Testosterone therapy reduces insulin resistance and inflammation in men with type 2 diabetes

January 2016

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 (a surrogate measure for obesity), the prevalence of subnormal free testosterone levels in men with type 2 diabetes is higher than in men without.3

Insulin resistance occurs when the body’s cells become insensitive to the insulin, which is a hormone that is necessary for transport of blood sugar (glucose) into cells. To compensate for the resistance to insulin, the pancreas increases insulin production up to the point until the pancreas’ capability to produce insulin is exhausted.

Here we summarize the results of a study conducted by a research team at the Division of Endocrinology, Diabetes and Metabolism, State University of New York. This study specifically selected men with type 2 diabetes based on low free testosterone levels.4 The aims of the study were to investigate:4

1) The impact of testosterone deficiency 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.


  • Men with testosterone deficiency and type 2 diabetes had higher subcutaneous and intra-abdominal fat mass, and more severe insulin resistance, than men with type 2 diabetes without testosterone deficiency.
  • Testosterone treatment for 6 months in deficient men reduced insulin resistance and subcutaneous fat mass (approx. 3 kg) and increased muscle mass (approx. 3 kg), without changing body weight.
  • The expression of insulin signaling genes (IR-beta, IRS-1, AKT-2, and GLUT4) was significantly lower in testosterone deficient men and was upregulated after testosterone treatment.
  • Testosterone treatment also caused a significant fall in blood levels of inflammatory mediators.
  • Testosterone treatment additionally improved parameters of sexual function.
  • In this study PSA levels did not change, and no subject developed excessively high levels of hemoglobin or blood thickening (hematocrit), or a prostate nodule.

What is known

Men with type 2 diabetes more commonly have low free testosterone levels than low total testosterone levels.2,5-7

Diabetic men who are testosterone deficient also have significantly higher blood levels of C-reactive protein (CRP)8, which is a parameter that indicates the degree of whole body inflammation. CRP is also suggestive of increased insulin resistance9 and atherosclerosis.10 In line with this, men with low testosterone levels - irrespective of diabetes - have increased insulin resistance11,12, 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, a commonly used index of insulin resistance based on fasting blood levels of glucose and insulin23,24, is unclear.25

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 loss of pancreatic cells can lead to inappropriately low insulin levels and a falsely low HOMA-IR.24,26,27 The most accurate way to assess insulin resistance is through a test called hyperinsulinemic-euglycemic (HE) clamps.

During a clamp test, a defined amount of insulin is injected intravenously with simultaneous infusion of variable amounts of glucose, so that a stable blood glucose level of 100 mg/dl is constantly maintained. The better the cells can sense and “understand” the insulin signal – in other words, the lower their insulin resistance – the more glucose they are able to take up. Therefore, an increased glucose infusion rate means an increased insulin sensitivity and reduced insulin resistance.

What this study adds

The study by this research team used the clamp test 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 was conducted, as well as measurement of inflammatory mediators, including CRP.

The study first compared 50 type 2 diabetic men without testosterone deficiency with 44 type 2 diabetic men with testosterone deficiency. Then the deficient 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.

1) Comparison of non-deficient and testosterone deficient type 2 diabetic men

As expected, when compared to non-deficient men, testosterone deficient 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 testosterone deficient men was primarily explained by their larger body fat depots.

Testosterone deficient men also had lower expression of genes that mediate insulin signaling.

2) Results of testosterone treatment

24 weeks of testosterone treatment significantly increased both total and free testosterone levels, and reduced insulin and glucose levels.

Men treated with testosterone lost on average 3 kg of fat mass and gained 3 kg of muscle mass. The fat loss was primarily around the belly and arms. No body composition changes were seen in the placebo group.

As illustrated in figures 1 and 2, insulin sensitivity was significantly improved in the testosterone group, as indicated by a 32% increase in glucose infusion rate during the clamp, and insulin resistance (as indicated by HOMA-IR) was reduced accordingly.

Increase in insulin sensitivity after 6 months of testosterone treatment in testosterone deficient type 2 diabetic men

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

Reduction in insulin resistance after 6 months of testosterone treatment in testosterone deficient type 2 diabetic men

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

Compared to placebo treatment, insulin signaling genes were significantly upregulated after testosterone treatment. This was accompanied by a significant fall in blood levels of inflammatory mediators; CRP dropped by 19%.

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 a little but stayed within the normal range.

It was concluded that testosterone treatment in men with type 2 diabetes who are testosterone deficient has insulin-sensitizing and anti-inflammatory effects, and results in fat loss and muscle mass gain, and improved sexual function. This could possibly reduce need for anti-diabetic medications in testosterone deficient diabetic men receiving testosterone therapy.


  • 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. Med. 2008;66(3):103-109. Return to content
  • 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. Return to content
  • Dhindsa S, Miller MG, McWhirter CL, et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care. 2010;33(6):1186-1192. Return to content
  • 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. Return to content
  • 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. Return to content
  • 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. Return to content
  • Dandona P, Dhindsa S. Update: Hypogonadotropic hypogonadism in type 2 diabetes and obesity. J. Clin. Endocrinol. Metab. 2011;96(9):2643-2651. Return to content
  • 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. Return to content
  • Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J. Clin. Invest. 2006;116(7):1793-1801. Return to content
  • 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. Return to content
  • 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. Return to content
  • 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. Return to content
  • 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. Return to content
  • 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. Return to content
  • Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends in immunology. 2004;25(1):4-7. Return to content
  • de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582(1):97-105. Return to content
  • Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132(6):2169-2180. Return to content
  • 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. Return to content
  • 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. Return to content
  • 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. Return to content
  • 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. Return to content
  • Yassin A, Almehmadi Y, Saad F, Doros G, Gooren L. Effects of intermission and resumption of long-term testosterone therapy on body weight and metabolic parameters in hypogonadal in middle-aged and elderly men. Clin. Endocrinol. (Oxf). 2016;84(1):107-114. Return to content
  • 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. Return to content
  • 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. Return to content
  • 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. Return to content
  • Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27(6):1487-1495. Return to content
  • 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. Return to content