Genetic and biochemical mechanisms of hormone resistance in endocrine disorders: Insights from Indian populations

Background: Hormone resistance is an important factor in understanding the mechanism of the pathophysiology of multiple endocrine disorders, such as that of the insulin, thyroid hormone, glucocorticoid, and androgen resistance, which emerge as a constituent part of their natural history. Hormone resistance is common, but its associated biochemical and genetic mechanisms are not well characterized. In this study, we examine the mutations responsible for the hormone-resistance phenotype at the genetic, biochemical, and pathway level, in a large cohort of 1038, including those strictly selected for the presence of mutations in India. Objective: To investigate the biochemical pathways and genetic mutations linked to hormone resistance in individuals diagnosed with type 2 diabetes, thyroid hormone resistance, glucocorticoid resistance, and androgen resistance, focusing specifically on mutations identified in Indian populations. Materials and Methods: A group of 1038 patients diagnosed with diverse types of hormone resistance were examined. Blood samples were collected for hormonal profiling (insulin, thyroid-stimulating hormone, cortisol, testosterone, etc.), receptor expression analysis, and genetic sequencing. Whole-exome sequencing was employed to detect alterations in critical receptor genes (INSR, thyroid hormone receptor β [THRB], NR3C1, AR). Statistical techniques were utilized to associate genetic alterations with biological indicators of hormone resistance. The ethical clearance was taken from the institution ethical committee from Desh Bhagat University. The informed consent form was collected from the patients in both English and regional Language. Patients were strictly selected based on a clinical diagnosis of hormone resistance and a detailed medical history, ensuring they exhibited relevant endocrine disorders such as insulin resistance, thyroid dysfunction, or androgen imbalances and low levels of Vitamin B12 and Vitamin D3. Only those with no other confounding genetic conditions or significant comorbidities were included in the study to ensure the focus remained on genetic mutations specifically related to hormone resistance. Results: Whole-exome sequencing was conducted on strictly selected patients to identify mutations linked to hormone resistance, focusing on receptor genes (insulin, thyroid, and androgen) and the PI3K/Akt pathway for insulin resistance. Copy number variations and single-nucleotide polymorphisms were also examined, with special attention to mutations in Indian populations, given their potential role in the higher prevalence of endocrine disorders in these groups. Our study identified several critical mutations in the genes INSR, THRB, NR3C1, and AR linked to hormone resistance. The specific mutations found in Indian populations were INSR: p.Arg1347Trp (R1347W), p.Val1778Met (V1778M), THRB: p.Arg243His (R243H), p.Cys277Tyr (C277Y), NR3C1: p.Asp642Ser (D642S), p.Arg611Gln (R611Q), and AR: p.Tyr734Cys (Y734C), p.Gln512His (Q512H). These mutations were linked to lower sensitivity of the receptors and problems with signaling inside the cells, which led to the hormonal imbalances seen in the patients. Conclusion: The results indicate that genetic changes significantly contribute to hormone resistance in endocrine illnesses, especially among Indian populations. These genetic modifications, encompassing mutations in insulin, thyroid hormone, glucocorticoid, and androgen receptors, offer significant insight into the molecular underpinnings of resistance and may inform the creation of individualized treatment approaches. Additional research is required to enhance genetic screening instruments and therapeutic strategies for individuals with hormone-resistant endocrine diseases.