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The link between low testosterone and diabetes is well-established. Testosterone screening and treatment in hypogonadal men with diabetes is gaining acceptance.
About 20 years ago, researchers uncovered the link between men with low testosterone and the prevalence of type 2 diabetes (T2D). Over the last decade, multiple studies have demonstrated that testosterone replacement therapy (TRT) can improve the symptoms, prevent, and reverse the course of T2D.
Two of the most pivotal studies involve the reversal and decreased risk of diabetes with TRT:
- A recent meta-analysis of over 3000 patients demonstrated that hypogonadal patients with T2D who underwent long-term testosterone replacement therapy (TRT) had a sustained remission of their diabetes. TRT improved glycemic control, decreased total cholesterol, HDL levels, triglycerides, and reduced body mass index (BMI) and waist circumference. The study's authors recommend adding TRT to anti-diabetes medications for these patients.
- Higher testosterone levels appear to protect against T2D. A meta-analysis with 16,709 subjects showed that higher total testosterone levels could significantly decrease the risk of type 2 diabetes in men. Testosterone treatment seems to aid in preventing T2D. A study compared patients receiving testosterone treatment for two years with a placebo. Compared with placebo, patients in the testosterone group had a 40% decreased prevalence of T2D at two years and significantly improved glucose tolerance.
Studies like these broaden the acceptance of TRT, as seen in the gradual shift in treatment guidelines. Still, due to outdated concerns about risks, testosterone therapy in clinical practice has lagged well behind the research.
According to Paresh Dandona, SUNY Distinguished Professor in the Department of Medicine in the Jacobs School of Medicine and Biomedical Sciences at UB, "With appropriate testosterone replacement, obesity, insulin resistance, and diabetes may be reversible."
Low Testosterone
Approximately 40% of men over 45 have testosterone deficiency. Factors that can lower testosterone levels or decrease the body's ability to respond to testosterone include aging, chemotherapy, stress, smoking, and lack of exercise. A natural decrease in the testosterone level of about 1.6% each year begins around age 40. Hypogonadism (testosterone deficiency) is diagnosed when the testosterone level is less than 300 ng/dL and symptoms of low testosterone are present. Symptoms of testosterone deficiency can include reduced libido, erectile dysfunction, and increased body fat.
Type-2 Diabetes
About 1 in 10 people in the US have T2D, the 7th leading cause of death. At age 50, life expectancy is six years shorter for people with T2D than those without it. Type 2 diabetes occurs when the body does not properly produce or use insulin, a hormone produced by the pancreas that helps move blood glucose into cells. Eventually, the body becomes resistant to insulin, causing blood sugars to rise. If you have diabetes, you are twice as likely to suffer from low testosterone than a man without diabetes.
Low Testosterone and Type 2 Diabetes Connection
Low testosterone levels can likely lead to T2DM via insulin sensitivity and glycemic control. Insulin sensitivity occurs when your body's ability to respond to insulin is compromised. Glycemic control refers to the management of blood sugar for those with diabetes.
The results of one study showed that TRT decreased insulin resistance by 15.2% after six months of therapy and 16.4% after one year. Testosterone therapy also improved glycemic control for patients.
Men with diabetes are more likely to have low testosterone, and men with low testosterone are more likely to develop diabetes. The pancreas releases insulin after you eat a meal, telling cells to take in sugar from the blood. Insulin resistance occurs when your cells stop responding to insulin: glucose is taken up by the tissues at a slower rate. Having low testosterone can raise blood sugar because low testosterone increases insulin resistance. Testosterone likely plays a role in facilitating this blood sugar uptake into cells. As testosterone levels decrease, it hinders blood sugar uptake, increasing insulin resistance–likely the link between testosterone and diabetes. Testosterone therapy increases insulin responsiveness and improves glycemic control in hypogonadal men with T2D.
Multiple studies demonstrate that low testosterone directly increases T2D risk, independent of other factors. According to a recent meta-analysis that included 1,822 men with diabetes and 10,009 nondiabetic control patients, total testosterone is significantly lower in patients with T2D compared with controls, independent of other risk factors, such as obesity and age.
Another study showed that irrespective of baseline clinical, lifestyle, or demographic characteristics, patients with T2D have a high incidence of testosterone deficiency. The study compared 150 men with T2D with 150 healthy men and found that the rate of hypogonadism for patients with T2D was almost three times that of patients without diabetes.
