Endocrinology & Metabolic Syndrome
Open Access

Hormonal Therapies in Metabolic Syndrome: Advances in Insulin Resistance, Adipokine Regulation and Endocrine Modulation

Wenxing Liu^{* *}Correspondence: Wenxing Liu, Department of Toxicology, University of Montpellier, Montpellier, France, Email:

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Description

Metabolic syndrome is a multifactorial disorder characterized by a cluster of conditions, including central obesity, insulin resistance, dyslipidemia, hypertension, and elevated fasting glucose levels. It significantly increases the risk of developing cardiovascular diseases and Type 2 Diabetes Mellitus (T2DM). Hormonal imbalances, particularly involving insulin, cortisol, adipokines, and sex hormones, play a fundamental role in the pathogenesis of metabolic syndrome. As our understanding of the syndrome advances, targeted therapies focusing on these hormonal pathways are emerging as promising strategies for managing and potentially reversing the condition.

Insulin resistance and targeted therapies

Insulin resistance is a characteristic of metabolic syndrome, driven by impaired insulin signaling pathways in adipose tissue, liver, and skeletal muscles. Drugs such as metformin, Thiazolidinediones (TZDs), and Glucagon-Like Peptide-1 (GLP-1) receptor agonists are commonly used to enhance insulin sensitivity.

Metformin, an established first-line drug for T2DM, improves insulin sensitivity by activating AMP-Activated Protein Kinase (AMPK), reducing hepatic glucose production, and improving peripheral glucose uptake. Similarly, TZDs, such as pioglitazone, activate Peroxisome Proliferator-Activated Receptor-Gamma (PPAR-γ), which regulates genes involved in glucose and lipid metabolism, enhancing insulin sensitivity and reducing inflammation.

GLP-1 receptor agonists, including liraglutide and semaglutide, mimic the action of the endogenous GLP-1 hormone, promoting insulin secretion, suppressing glucagon release, and reducing appetite. These therapies not only address hyperglycemia but also contribute to weight loss and improved lipid profiles, making them ideal for metabolic syndrome management.

Adipokines and inflammatory pathways

Adipose tissue functions as an endocrine organ, secreting hormones called adipokines, including leptin and adiponectin, which regulate metabolism and inflammation. In metabolic syndrome, there is an imbalance in adipokine secretion, with increased leptin levels (leptin resistance) and decreased adiponectin levels contributing to insulin resistance and inflammation.

Targeting adipokine pathways is an emerging therapeutic approach. Agents that increase adiponectin levels, such as TZDs, have shown promise in improving insulin sensitivity and reducing inflammatory cytokines. Additionally, antiinflammatory agents like canakinumab, an Interleukin-1 Beta (IL-1β) inhibitor, have been explored for their role in reducing systemic inflammation in metabolic syndrome.

Cortisol dysregulation and therapeutic approaches

Excess cortisol, often linked to chronic stress, can exacerbate metabolic syndrome by increasing visceral fat deposition, impairing insulin sensitivity, and elevating blood pressure. The enzyme 11Beta-Hydroxysteroid Dehydrogenase Type 1 (11β- HSD1) converts inactive cortisone to active cortisol in tissues such as adipose tissue and liver.

Selective inhibitors of 11β-HSD1, including compounds like AZD4017, have shown potential in reducing cortisol levels locally in tissues, thereby improving insulin sensitivity and reducing central obesity. While these therapies are still under clinical evaluation, they represent a novel strategy for managing cortisolrelated metabolic dysregulation.

Sex hormones and metabolic syndrome

Sex hormones, including estrogen and testosterone, influence metabolic health. Postmenopausal women are at increased risk of metabolic syndrome due to declining estrogen levels, which impact lipid metabolism, glucose homeostasis, and fat distribution.

Hormone Replacement Therapy (HRT) with estrogen has shown benefits in improving insulin sensitivity, reducing abdominal fat, and improving lipid profiles in postmenopausal women. In men, low testosterone levels are associated with increased visceral adiposity, insulin resistance, and dyslipidemia. Testosterone Replacement Therapy (TRT) can improve these parameters, though the long-term safety and cardiovascular risks require further investigation.

Gut microbiota and hormonal interplay

Emerging evidence suggests that gut microbiota plays an important role in metabolic homeostasis through interactions with hormonal pathways. Short-Chain Fatty Acids (SCFAs) produced by gut bacteria influence insulin sensitivity, appetite regulation, and inflammation.

Probiotics, prebiotics, and Fecal Microbiota Transplantation (FMT) are being explored as potential therapies to modulate gut microbiota composition and improve hormonal balance. These approaches hold promise in managing metabolic syndrome by reducing systemic inflammation, enhancing gut-derived hormone secretion (e.g., GLP-1), and improving metabolic outcomes.

Future perspectives and challenges

While targeted therapies for hormonal imbalances offer significant potential, challenges remain. Individual variability in hormone levels, genetic predispositions, and lifestyle factors make it difficult to develop a one-size-fits-all approach. Personalized medicine, guided by biomarkers and precision diagnostics, may address these challenges and optimize therapeutic outcomes.

Additionally, combining pharmacological therapies with lifestyle interventions, including diet, exercise, and stress management, remains essential for long-term success.

Conclusion

Targeted therapies addressing hormonal imbalances in metabolic syndrome represent a promising avenue for managing and potentially reversing the condition. Therapies targeting insulin resistance, adipokine dysregulation, cortisol imbalance, and gut microbiota are showing encouraging results in clinical and preclinical studies. However, further research is needed to fully understand the long-term efficacy and safety of these therapies. A multidisciplinary approach, integrating pharmacological treatments, lifestyle modifications, and precision medicine, is essential to combat the rising problem of metabolic syndrome effectively.