Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes

Diabetes Care. 2016 Jan;39(1):82-91. doi: 10.2337/dc15-1518. Epub 2015 Nov 29.


Objective: One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH). We conducted a randomized placebo-controlled trial to evaluate the effect of testosterone replacement on insulin resistance in men with type 2 diabetes and HH.

Research design and methods: A total of 94 men with type 2 diabetes were recruited into the study; 50 men were eugonadal, while 44 men had HH. Insulin sensitivity was calculated from the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Lean body mass and fat mass were measured by DEXA and MRI. Subcutaneous fat samples were taken to assess insulin signaling genes. Men with HH were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks.

Results: Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. GIR was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (-3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR-β, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1β, tumor necrosis factor-α, and leptin (P < 0.05 for all).

Conclusions: Testosterone treatment in men with type 2 diabetes and HH increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat.

Trial registration: NCT01127659.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Body Composition
  • C-Reactive Protein / metabolism
  • Diabetes Mellitus, Type 2 / complications*
  • Fatty Acids, Nonesterified / blood
  • Hormone Replacement Therapy*
  • Humans
  • Hypogonadism / complications
  • Hypogonadism / drug therapy*
  • Inflammation / blood*
  • Insulin / therapeutic use
  • Insulin Resistance*
  • Interleukin-1beta / blood
  • Intra-Abdominal Fat / metabolism
  • Leptin / blood
  • Male
  • Middle Aged
  • Subcutaneous Fat / metabolism
  • Testosterone / therapeutic use*
  • Tumor Necrosis Factor-alpha / blood


  • Fatty Acids, Nonesterified
  • IL1B protein, human
  • Insulin
  • Interleukin-1beta
  • Leptin
  • Tumor Necrosis Factor-alpha
  • Testosterone
  • C-Reactive Protein

Associated data