The present study aimed to examine the sex-specific relationship between testosterone and glucose metabolism in prediabetic men and women. Prediabetic females were characterized by lower FPG levels and a lower FLI but had a higher risk of developing manifest diabetes in the next 10 years when compared to prediabetic men. Interestingly, testosterone seemed to have an overall favorable effect on metabolic profiles in prediabetic males, showing that there was a negative relationship with insulin resistance, HbA1c, stimulated glucose levels during the OGTT, FLI and BMI. Additionally, the increase in testosterone was related to a more favorable lipid profile in prediabetic men; however, in females we could not find a relationship between testosterone and metabolic parameters.
Although there is an abundance of available data showing an effect of testosterone on glucose metabolism in general or, more specifically, T2DM, there is only a limited amount of information on the influence of testosterone in the prediabetic state; however, existing data clearly indicate that prediabetic men show decreased testosterone or SHBG levels [12
]. In males, decreased testosterone levels are related to the development of disturbances in glucose metabolism, including increased risk of developing diabetes, and also showed a relationship with increased all-cause and cardiovascular mortality risk [6
] as well as greater risk of developing a metabolic syndrome [14
]. The significant role of testosterone in glucose metabolism in males is also reflected in the higher likelihood of lowered testosterone levels in T2DM patients compared to non-diabetics [15
]. So far, it is not entirely known whether decreased levels of testosterone are the causal factor for metabolic derailment [9
]. Nevertheless, one has to keep in mind that testosterone replacement therapy in hypogonadal diabetic males is related to an improvement of insulin sensitivity in patients with T2DM, metabolic syndrome or both [16
]. Additionally, in patients receiving an androgen-lowering therapeutic regimen for the treatment of prostate cancer, the amount of visceral fat and insulin resistance increases under this therapy [15
]. Furthermore, the detrimental effects androgen deficiency exerts on glucose homeostasis were also demonstrated in animal studies and cell culture experiments in which insulin secretion was impaired on top of testosterone deprivation [17
]. Notably, there seems to be a bidirectional relationship between plasma testosterone and the integrity of glucose homeostasis. On the one hand, hyperglycemia suppresses gonadal testosterone production [18
], while on the other hand testosterone deficiency leads to decreased muscle mass [19
] and hence reduced glucose uptake in muscle [20
]. Strikingly, in a prediabetic population, testosterone treatment showed a reduction in waist circumference and body weight, as well as an improvement in HbA1c and FPG—in comparison, 40% of the prediabetic participants in the control group progressed to T2DM [21
]. Interestingly, the effect of testosterone on the glucose metabolism seems to play a central role in the development of prediabetes. In a prospective clinical study, Minooee et al. detected that low testosterone levels were related to the development of prediabetes but could not find a relationship between the conversion of prediabetes to T2DM [22
]. In the present study, we could show that especially in prediabetic men there is a significant relationship between testosterone and metabolic profiles. Increases in testosterone were related to a lower FLI, better insulin sensitivity, lower HbA1c and lower stimulated glucose levels, which are all markers directly related to the development of T2DM. One possible explanation for improved peripheral insulin sensitivity when testosterone levels are higher is the facilitation of glucose transporter type 4 (GLUT4) translocation to the myocytal membrane and, consequently, greater capacity for peripheral glucose uptake [20
]. Furthermore, the protective effect testosterone exerts on peripheral glucose tolerance seems to be robust when correcting for age. Unlike in males, negative effects of testosterone on glucose metabolism have been reported in women [9
]. For instance, elevated testosterone levels have been demonstrated in women with diabetes [23
]—a constellation also typically present in polycystic ovary syndrome [24
]. The role of testosterone in the prediabetic state in females is, overall, an unexplored area. Based on earlier results [9
], expectation of a negative effect of testosterone on the glucose metabolism in prediabetic females was high; however, in the present study we could not find a relationship between testosterone and insulin resistance, HbA1c, stimulated glucose levels during the OGTT or under fasting conditions and FLI or anthropometric parameters in prediabetic female subjects.
Our study has limitations which have to be reported. Firstly, the present study has a cross-sectional study design and thus, we assessed correlations but not causal relationships. Secondly, we did not measure the levels of estrogen as well as the visceral fat content in the liver using gold standard methods such as magnetic resonance spectroscopy or ultrasound. Furthermore, we only assessed bivariate correlations between testosterone and metabolic parameters and therefore cannot rule out that the correlation in females is masked by a correlation with unobserved confounders; however, we noted that both males and females had comparable distributions of age and BMI. We had a smaller sample of females than males, which renders significant results in females less likely; however, males not only had lower p-values but also had slightly higher correlation coefficients.
In conclusion, our results show that there is a weak favorable relationship between testosterone and both glucose and lipid metabolism as well as with the visceral fat content in the liver, measured by FLI in prediabetic males. Interestingly, testosterone was not related to the metabolic profile in prediabetic females. Large prospective clinical studies are needed in order to investigate the sex-specific role of testosterone on metabolic profiles in more detail.