as measurement of inflammatory mediators (CRP, interleukin-1b, tumor necrosis factor-a).

The study first compared 50 eugonadal type 2 diabetic men with 44 hypogonadal type 2 diabetic men. Then the hypogonadal type 2 diabetic men received testosterone therapy - 250 mg testosterone cypionate - or placebo (saline injections), every 2 weeks for 6 months. The dose of testosterone was adjusted to keep free testosterone levels in normal range (6.5 to 25 ng/dL).

The men randomized to testosterone or placebo arms were similar in age (55 years), duration of diabetes (10 years), or use of anti-diabetes medications (primarily metformin, sulfonylureas and insulin). There was no significant difference in any of the baseline measures of body composition, insulin sensitivity, or inflammation of men randomized to testosterone or placebo arms.

1) Comparison of Eugonadal and Hypogonadal Type 2 Diabetic Men.

As expected, when compared to eugonadal men, hypogonadal men had larger waist circumference and more total body subcutaneous fat mass, as well as trunk fat and visceral fat mass, and less lean mass expressed as a percentage of total body weight. They scored lower on measures of sexual function and were more insulin resistant. The greater insulin resistance in hypogonadal men was primarily explained by visceral fat, hepatic fat, and total body subcutaneous fat.

Hypogonadal men also had lower expression of genes that mediate insulin signaling. However, there were no differences in expression of proinflammatory mediators known to interfere with insulin signaling (JNK-1, IKKb, SOCS-3, PTP-1B, and TLR-4 in MNC and in adipose tissue), nor inflammatory mediators (CRP, IL-1β, and TNF-α).

2) Results of Testosterone Treatment

Effects of 24 weeks of testosterone treatment on hormonal parameters and glucose are summarized in table 1. All listed changes in the testosterone group were statistically significant.

Table 1: Effect of testosterone treatment on hormonal parameters and glucose.

  Testosterone group Placebo group
Total T
(ng/dL)
259 561 239 280
Calculated free T
(ng/dL)
5.5 17.6 5.2 5.7
Total estradiol
(pg/mL)
30.1 62.6 26.1 26.4
Free estradiol
(pg/mL)
0.66 1.55 0.57 0.59
Insulin, fasting
(µU/mL)
13.6 9.9 11.8 13.9
Glucose, fasting
(mg/dL)
126 115 119 132

Despite reductions in fasting glucose and insulin, there was no change in HbA1c. There was also no change in serum lipids.

The testosterone group had an increase in lean body mass of almost 3 kg, and a reduction in total body subcutaneous fat of 2.4 kg. No body composition changes were seen in the placebo group. As illustrated in figure 1 and 2, Insulin sensitivity was significantly improved in the testosterone group, as indicated by a 32% increase in glucose infusion rate during the HE clamp, and insulin resistance (as indicated by HOMA-IR) was reduced accordingly.

Figure 1: Increase in insulin sensitivity after 6 months of testosterone treatment in hypogonadal type 2 diabetic men.

Figure 1: Increase in insulin sensitivity after 6 months of testosterone treatment in hypogonadal type 2 diabetic men.



Figure 2: Reduction in insulin resistance after 6 months of testosterone treatment in hypogonadal type 2 diabetic men.

Figure 2: Reduction in insulin resistance after 6 months of testosterone treatment in hypogonadal type 2 diabetic men.

Compared to placebo treatment, the expression of insulin signaling genes (Rb, IRS-1, AkT-2 and GLUT4) was significantly upregulated in adipose tissue after testosterone treatment. This was accompanied by a significant fall in circulating levels of FFA, CRP, IL-1β, TNF-α, and leptin, while there was no significant change in adiponectin levels. The reductions in CRP and were TNF-α were 19% and 16%, respectively. In mononuclear cells, testosterone treatment suppressed expression of proinflammatory and insulin resistance mediators (SOCS-3, IKK-b, and PTEN) as well as protein levels of SOCS-3. Notably, these changes in inflammatory mediators were not apparent until 15 weeks after the start of the treatment.

