Androgen Receptor-Independent Actions of Testosterone Are Equivalent to Metformin on Glucose Utilisation in Hepatocytes

Program: Abstracts - Orals, Poster Previews, and Posters
Session: SUN 203-235-Steroid Hormone Actions, Biosynthesis and Metabolism (posters)
Bench to Bedside
Sunday, April 3, 2016: 1:15 PM-3:15 PM
Exhibit/Poster Hall (BCEC)

Poster Board SUN 230
Daniel Marcus Kelly*1, Samia Akhtar1, Emma Morganti1 and Thomas Hugh Jones2
1University of Sheffield, Sheffield, United Kingdom, 2Barnsley Hospital NHS Foundation Trust, Barnsley, United Kingdom
Background-Testosterone deficiency is associated with insulin resistance which is improved when testosterone is replaced in men with metabolic syndrome and/or type 2 diabetes (T2D)1. The liver is a key tissue involved in insulin sensitivity and glucose utilisation. The mechanisms by which testosterone effects glucose metabolism are not known. Testosterone is however known to protect against the development of fatty liver.2 We have investigated the action of testosterone (and compared it to metformin) on glucose utilisation in human hepatocytes (HepG2).

Methods  HepG2 cells cultured in hyperglycaemic conditions were used to investigate the effects of 24h testosterone treatment (10nM, 100nM) on glucose uptake with or without androgen receptor (AR) blockade (flutamide). Metformin treatment (5μM, 10μM) combined with and without testosterone was studied. The expression of key regulatory targets of glucose uptake and metabolism were assessed by qPCR and western blot. Cellular bioenergetics were analysed by XF metabolic assays (Seahorse Bioscience).

Results -Glucose uptake was increased by approximately 20% in testosterone treated cells and equivalent to the effect of metformin. Combined metformin and testosterone treatment had no additive effect. Flutamide had no effect on testosterone action on glucose uptake. Glucose transporter-2 (GLUT2) expression was increased by testosterone treatment as were the regulatory glycolytic enzymes glucokinase and phosphofructokinase and glycogen synthase. G6PD the regulatory enzyme in the pentose phosphate shunt pathway was decreased by testosterone treatment. Testosterone increased extracellular acidification rate as an indicator of changes in the rate of glycolysis.

Conclusion-Testosterone stimulates glucose utilisation in hepatocytes which is comparable to the efficacy of metformin. This study suggests that testosterone mediates this action by up-regulating the expression of GLUT2, regulatory enzymes of glycolysis combining to increase the rate of glycolysis and potentially storage of glycogen. These effects are AR-independent and have a rapid onset of effect. These findings may in part explain the beneficial effect of testosterone on insulin resistance in men with metabolic syndrome and/or T2D.

(1) Jones TH et al. Diabetes CareĀ  2011;34:828-37. (2) Kelly DM et al. Life Sciences 2014;109:95-10.

Nothing to Disclose: DMK, SA, EM, THJ

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