Endocrine Abstracts

Introduction: There is a strong association between testosterone deficiency and the incidence of type 2 diabetes (T2D) in men. Physiological testosterone replacement (TRT) improves insulin resistance and glycaemic control in hypogonadal men. The mechanism by which testosterone mediates these beneficial actions are unknown but may be due to an effect on major metabolically active tissues such as liver and muscle. This study investigates the expression of key regulatory targets of glucose control in liver and muscle tissue of the testicular feminised mouse (Tfm) which exhibit non-functional androgen receptors and low circulating testosterone.

Methods: Tfm mice fed a high-cholesterol diet ad libitum for 28 weeks received either physiological testosterone replacement or placebo and were compared to WT littermates (WT). Liver and muscle tissue was collected and relative concentrations of mRNA and protein were analysed by qPCR and western blotting for expression of hexokinase 2 and 4 (Hk2 and Hk4), glucose transporter 4 (Glut4), phosphofructokinase (Pfk), insulin receptor substrate 1 (Irs1), MAPKK1 (Map2k), carbohydrate regulatory element binding protein (Chrebp), glucose-6-phosphate 1-dehydrogenase X (G6pdx), and glycogen synthase (Gys1).

Results: There was a significant decrease in the relative mRNA expression of Hk4, Pfk and Map2k in liver and Glut4, Hk2, Pfk and Map2k in muscle of Tfm mice compared to WT. G6pdx was increased in Tfm liver. TRT increased hepatic Hk4 mRNA and decreased G6pdx. TRT had no effect on muscle mRNA expression. Western blotting confirmed reduced muscle protein expression of Hk2 and Glut4, and decreased hepatic HK4, PFK in Tfm mice compared to WT with TRT increasing hepatic Hk4. This suggests both AR-independent and dependent mechanisms. No differences were observed between animal groups for the expression of Irs1, Chrebp, and Gys1.

Conclusion: Testosterone differentially regulates the expression of key targets involved in glucose homeostasis in liver and muscle as a mechanism to potentially improve T2D.