Husam Ghanim, Sandeep Dhindsa, Sanaa Abuaysheh, Manav Batra, Nitesh D Kuhadiya, Antoine Makdissi, Ajay Chaudhuri and Paresh Dandona
One-third of males with type 2 diabetes (T2DM) have hypogonadism, characterized by low total and free testosterone concentrations. We hypothesized that this condition is associated with a compensatory increase in the expression of androgen receptors (AR) and that testosterone replacement reverses these changes. We also measured estrogen receptor and aromatase expression.
Materials and methods
This is a randomized double-blind placebo-controlled trial. Thirty-two hypogonadal and 32 eugonadal men with T2DM were recruited. Hypogonadal men were randomized to receive intramuscular testosterone or saline every 2 weeks for 22 weeks. We measured AR, ERα and aromatase expression in peripheral blood mononuclear cells (MNC), adipose tissue and skeletal muscle in hypogonadal and eugonadal males with T2DM at baseline and after 22 weeks of treatment in those with hypogonadism.
The mRNA expression of AR, ERα (ESR1) and aromatase in adipose tissue from hypogonadal men was significantly lower as compared to eugonadal men, and it increased significantly to levels comparable to those in eugonadal patients with T2DM following testosterone treatment. AR mRNA expression was also significantly lower in MNC from hypogonadal patients compared to eugonadal T2DM patients. Testosterone administration in hypogonadal patients also restored AR mRNA and nuclear extract protein levels from MNC to that in eugonadal patients. In the skeletal muscle, AR mRNA and protein expression are lower in men with hypogonadism. Testosterone treatment restored AR expression levels to that comparable to levels in eugonadal men.
We conclude that, contrary to our hypothesis, the expression of AR, ERα and aromatase is significantly diminished in hypogonadal men as compared to eugonadal men with type 2 diabetes. Following testosterone replacement, there is a reversal of these deficits.
Sandeep Dhindsa, Anand Reddy, Jyotheen Sukhmoy Karam, Sayeeda Bilkis, Archana Chaurasia, Aditya Mehta, Keerthi P Raja, Manav Batra and Paresh Dandona
One-third of men with type 2 diabetes have subnormal testosterone concentrations along with inappropriately normal LH and FSH concentrations. It is not known if the presence of renal insufficiency affects free testosterone concentrations in men with type 2 diabetes.
We hypothesized that type 2 diabetic men with chronic renal disease (CKD; estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2) have lower free testosterone concentrations than men with normal renal function (eGFR ≥60 ml/min per 1.73 m2).
Study design and setting
This is a retrospective chart review of patients attending diabetes and nephrology clinics. Men with type 2 diabetes who had the following information available were included in the study: testosterone (total and free) done by LC/MS-MS followed by equilibrium dialysis, sex hormone binding globulin, LH, FSH and prolactin concentrations.
We present data on T and gonadotropin concentrations in 111 men with type 2 diabetes and CKD (stages 3–5) and 182 type 2 diabetic men without CKD.
The prevalence of subnormal free testosterone concentrations was higher in men with type 2 diabetes and CKD as compared to those without CKD (66% vs 37%, P<0.001). Men with CKD had a higher prevalence of hypergonadotropic hypogonadism (26% vs 5%, P<0.001) but not of hypogonadotropic hypogonadism (HH; 40% vs 32%, P=0.22). There was an increase in the prevalence of hypergonadotropic hypogonadism with decreasing eGFR. Fifty-two percent of men with renal failure (CKD stage 5) had hypergonadotropic hypogonadism and 25% had HH. In men with CKD, the hemoglobin concentrations were lower in those with subnormal free T concentrations as compared to men with normal free T concentrations (119±19 vs 128±19 g/l, P=0.04).
Two-thirds of men with type 2 diabetes and CKD have subnormal free T concentrations. The hypogonadism associated with CKD is predominantly hypergonadotropic.
Sandeep Dhindsa, Husam Ghanim, Kelly Green, Sanaa Abuaysheh, Manav Batra, Antoine Makdissi, Ajay Chaudhuri, Sartaj Sandhu and Paresh Dandona
Insulin has anabolic effects on skeletal muscle. However, there is limited understanding of the molecular mechanisms underlying this effect in humans. We evaluated whether the skeletal muscle expression of satellite cell activator fibroblast growth factor 2 (FGF2) and muscle growth and differentiation factors are modulated acutely by insulin during euglycemic–hyperinsulinemic clamp (EHC).
Design and methods
This is a secondary investigation and analysis of samples obtained from a previously completed trial investigating the effect of testosterone replacement in males with hypogonadotropic hypogonadism and type 2 diabetes. Twenty men with type 2 diabetes underwent quadriceps muscle biopsies before and after 4 h of EHC.
The infusion of insulin during EHC raised the expression of myogenic growth factors, myogenin (by 72 ± 20%) and myogenin differentiation protein (MyoD; by 81 ± 22%). Insulin reduced the expression of muscle hypertrophy suppressor, myogenic regulatory factor 4 (MRF4) by 34 ± 14%. In addition, there was an increase in expression of FGF receptor 2, but not FGF2, following EHC. The expression of myostatin did not change.
Insulin has an acute potent effect on expression of genes that can stimulate muscle differentiation and growth.