As expected, men in the testosterone group reported an improvement in some measures of sexual function. PSA levels did not change during the study. Hemoglobin and hematocrit increased by mean between-group difference of 0.54 g/dL and 2.3%, respectively (P = 0.10 and 0.03). No subject developed hemoglobin >18 g/dL, hematocrit >55%, supranormal PSA concentrations (>4 ng/mL), or a prostate nodule during the trial.

It was concluded that testosterone treatment in hypogonadal men with type 2 diabetes has insulin-sensitizing and anti-inflammatory effects in addition to a reduction in adiposity and an increase in lean body mass. The increase in expression of genes related to insulin signal transduction and the suppression of genes interfering with the action of insulin probably account for this insulin sensitizing effect. There is also an improvement in sexual function.

Comment

This study is notable in that it first compared hypogonadal and eugonadal type 2 diabetic men, and then treated those same hypogonadal men with testosterone to show improvements in hormonal, metabolic and inflammatory parameters. This study is also the first to demonstrate an insulin-sensitizing effect of testosterone therapy, using the gold standard HE clamp in hypogonadal men with type 2 diabetes.

While there were significant reductions in insulin resistance and fasting glucose, there was no change in HbA1c. This is likely because the duration of the study was too short to induce a change in HbA1c. Nevertheless, the evidence that testosterone increases insulin sensitivity and reduces fasting glucose concentrations is promising and suggests that long-term testosterone treatment may improve overall diabetes control. Support for this comes from multiple observational studies of long-term (5 to 10 years) testosterone treatment in men with obesity, metabolic syndrome and/or diabetes.20,21,30-33

It should be underscored that the improvement in inflammatory mediators did not emerge until 15 weeks (almost 4 months) after the start of testosterone therapy, and this study also suggests that even 6 months may be too short to show improvement in HBA1c. This is important to consider when offering patient with symptoms but low-normal testosterone levels – which is a common presentation in the clinic - a therapeutic trial to assess response to testosterone therapy. The Canadian34 and the US Endocrine Society35 guidelines recommend a therapeutic trial of only 3 months, while the International Society for Sexual Medicine guideline36 recommends 6 months. However, a previous randomized controlled trial of testosterone undecanoate in men with type 2 diabetes showed that improvements in insulin resistance and metabolic parameters continued for 12 months.37 This suggests that a therapeutic trial of a longer duration than 3-6 months may be warranted in men with metabolic dysfunction.

Overall, this well conducted RCT coupled with multiple observational studies of long-term testosterone treatment in real life clinical practices, provides evidence that testosterone therapy may help improve glycemic control in hypogonadal type 2 diabetic men, by conferring insulin-sensitizing and anti-inflammatory effects and improvement in body composition. This could possibly reduce need for anti-diabetic medications in hypogonadal diabetics receiving testosterone therapy.

