Molecular Science Laboratory, National Institute of Immunology, New Delhi, India.
Molecular Toxicology Laboratory, Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India.
PLoS One. 2019 Nov 6;14(11):e0224162. doi: 10.1371/journal.pone.0224162. eCollection 2019.
Type 2 Diabetes Mellitus (T2DM) is characterised by hyperglycemia due to the incidence of insulin resistance. Testosterone supplementation has been shown to have a positive co-relation with improved glycemic control in T2DM males. Clinical studies have reported that Androgen Replacement Therapy (ART) to hypogonadic males with T2DM resulted in improved glycemic control and metabolic parameters, but, these studies did not address in detail how testosterone acted on the key glucose homeostatic organs.
In this study, we delineate the effect of testosterone supplementation to high-fat diet (HFD) induced T2DM in male C57BL6J mice and the effect of testosterone supplementation on the skeletal muscle insulin responsiveness. We also studied the effect of testosterone on the insulin signaling pathway proteins in C2C12 myocyte cells to validate the in vivo findings.
We found that testosterone had a potentiating effect on the skeletal muscle insulin signaling pathway to improve glycaemic control. We demonstrate that, in males, testosterone improves skeletal muscle insulin responsiveness by potentiating the PI3K-AKT pathway. The testosterone treated animals showed significant increase in the skeletal muscle Insulin Receptor (IR), p85 subunit of PI3K, P-GSK3α (Ser-21), and P-AKT (Ser-473) levels as compared to the control animals; but there was no significant change in total AKT and GSK3α. Testosterone supplementation inhibited GSK3α in the myocytes in a PI3K/AKT pathway dependent manner; on the other hand GSK3β gene expression was reduced in the skeletal muscle upon testosterone supplementation.
Testosterone increases insulin responsiveness by potentiating insulin signaling in the skeletal muscle cells, which is in contrast to the increased insulin resistance in the liver of testosterone treated T2DM male animals.
2 型糖尿病（T2DM）的特征是由于胰岛素抵抗而发生的高血糖。睾酮补充已被证明与 T2DM 男性的血糖控制改善呈正相关。临床研究报告称，雄激素替代疗法（ART）可改善 T2DM 伴性腺功能减退症男性的血糖控制和代谢参数，但这些研究并未详细说明睾酮如何作用于关键的葡萄糖稳态器官。
在这项研究中，我们描述了睾酮补充对高脂肪饮食（HFD）诱导的雄性 C57BL6J 小鼠 T2DM 的影响，以及睾酮补充对骨骼肌胰岛素反应性的影响。我们还研究了睾酮对 C2C12 肌母细胞胰岛素信号通路蛋白的影响，以验证体内发现。
我们发现睾酮对骨骼肌胰岛素信号通路有增强作用，可改善血糖控制。我们证明，在男性中，睾酮通过增强 PI3K-AKT 通路来改善骨骼肌胰岛素反应性。与对照组相比，接受睾酮治疗的动物骨骼肌胰岛素受体（IR）、PI3K 的 p85 亚基、P-GSK3α（Ser-21）和 P-AKT（Ser-473）水平显著增加；而总 AKT 和 GSK3α 没有显著变化。睾酮补充以依赖于 PI3K/AKT 通路的方式抑制肌细胞中的 GSK3α；另一方面，睾酮补充可降低骨骼肌中的 GSK3β 基因表达。
睾酮通过增强骨骼肌细胞中的胰岛素信号来增加胰岛素反应性，这与接受睾酮治疗的 T2DM 男性动物肝脏中胰岛素抵抗增加形成对比。