Research tells us low testosterone is common in male T2DM patients and is also associated with poorer outcomes related to diabetes.
Treatment
Several studies demonstrate long-term TRT in men with hypogonadism, and T2D improves glycemic control and insulin sensitivity and leads to remission of diabetes in some patients.
For example, a 2020 study of 356 men with low testosterone and hypogonadism symptoms investigated whether adding TRT improves glycemic control and insulin sensitivity and results in the remission of T2DM. Results demonstrated that adding long-term testosterone treatment to standard diabetic treatment improved glycemic control and insulin resistance. Moreover, remission of diabetes occurred in 33% of patients treated with testosterone. This study supports the potential of TRT as a novel therapy for men with T2D and hypogonadism.
TRT improves the prognosis of diabetes in patients with low testosterone. A 2020 study of 356 men with low testosterone and diabetes found that TRT improved glycemic control and insulin resistance. In addition, one-third of the participants experienced remission of their diabetes, and most reached their HbA1C (average blood sugar level over the past few months) target level.
Prevention
Data from a 2019 study suggest testosterone therapy may be able to prevent T2D in men with hypogonadism who are pre-diabetic. In a study of 316 hypogonadal men with prediabetes, those treated with testosterone undecanoate had a decline in HbA1c. In contrast, patients who did not receive testosterone had a slight increase in HbA1c, and 40% progressed to T2D. According to W. Timothy Garvey, MD, professor of medicine at the University of Alabama at Birmingham and director of the UAB Diabetes Research Center, "The natural history of [patients not treated with testosterone] is they deteriorate. This was a long-term study with eight years of follow-up. Over that period, there was a significant deterioration in metabolism concerning glycemic control, and more patients were being diagnosed with T2D."
Screening
Using TRT in hypogonadal men to treat obesity and diabetes remains controversial. First, there are still concerns surrounding the cardiovascular risk associated with TRT. It is possible that the results of the recent TRAVERSE study, which found no increase in CV events with TRT, will help ease the fear. Second, there remains largely unfounded concern about TRT's association with prostate cancer. According to T. Hugh Jones, MD, consultant physician and endocrinologist at Barnsley Hospital, doctors remember from medical school the association between TRT and prostate cancer, but "it is widely accepted that there is no current evidence to link TRT with a new development of prostate carcinoma."
According to SUNY distinguished professor and chief of endocrinology at the University of Buffalo, New York, Paresh Dandona, MD, Ph.D., "Every type 2 diabetic and every obese male should have his testosterone measured. Once the testosterone is found to be low, it should be replaced."
Abraham Morgentaler, MD, FACS, associate professor of surgery in the division of urology at Beth Israel Deaconess Medical Center, Harvard Medical School, stated, regarding testosterone testing and treatment in patients who are obese or have T2D, "There's no other blood test that will tell us so much about a man's physical condition, about his prognosis, and also allow treating and improving his quality of life in a variety of ways."
Guidelines
The American Diabetes Association Standards of Care in Diabetes–2023 advises providers to measure morning serum testosterone levels in men with diabetes and symptoms of hypogonadism. The guidelines state that TRT could improve sexual function, well-being, muscle mass and strength, and bone density in men with hypogonadal symptoms. In addition, the current guidelines state that in addition to diet and exercise, people at high risk of diabetes may benefit from additional pharmacotherapeutic options such as testosterone.
The American Academy of Clinical Endocrinologists recommends screening for hypogonadism in all men with type 2 diabetes and a BMI of 30 or a waist circumference of 104 centimeters.
However, even though hypogonadism is common in patients with T2D, the 2018 Endocrine Society guidelines still advise against testosterone monitoring.
Testosterone therapy is gaining ground as a standard treatment for hypogonadism and other diseases such as obesity and T2D. Along with more studies, providers need to be educated on current data to dispel hesitation about fears of TRT-causing CV events and prostate cancer. According to a recent study, TRT can improve glycemic control, hormone levels, and cholesterol profile. In these patients, TRT is recommended in addition to standard diabetes care.
Further research is needed to understand testosterone therapy's benefits on glucose metabolism fully. For instance, multiple studies indicate that TRT is associated with sustained weight loss and a significant reduction in cardiometabolic risk factors. However, testosterone therapy's long-term durability, safety, and effects require further study as its use is expanded into clinical practice.
