Can testosterone treatment reverse diabetes?

Description

Professor Dhindsa presents evidence showing that testosterone therapy improves insulin sensitivity and glucose uptake,1 and can result in remission of type 2 diabetes. The beneficial metabolic effects of testosterone therapy can be explained, at least in part, by reduction in obesity, sarcopenia and inflammation.

In a landmark randomised, placebo-controlled trial, Dr Dhindsa’s research group investigated metabolic changes following testosterone therapy in men with type 2 diabetes and hypogonadism (defined as free testosterone levels <6.5 ng/dL (0.285 nmol/L) with normal or low LH). Subjects (n=44) were randomised to receive intramuscular testosterone injection or placebo (saline) injection every 2 weeks for 24 weeks. Dose of testosterone injection was adjusted to maintain free testosterone levels in the mid-normal range for young healthy men. Hyperinsulinemic-euglycemic clamp (the gold standard technique for assessing insulin sensitivity) was performed to measure insulin sensitivity. Body composition was assessed by DEXA and MRI. Subcutaneous abdominal fat biopsies and muscle biopsies in lateral thigh were performed. Results showed a significant increase in total lean mass (+3.4 kg) and decrease in total subcutaneous fat mass (-3.3 kg). Reduction was also seen in visceral fat and hepatic fat, but these improvements did not reach statistical significance, likely due to the short study duration of 24 weeks. As expected, the increased muscle mass translated to an increased insulin sensitivity by 30% (measured by glucose infusion rate) in testosterone treated men, while no effect was seen in the placebo group.

Testosterone treated men also had reduced inflammation (as shown by significant reductions in mRNA expression in mononuclear cells, and levels of plasma CRP and TNF-α), as well as a significant reduction in serum levels of free fatty acids and leptin. The improvement in insulin sensitivity was accompanied by increased insulin signaling and glucose uptake in fat tissue (measured by mRNA expression of insulin signaling mediators in adipose tissue) and increased muscle AMPK-α (Adenosine 5’-monophosphate-activated protein kinase) activity (another glucose uptake mediator). For more information about this study, see “Testosterone therapy reduces insulin resistance and inflammation in men with type 2 diabetes” Dhindsa’s group further investigated the effect of testosterone therapy on mediators of muscle growth. Compared to placebo, men receiving testosterone therapy had significant elevations in plasma levels of IGF-1 and fibroblast growth factor (FGF-2), an important stimulatory modulator of satellite cells in the skeletal muscle that plays a cardinal role in muscle growth and repair.

Another double-blind randomised placebo-controlled trial examined the effect of treatment with testosterone undecanoate injections (1000 mg i.m. every 10 weeks, after an initial 6-week interval) or placebo injection (n=27) for 1 year on glycemic control in men with obesity and type 2 diabetes. Men receiving testosterone therapy had a significant improvement in HbA1c, endothelial function (FMD) and atherosclerosis (CIMT). For more information about this study, see “Effect of testosterone therapy on insulin resistance, glycemic control, endothelial function and atherosclerosis” In a review paper, Professor Dhindsa summarized data from randomised controlled trials that examined the effects of testosterone therapy on metabolic parameters in men with obesity, type 2 diabetes or metabolic syndrome. Consistent findings include reduced body fat mass, increased lean (muscle) mass and improved insulin sensitivity and glycemic control. These are clearly beneficial effects of testosterone. But what are the implications for clinical practice?

The answer can be found in long-term real-world evidence studies, showing that treatment with testosterone undecanoate injections for 8-11 years completely prevents progression from prediabetes to type 2 diabetes, and results in remission of established type 2 diabetes in over one third (34.3%) of testosterone treated men. This was accompanied by a significant and progressive weight loss throughout the entire follow-up duration, as well as reduced mortality. In contrast, men not receiving treatment with testosterone undecanoate injections had a significant weight gain, deteriorated glucose control and increased mortality.

For more information about these studies, see:

Remission of type 2 diabetes during long-term treatment with testosterone undecanoate injections

Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes

In conclusion

  • Testosterone is not merely a “sexual” or “lifestyle hormone”. Testosterone is also a powerful metabolic hormone that provides a wide range of health benefits to the growing population of men with obesity and/or type 2 diabetes.
  • Testosterone therapy decreases fat mass, increases lean mass and enhances insulin sensitivity.
  • Long-term testosterone therapy can induce remission of type 2 diabetes.

For more information, see “Benefits of testosterone therapy in men with testosterone deficiency

In a landmark randomised, placebo-controlled trial, Dr Dhindsa’s research group investigated metabolic changes following testosterone therapy in men with type 2 diabetes and hypogonadism (defined as free testosterone levels <6.5 ng/dL (0.285 nmol/L) with normal or low LH).1 Subjects (n=44) were randomised to receive intramuscular testosterone injection or placebo (saline) injection every 2 weeks for 24 weeks. Dose of testosterone injection was adjusted to maintain free testosterone levels in the mid-normal range for young healthy men. Hyperinsulinemic-euglycemic clamp (the gold standard technique for assessing insulin sensitivity) was performed to measure insulin sensitivity. Body composition was assessed by DEXA and MRI. Subcutaneous abdominal fat biopsies and muscle biopsies in lateral thigh were performed. Results showed a significant increase in total lean mass (+3.4 kg) and decrease in total subcutaneous fat mass (-3.3 kg). Reduction was also seen in visceral fat and hepatic fat, but these improvements did not reach statistical significance, likely due to the short study duration of 24 weeks.1 As expected, the increased muscle mass translated to an increased insulin sensitivity by 30% (measured by glucose infusion rate) in testosterone treated men, while no effect was seen in the placebo group.

