Increasing Insulin Resistance Is Associated with a Decrease in Leydig Cell Testosterone Secretion in Men

Abstract

Insulin resistance is associated with low testosterone (T) levels in men, the mechanism of which is unclear. Thus, the aim of this study was to evaluate the hypothalamic-pituitary-gonadal axis in men with a spectrum of insulin sensitivity. Twenty-one men (aged 25-65 yr) had a glucose tolerance test and assessment of insulin sensitivity using a hyperinsulinemic-euglycemic clamp. Insulin sensitivity, expressed as the M value (milligrams per kilograms(-1) per minute(-1)), was calculated from the glucose disposal rate during the final 30 min of the clamp. Eighteen subjects had blood sampling every 10 min for 12 h to assess LH pulsatility. Hypogonadism was then induced with a GnRH antagonist, followed by sequential stimulation testing with GnRH (750 ng/kg, iv) and human chorionic gonadotropin (hCG; 1000 IU, im) to assess pituitary and testicular responsiveness, respectively. Nine subjects had normal glucose tolerance, nine had impaired glucose tolerance, and three had diabetes mellitus. There was a positive relationship between M and T levels (r = 0.46; P < 0.05). No relationship was seen between M and parameters of LH secretion, including mean LH levels, LH pulse amplitude, LH pulse frequency, and LH response to exogenous GnRH administration. In contrast, a strong correlation was observed between M and the T response to hCG (r = 0.73; P < 0.005). Baseline T levels correlated with the increase in T after hCG administration (r = 0.47; P < 0.05). During the clamp, T levels increased from a baseline level of 367 +/- 30 to 419 +/- 38 ng/dl during the last 30 min (P < 0.05). From these data we conclude that insulin resistance is associated with a decrease in Leydig cell T secretion in men. Additional studies are required to determine the mechanism of this effect.

Relationship between insulin and hypogonadism in men with metabolic syndrome

“…The pathological increase in Homa-β possibly represents an attempt to overcome the insulin resistance action by enhancing the function of the pancreatic beta cell. This hypothesis is also reinforced by the fact that increased testosterone levels were observed during the hyperinsulinemic state of the clamp glucose test (29,39).…”

“…At the same time, pro-inflammatory cytokines, such as TNF alpha, IL-1 and IL-6, produced by visceral adipocytes, are also associated with insulin resistance (27,28). It was demonstrated that there is a strong correlation between insulin sensitivity and the function of Leydig's cell (29), but other studies have not confirmed such findings (23,30).…”

“…However, the precise mechanisms involved in insulin action that result in low testosterone and SHBG levels are not clear yet, but might be due to a functional defect at one or more levels of the hypothalamus-pituitary-gonadal axis (29).…”

Are declining testosterone levels a major risk factor for ill-health in aging men?

“…113,114 The direction of causation is debatable as marked obesity predisposes to type II diabetes and atherosclerosis, and may reduce LH pulse amplitude and testicular responses to LH. 115,116 However, testosterone therapy increases lean body mass and reduces fat mass, thus modulating insulin resistance and risk of metabolic syndrome. 66,117,118 Testosterone may also exhibit antiatherogenic effects at the tissue level, whether mediated by classical or nonclassical pathways.…”

Diabetes mellitus-induced male reproductive impairment: The role of natural products: A review

“…Baccetti et al (2002) have shown that DM significantly suppresses the HPG axis and lowers FSH and LH responses to exogenous gonadotropin releasing hormone (GnRH) in T1DM patients. Suppressed testosterone secretion as a result of diminished Leydig cell function (Pitteloud et al, 2005) has been reported in T2DM. Decreased serum concentrations of reproductive hormones (testosterone, FSH and LH) have also been reported in DM animal models induced by STZ (Mohasseb et al, 2011;Kanter et al, 2013), alloxan (Hafez, 2010;Ghlissi et al, 2012) and nicotinamide+STZ (Ahangarpour et al, 2015), and in BB rats (Cameron et al, 1990).…”