What is known about testosterone, insulin sensitivity / resistance and diabetes
Low testosterone can cause elevated blood sugar levels both directly and indirectly. Low testosterone increases body fat and reduces lean body (muscle) mass, which in turn results in insulin resistance followed by elevated blood sugar levels.9 Testosterone also directly affects the glucose transporter, which is required by most cells to take up glucose from the blood (blood sugar), and carbohydrate metabolism.
Several studies with long follow-up periods of up to 15 years show that low testosterone levels significantly increased risk for development of insulin resistance, the metabolic syndrome and type 2 diabetes, even in men who were not obese at baseline.10-12 Among men with low testosterone, half already have prediabetes.13,14 A comprehensive analysis found that a testosterone level below 16 nmol/L predicts 5 year risk of developing type 2 diabetes in men, independently of age, impaired fasting glucose, physical inactivity, waist circumference, body weight and blood fats (triglycerides).15 This suggests that screening for low testosterone - in other words, measuring testosterone levels in men as part of routine health checkups - would identify a large group of men at risk for type 2 diabetes who otherwise would get missed by reliance on traditional risk factors.15
Several long-term “real life” studies of testosterone therapy for up to 6 years in men with low testosterone and the metabolic syndrome or type 2 diabetes show marked improvement in glycemic control (reduction in fasting glucose and HbA1c), weight loss and reduced overall cardiovascular risk.16-18
All medical organizations recommend lifestyle intervention for prevention and management of type 2 diabetes.19,20 In this regard, it is particularly notable that the benefits of testosterone therapy are greatest when combined with lifestyle intervention.21 Addition of testosterone therapy to a supervised diet and exercise program results in greater improvements in blood sugar control, waist circumference and cholesterol profile than that achieved with the supervised diet and exercise program alone.21
However, up to this point no large-scale study has evaluated the effect of testosterone therapy combined with lifestyle intervention versus lifestyle intervention alone. Therefore, the “Testosterone 4 Diabetes Mellitus” study, also known as the T4DM trial, was undertaken.
What the “Testosterone 4 Diabetes Mellitus” study will teach us
The T4DM study is designed to find out if testosterone treatment combined with lifestyle intervention (Weight Watchers®) for 2 years versus lifestyle intervention alone, improves glucose tolerance (defined as blood sugar levels after a consumption of a glucose drink) and reduces incidence of type 2 diabetes.8
Approximately 1000 overweight or obese men aged 50-74 years were recruited as subjects for the T4DM study. All men had testosterone levels of 14nmol/L or less, impaired glucose tolerance or newly diagnosed type 2 diabetes, as well as abdominal obesity (defined as waist circumference of 95 cm or higher).
Subjects were randomly allocated to receive testosterone treatment or placebo, for 2 years. The lifestyle intervention was provided by Weight Watchers®, with an interactive website providing diet and activity guidelines, and self-monitoring tools allowing men to log food, physical activity and weigh-in details. Men were encouraged to achieve a 5% reduction in body weight each year and to monitor and record their own body weight weekly. Adherence with the overall lifestyle program was monitored via website logins and activity, meeting attendance and information collected at 3-monthly clinic visits.
Besides examining the effects of testosterone therapy on glucose tolerance and development of type 2 diabetes, the following secondary endpoints will be examined:
Initiation of antidiabetic pharmacotherapy
Glucose metabolism: fasting plasma glucose, insulin and HbA1c
Body weight, waist circumference
Body composition: DEXA measurements of body fat and lean (muscle) body mass
Muscle strength (handgrip test)
Hormone profile: testosterone, estrogen
Sexual function and lower urinary tract symptoms (LUTS)
Cholesterol profile: total cholesterol, LDL, triglycerides, HDL)
Compliance with the lifestyle intervention program
Health care expenditure
Three sub-studies of T4DM will be conducted to determine the effects of testosterone therapy on:
- Bone quality and bone mineral density (T4Bone).
- Motivation and behaviour (T4M&B).
- Telomere length (T4Telomeres).
Two additional sub-studies will investigate the effects of extended testosterone therapy for up to 4 years (T4DM run-on), and rate of recovery of the body’s testosterone production at the end of the initial 2-year treatment period (T4DM run-off), respectively.
The first results from the T4DM study are expected to get published end of 2019. With 1000 subjects, this is the largest high-quality study investigating the effects of testosterone therapy. The Testosterone Trials (TTrials) had 790 subjects and lasted 1 year. The TEAAM (Testosterone’s Effects on Atherosclerosis Progression in Aging Men) trial lasted 3 years, but only included 156 subjects.
A particularly notable aspect of the T4DM study is that it includes men with a baseline testosterone level of up to14 nmol/L (404 ng/dL). This threshold is higher than the threshold recommended by most clinical guidelines for the diagnosis of hypogonadism, which is 12 nmol/L (345 ng/dL). The higher threshold of 14 nmol/L was chosen because the association of low testosterone levels and insulin resistance in men with type 2 diabetes remains present within the “normal” testosterone level range, and does not have a clear cutoff point.5
The T4DM trial will be the first ever study to investigate the effects of testosterone therapy on two emerging research areas; motivation for physical activity and telomere length, which is a biomarker of aging, in humans.22 In the context of lifestyle change, the potential effect of testosterone therapy on motivation to increase physical activity levels is of particular interest.
The upcoming year will be a milestone in testosterone science. Stay tuned for the first T4DM results, which are expected get published end of 2019 and will be reported here on www.nebido.com