Metabolic patterns in insulin-sensitive male hypogonadism

Abstract

Male hypogonadism is a disorder characterised by low levels of the hormone testosterone. At beginning subjects with low levels of testosterone do not show insulin resistance (insulin-sensitive patients), which develops over time (insulin-resistance patients). To analyse the metabolic alterations mainly related to decreased testosterone, we performed metabolomics investigations on the plasma of males with hypogonadism who showed normal insulin levels. Plasma from patients with low testosterone (<8 nmol/l) and homeostatic model assessment for insulin-resistance-index (HOMAi) < 2.5, as well as matched controls, was analysed by UHPLC and mass spectrometry. Then metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathways. Glycolysis was not altered, as expected for the presence of insulin activity, but imbalances in several other pathways were found, such as the pentose phosphate pathway (PPP), glycerol shuttle, malate shuttle, Krebs cycle (TCA) and lipid metabolism. The PPP was significantly upregulated. Moreover, while the first steps of the Krebs cycle were downregulated, 2-oxoglutarate was replenished via glutaminolysis. Since glutaminolysis leads to an activation of the malate aspartate cycle, greater amounts of NADH and ATP with respect to the control were recorded. The activation of the glycerol shuttle was also recorded, with consequent lower triglyceride production and downregulation of beta-oxidation. This explained the moderately increased dyslipidaemia, as well as the mild increase in body mass index (BMI) observed in insulin-sensitive hypogonadism. Finally, a significant decrease in carnosine was recorded, explaining the muscle weakness commonly observed.

Short-Term Effect of Induced Alterations in Testosterone Levels on Fasting Plasma Amino Acid Levels in Healthy Young Men

“…Most of the AA changes in the present study were observed in previous studies on hypogonadism or T related disease as well as DM2 [9,19,20]. Notably, Tyr was reported significantly up regulated in hypogonadal males versus controls, while both Tyr and Phe were among the best risk predictors of developing DM2 [19].…”

“…Testosterone (T) has a highly complex metabolic effect on the major tissues involved in insulin action, such as the liver, fat and muscle tissues [2,9,10]. Research suggests that long-term T deficiency causes metabolic changes, such as favoring net protein breakdown resulting in decreased muscle mass.…”

Novel protein markers of androgen activity in humans: proteomic study of plasma from young chemically castrated men

“…The expression of the gene is regulated by hepatocyte-specific and liver-enriched transcription factors, as well as by hormones (24). Tyrosine has previously been reported to be upregulated in hypogonadal men and both tyrosine and phenylalanine levels were suggested as predictors of the risk of developing diabetes many years before manifest disease (43)(44)(45). In male tyrosine hydroxylase knock-out mice normal body weight, puberty onset, and basal gonadotropin levels in adulthood were evident, although T was significantly elevated in adult mice (46).…”

Individual variability in human urinary metabolites identifies age‐related, body mass index‐related, and sex‐related biomarkers

“…To explore the age‐, BMI‐, and sex‐relevant metabolic functions and pathways for understanding the biological meaning of the observed metabolic changes, a metabolite pathway enrichment analysis was conducted using the widely applied MetaboAnalyst 4.0 web tool (Xia et al, 2015). Human species and hypergeometric test were selected as parameters for the pathway analysis and the threshold of FDR was set at 0.05 for allowing the research discovery (Fanelli et al, 2018).…”