References

1. Hofstra J, Loves S, van Wageningen B, Ruinemans-Koerts J, Jansen I, de Boer H. High prevalence of hypogonadotropic hypogonadism in men referred for obesity treatment. Neth. J. Me. 2008;66(3):103-109.
2. Biswas M, Hampton D, Newcombe RG, Rees DA. Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life. Clin. Endocrinol. (Oxf). 2012;76(5):665-673.
3. Dhindsa S, Miller MG, McWhirter CL, et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care. 2010;33(6):1186-1192.
4. Dhindsa S, Ghanim H, Batra M, et al. Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes. Diabetes Care. 2016;39(1):82-91.
5. Grossmann M, Thomas MC, Panagiotopoulos S, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J. Clin. Endocrinol. Metab. 2008;93(5):1834-1840.
6. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J. Clin. Endocrinol. Metab. 2004;89(11):5462-5468.
7. Dandona P, Dhindsa S. Update: Hypogonadotropic hypogonadism in type 2 diabetes and obesity. J. Clin. Endocrinol. Metab. 2011;96(9):2643-2651.
8. Bhatia V, Chaudhuri A, Tomar R, Dhindsa S, Ghanim H, Dandona P. Low testosterone and high C-reactive protein concentrations predict low hematocrit in type 2 diabetes. Diabetes Care. 2006;29(10):2289-2294.
9. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J. Clin. Invest. 2006;116(7):1793-1801.
10. Ridker PM, Kastelein JJ, Genest J, Koenig W. C-reactive protein and cholesterol are equally strong predictors of cardiovascular risk and both are important for quality clinical care. Eur. Heart J. 2013;34(17):1258-1261.
11. Hamilton EJ, Gianatti E, Strauss BJ, et al. Increase in visceral and subcutaneous abdominal fat in men with prostate cancer treated with androgen deprivation therapy. Clin. Endocrinol. (Oxf). 2011;74(3):377-383.
12. Tsai EC, Matsumoto AM, Fujimoto WY, Boyko EJ. Association of bioavailable, free, and total testosterone with insulin resistance: influence of sex hormone-binding globulin and body fat. Diabetes Care. 2004;27(4):861-868.
13. Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin. Proc. 2015;90(2):224-251.
14. Bastard JP, Maachi M, Lagathu C, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur. Cytokine Netw. 2006;17(1):4-12.
15. Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends in immunology. 2004;25(1):4-7.
16. de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582(1):97-105.
17. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132(6):2169-2180.
18. McArdle MA, Finucane OM, Connaughton RM, McMorrow AM, Roche HM. Mechanisms of obesity-induced inflammation and insulin resistance: insights into the emerging role of nutritional strategies. Frontiers in endocrinology. 2013;4:52.
19. Khodabandehloo H, Gorgani-Firuzjaee S, Panahi G, Meshkani R. Molecular and cellular mechanisms linking inflammation to insulin resistance and beta-cell dysfunction. Translational research : the journal of laboratory and clinical medicine. 2016;167(1):228-256.
20. Haider A, Yassin A, Doros G, Saad F. Effects of long-term testosterone therapy on patients with "diabesity": results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. International journal of endocrinology. 2014;2014:683515.
21. Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int. J. Clin. Pract. 2014;68(3):314-329.
22. Yassin A, Almehmadi Y, Saad F, Doros G, Gooren L. Effects of intermission and resumption of long-term testosterone replacement therapy on body weight and metabolic parameters in hypogonadal in middle-aged and elderly men. Clin. Endocrinol. (Oxf). 2016;84(1):107-114.
23. Grossmann M, Hoermann R, Wittert G, Yeap BB. Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Clin. Endocrinol. (Oxf). 2015;83(3):344-351.
24. Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011;34(4):828-837.
25. Gianatti EJ, Dupuis P, Hoermann R, et al. Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2014;37(8):2098-2107.
26. Bonora E, Targher G, Alberiche M, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care. 2000;23(1):57-63.
27. Borai A, Livingstone C, Kaddam I, Ferns G. Selection of the appropriate method for the assessment of insulin resistance. BMC medical research methodology. 2011;11:158.
28. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27(6):1487-1495.
29. Yang G, Li C, Gong Y, et al. Assessment of Insulin Resistance in Subjects with Normal Glucose Tolerance, Hyperinsulinemia with Normal Blood Glucose Tolerance, Impaired Glucose Tolerance, and Newly Diagnosed Type 2 Diabetes (Prediabetes Insulin Resistance Research). Journal of diabetes research. 2016;2016:9270768.
30. Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. International journal of endocrinology. 2014;2014:527470.
31. Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study. Obes Res Clin Pract. 2014;8(4):e339-349.
32. Yassin DJ, Doros G, Hammerer PG, Yassin AA. Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. The journal of sexual medicine. 2014;11(6):1567-1576.
33. Yassin AA, Nettleship J, Almehmadi Y, Salman M, Saad F. Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study. Andrologia. 2016.
34. Morales A, Bebb RA, Manjoo P, et al. Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. CMAJ. 2015;187(18):1369-1377. Appendix available at: http://www.cmaj.ca/content/suppl/2015/10/26/cmaj.150033.DC1/15-0033-1-at.pdf (accessed Jan 10, 2016).
35. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2010;95(6):2536-2559.
36. Dean JD, McMahon CG, Guay AT, et al. The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. The journal of sexual medicine. 2015;12(8):1660-1686.
37. Hackett G, Cole N, Bhartia M, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int. J. Clin. Pract. 2014;68(2):203-215.

Last updated: 2018
G.MKT.GM.MH.01.2018.0500