Pal, M and Khan, J and Kumar, R and Surolia, A and Gupta, S (2019) Testosterone supplementation improves insulin responsiveness in HFD fed male T2DM mice and potentiates insulin signaling in the skeletal muscle and C2C12 myocyte cell line. In: PLoS ONE, 14 (11).
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Abstract
Background 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. Method 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. Results 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. Conclusion 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. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
| Item Type: | Journal Article |
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| Publication: | PLoS ONE |
| Publisher: | Public Library of Science |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | glucose; glycogen synthase kinase 3; insulin receptor; phosphatidylinositol 3 kinase; protein p85; testosterone; transcription factor FKHR; glycogen synthase kinase 3beta; Gsk3b protein, mouse; insulin; insulin receptor; testosterone, adipose tissue; AKT gene; animal cell; animal experiment; animal model; Article; body mass; C2C12 cell line; drug efficacy; drug response; fat content; gene; gene expression; glucose blood level; glucose homeostasis; glucose tolerance; glucose transport; glycemic control; glycogen synthesis; GSK3alpha gene; insulin release; insulin response; insulin sensitivity; male; mouse; muscle mass; non insulin dependent diabetes mellitus; nonhuman; protein phosphorylation; skeletal muscle; testosterone blood level; adverse event; animal; cell line; disease model; drug effect; human; insulin resistance; lipid diet; liver; metabolism; muscle cell; non insulin dependent diabetes mellitus; signal transduction, Animals; Blood Glucose; Cell Line; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Humans; Insulin; Insulin Resistance; Liver; Male; Mice; Muscle Cells; Muscle, Skeletal; Receptor, Insulin; Signal Transduction; Testosterone |
| Department/Centre: | Division of Biological Sciences > Molecular Biophysics Unit |
| Date Deposited: | 19 Oct 2022 08:57 |
| Last Modified: | 19 Oct 2022 08:57 |
| URI: | https://eprints.iisc.ac.in/id/eprint/77332 |
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