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.

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 resistance^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, a commonly used index of insulin resistance based on fasting blood levels of glucose and insulin^23,24, 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.

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.

Figure 1: Increase in insulin sensitivity 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.