Testosterone treated men also had reduced inflammation (as shown by significant reductions in mRNA expression in mononuclear cells, and levels of plasma CRP and TNF-α), as well as a significant reduction in serum levels of free fatty acids and leptin.1 The improvement in insulin sensitivity was accompanied by increased insulin signaling and glucose uptake in fat tissue (measured by mRNA expression of insulin signaling mediators in adipose tissue) and increased muscle AMPK-α (Adenosine 5’-monophosphate-activated protein kinase) activity (another glucose uptake mediator). For more information about this study, see “Testosterone therapy reduces insulin resistance and inflammation in men with type 2 diabetes

Dhindsa’s group further investigated the effect of testosterone therapy on mediators of muscle growth.2 Compared to placebo, men receiving testosterone therapy had significant elevations in plasma levels of IGF-1 and fibroblast growth factor (FGF-2),2 an important stimulatory modulator of satellite cells in skeletal muscle that plays an essential role in muscle growth and repair.

Another double-blind randomised placebo-controlled trial examined the effect of treatment with testosterone undecanoate injections (1000 mg i.m. every 10 weeks, after an initial 6-week interval) or placebo injection (n=27) for 1 year on glycemic control in men with obesity and type 2 diabetes.3 Men receiving testosterone therapy had a significant improvement in HbA1c, endothelial function (FMD) and atherosclerosis (CIMT). For more information about this study, see “Effect of testosterone therapy on insulin resistance, glycemic control, endothelial function and atherosclerosis

In a review paper, Professor Dhindsa summarized data from randomised controlled trials that examined the effects of testosterone therapy on metabolic parameters in men with obesity, type 2 diabetes or metabolic syndrome.4 Consistent findings include reduced body fat mass, increased lean (muscle) mass, and improved insulin sensitivity and glycemic control.4 These are clearly beneficial effects of testosterone therapy. But what are the implications for clinical practice?

The answer can be found in long-term real-world evidence studies, which have shown that treatment with testosterone undecanoate injections for 8-11 years completely prevents progression from prediabetes to type 2 diabetes and restores normoglycemia,5 and results in remission of established type 2 diabetes in over one third (34.3%) of testosterone treated men.6 This was accompanied by a significant and progressive weight loss throughout the entire follow-up duration, as well as reduced mortality. In contrast, men not receiving treatment with testosterone undecanoate injections had a significant weight gain, deteriorated glucose control and increased mortality.5,6

For more information about these studies, see:

Remission of type 2 diabetes during long-term treatment with testosterone undecanoate injections

Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes

In conclusion,

  • Testosterone is not merely a “sexual” or “lifestyle hormone”. Testosterone is also a powerful metabolic hormone that provides a wide range of health benefits to the growing population of men with obesity and/or type 2 diabetes.
  • Testosterone therapy decreases fat mass, increases lean (muscle) mass and improves insulin sensitivity.
  • Long-term testosterone therapy can induce remission of type 2 diabetes.

For more information, see “Benefits of testosterone therapy in men with testosterone deficiency


 

Speakers

Dr. Sandeep Dhindsa

Sandeep Dhindsa, M.D.
Professor of Medicine
Chief, Division of Endocrinology, Diabetes and Metabolism
Saint Louis University School of Medicine, USA

References

  • 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. Jan 2016;39(1):82-91. Return to content
  • Ghanim H, Dhindsa S, Batra M, et al. Testosterone Increases the Expression and Phosphorylation of AMP Kinase α in Men With Hypogonadism and Type 2 Diabetes. J Clin Endocrinol Metab. Apr 1 2020;105(4):1169-75. Return to content
  • Groti K, Zuran I, Antonic B, Forsnaric L, Pfeifer M. The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes. The aging male : the official journal of the International Society for the Study of the Aging Male. Sep 2018;21(3):158-169. Return to content
  • Dhindsa S, Ghanim H, Batra M, Dandona P. Hypogonadotropic Hypogonadism in Men With Diabesity. Diabetes Care. Jul 2018;41(7):1516-1525. Return to content
  • Yassin A, Haider A, Haider KS, et al. Testosterone Therapy in Men With Hypogonadism Prevents Progression From Prediabetes to Type 2 Diabetes: Eight-Year Data From a Registry Study. Diabetes Care. Jun 2019;6(42):1104-1111. Return to content
  • Haider KS, Haider A, Saad F, et al. Remission of type 2 diabetes following long-term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11-year data from a real-world registry study. Diabetes, obesity & metabolism. Nov 2020;22(11):2055-2068. Return to content