Dataset Information

Testosterone supplementation improves insulin responsiveness in HFD fed male T2DM mice and potentiates insulin signaling in the skeletal muscle and C2C12 myocyte cell line.

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-GSK3? (Ser-21), and P-AKT (Ser-473) levels as compared to the control animals; but there was no significant change in total AKT and GSK3?. Testosterone supplementation inhibited GSK3? in the myocytes in a PI3K/AKT pathway dependent manner; on the other hand GSK3? 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.

SUBMITTER: Pal M

PROVIDER: S-EPMC6834245 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Testosterone supplementation improves insulin responsiveness in HFD fed male T2DM mice and potentiates insulin signaling in the skeletal muscle and C2C12 myocyte cell line.

Pal Madhuraka M Khan Jasim J Kumar Ravi R Surolia Avadhesha A Gupta Sarika S

PloS one 20191106 11

<h4>Background</h4>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 gluco ...[more]

PMID: 31693697

Similar Datasets

Project description:Background:Gut microbiota dysbiosis has been linked to obesity-associated chronic inflammation. Microbiota manipulation may therefore affect obesity-related comorbidities. Blueberries are rich in anthocyanins, which have anti-inflammatory properties and may alter the gut microbiota. Objective:We hypothesized that blueberry supplementation would alter the gut microbiota, reduce systemic inflammation, and improve insulin resistance in high-fat (HF)-diet-fed rats. Methods:Twenty-four male Wistar rats (260-270 g; n = 8/group) were fed low-fat (LF; 10% fat), HF (45% fat), or HF with 10% by weight blueberry powder (HF_BB) diets for 8 wk. LF rats were fed ad libitum, whereas HF and HF_BB rats were pair-fed with diets matched for fiber and sugar contents. Glucose tolerance, microbiota composition (16S ribosomal RNA sequencing), intestinal integrity [villus height, gene expression of mucin 2 (Muc2) and ?-defensin 2 (Defb2)], and inflammation (gene expression of proinflammatory cytokines) were assessed. Results:Blueberry altered microbiota composition with an increase in Gammaproteobacteria abundance (P < 0.001) compared with LF and HF rats. HF feeding led to an ?15% decrease in ileal villus height compared with LF rats (P < 0.05), which was restored by blueberry supplementation. Ileal gene expression of Muc2 was ?150% higher in HF_BB rats compared with HF rats (P < 0.05), with expression in the LF group not being different from that in either the HF or HF_BB groups. Tumor necrosis factor ? (Tnfa) and interleukin 1? (Il1b) gene expression in visceral fat was increased by HF feeding when compared with the LF group (by 300% and 500%, respectively; P < 0.05) and normalized by blueberry supplementation. Finally, blueberry improved markers of insulin sensitivity. Hepatic insulin receptor substrate 1 (IRS1) phosphorylation at serine 307:IRS1 ratio was ?35% higher in HF rats compared with LF rats (P < 0.05) and HF_BB rats. Conclusion:In HF-diet-fed male rats, blueberry supplementation led to compositional changes in the gut microbiota associated with improvements in systemic inflammation and insulin signaling.

Project description:Testosterone induces cardiac hypertrophy through a mechanism that involves a concerted crosstalk between cytosolic and nuclear signaling pathways. Nuclear factor of activated T-cells (NFAT) is associated with the promotion of cardiac hypertrophy, glycogen synthase kinase-3? (GSK-3?) is considered to function as a negative regulator, mainly by modulating NFAT activity. However, the role played by calcineurin-NFAT and GSK-3? signaling in testosterone-induced cardiac hypertrophy has remained unknown. Here, we determined that testosterone stimulates cardiac myocyte hypertrophy through NFAT activation and GSK-3? inhibition. Testosterone increased the activity of NFAT-luciferase (NFAT-Luc) in a time- and dose-dependent manner, with the activity peaking after 24 h of stimulation with 100 nM testosterone. NFAT-Luc activity induced by testosterone was blocked by the calcineurin inhibitors FK506 and cyclosporine A and by 11R-VIVIT, a specific peptide inhibitor of NFAT. Conversely, testosterone inhibited GSK-3? activity as determined by increased GSK-3? phosphorylation at Ser9 and ?-catenin protein accumulation, and also by reduction in ?-catenin phosphorylation at residues Ser33, Ser37, and Thr41. GSK-3? inhibition with 1-azakenpaullone or a GSK-3?-targeting siRNA increased NFAT-Luc activity, whereas overexpression of a constitutively active GSK-3? mutant (GSK-3?S9A) inhibited NFAT-Luc activation mediated by testosterone. Testosterone-induced cardiac myocyte hypertrophy was established by increased cardiac myocyte size and [3H]-leucine incorporation (as a measurement of cellular protein synthesis). Calcineurin-NFAT inhibition abolished and GSK-3? inhibition promoted the hypertrophy stimulated by testosterone. GSK-3? activation by GSK-3?S9A blocked the increase of hypertrophic markers induced by testosterone. Moreover, inhibition of intracellular androgen receptor prevented testosterone-induced NFAT-Luc activation. Collectively, these results suggest that cardiac myocyte hypertrophy induced by testosterone involves a cooperative mechanism that links androgen signaling with the recruitment of NFAT through calcineurin activation and GSK-3? inhibition.

Dataset Information

Testosterone supplementation improves insulin responsiveness in HFD fed male T2DM mice and potentiates insulin signaling in the skeletal muscle and C2C12 myocyte cell line.

Background

Method

Results

Conclusion

Publications

Testosterone supplementation improves insulin responsiveness in HFD fed male T2DM mice and potentiates insulin signaling in the skeletal muscle and C2C12 myocyte cell line.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets