The Modulatory Effects of Testosterone on Diabetic Cardiomyopathy

[madman]

Diabetes is a prevalent disease, primarily characterized by high blood sugar (hyperglycemia). Significantly higher rates of myocardial dysfunction have been noted in individuals with diabetes, even in those without coronary artery disease or high blood pressure (hypertension). Numerous molecular mechanisms have been identified through which diabetes contributes to the pathology of diabetic cardiomyopathy, which presents as cardiac hypertrophy and fibrosis. At the cellular level, oxidative stress and inflammation in cardiomyocytes are triggered by hyperglycemia. Although males are generally more likely to develop cardiovascular disease than females, diabetic males are less likely to develop diabetic cardiomyopathy than diabetic females. One reason for these differences may be the higher levels of serum testosterone in males compared with females. Although testosterone appears to protect against cardiomyocyte oxidative stress and exacerbates hypertrophy, its role in inflammation and fibrosis is much less clear. Additional preclinical and clinical studies will be required to delineate testosterone’s effect on the diabetic heart.




The objective of this review is to identify potential interactions between the actions of testosterone and hyperglycemia in cardiomyocytes (Figure 1A). This review focuses on four mechanisms associated with DbCM: hypertrophy, oxidative stress, inflammation, and fibrosis. Particular attention will be placed on studies attempting to delineate the influence of hyperglycemia/hyperlipidemia on cardiomyocytes.




*Oxidative Stress

*Inflammation

*Hypertrophy

*Fibrosis




Conclusion and Future Directions

Overall, there is limited work directly investigating the impact of testosterone in animal models of diabetes. Given the presence of sex differences in the development of DbCM, it is important to investigate the potential impact of sex hormones such as testosterone on the development of this condition.23 Because previous evidence suggests that the impact of testosterone is dependent upon glycemic status, it is difficult to infer the role of testosterone in DbCM based on studies in nondiabetic animals124,129 (Table 1). Therefore, the influence of testosterone on the development of DbCM must be investigated by examining how testosterone administration directly impacts this pathology.

 

[madman]

Figure 1 A: Testosterone signaling. Testosterone binds to the androgen receptor in the cytoplasm, forming the androgen receptor (AR) complex. Upon dimerization, this complex translocases to the nucleus, binding to androgen response elements (AREs) in the promoters of specific genes thereby regulating gene transcription. Testosterone impacts numerous metabolic pathways generally promoting hypertrophy and attenuating oxidative stress in cardiomyocytes. B: Pathways involved in the pathogenesis of diabetic cardiomyopathy (DbCM), with the impacts of testosterone highlighted. Pathways positively regulated by testosterone are indicated in green, whereas negative regulation is indicated in red. ADA, adenosine deaminase; AGE, advanced glycation end products; GSHPx, glutathione peroxidase; GSK-3b, glycogen synthase kinase-3b; HDAC4, histone deacetylase-4; HO-1, heme oxygenase-1; KC, protein kinase C; MEF2, myocyte enhancer factor-2; mTOR, mammalian target of rapamycin; NFAT, nuclear factor of activated T-cells; NHE-1, sodium-hydrogen exchanger-1; NLRP3,nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3; NOX, NADPH oxidase; Nrf2, nuclear factor-erythroid factor 2-related factor2; PKC, protein kinase C; RAGE, receptor for AGEs; ROS, reactive oxygen species; SOD, superoxide dismutase; TLR4, toll-like receptor 4; XO, xanthine oxidase. Figure created with Biorender.com (Toronto, ON, Canada).

 

[madman]

Table 1 Summary of Animal Models Used to Study Diabetic Cardiomyopathy