Blocking Glucocorticoid Receptors: A Game-Changer for Insulin Resistance or Just Hype?

Insulin resistance is one of the key factors contributing to the development of type 2 diabetes, obesity, and metabolic syndrome. While lifestyle changes remain the cornerstone of therapy, researchers continue to explore new treatment methods. One promising yet still experimental approach involves blocking glucocorticoid receptors (GRs) to reduce insulin resistance.

Cortisol, the primary glucocorticoid, influences carbohydrate metabolism, fat storage, and tissue sensitivity to insulin (1). Chronically elevated cortisol levels’ whether due to stress, medication use, or conditions like Cushing’s syndromes’ lead to increased blood glucose levels, fat accumulation, and insulin resistance (2,3). Given these effects, researchers are investigating whether glucocorticoid receptor antagonists (GRAs) can improve blood sugar control and overall metabolic health.

How Glucocorticoid Receptor Antagonists Work

GRAs block cortisol from binding to its receptors, potentially reducing insulin resistance and improving carbohydrate metabolism (4). One well-known GRA is mifepristone, which is already used to treat Cushing’s syndrome (5). Studies show that mifepristone lowers fasting glucose levels, reduces insulin resistance, and improves metabolic markers in patients with Cushing’s syndrome (6).

These findings have sparked interest in whether blocking glucocorticoid receptors could benefit people with metabolic disorders, even those without Cushing’s syndrome . However, current research is still in its early stages, and there are significant challenges to address before GRAs can become a routine treatment for insulin resistance (7).

Challenges and Limitations

1. Not Everyone with Insulin Resistance Has High Cortisol Levels

Insulin resistance has multiple causes, including genetics, diet, inflammation, and changes in gut microbiota composition (8). Blocking GRs may only be beneficial for a subset of patients whose insulin resistance is directly linked to excess glucocorticoid activity.

2. Side Effects and Safety Concerns

Glucocorticoids regulate not only metabolism but also immune function, blood pressure, and stress responses (9). Blocking GRs may lead to adrenal insufficiency, fatigue, nausea, or immune dysfunction (10).

3. Compensatory Cortisol Production

When GRs are blocked, the body may compensate by increasing cortisol production, potentially counteracting the expected benefits (11).

4. Lack of Long-Term Human Studies

While small studies suggest that GRAs may improve blood sugar control, large-scale, long-term studies confirming their safety and effectiveness in individuals with insulin resistance not associated with Cushing’s syndrome are still lacking (12).

What is Next?

GRAs represent a promising yet unproven approach to treating insulin resistance. Future research should focus on:

1. Identifying which patients would benefit most from GRAs

2. Developing more selective GRAs with fewer side effects

3. Conducting large-scale clinical trials to assess long-term safety and effectiveness

For now, the optimal approach to managing insulin resistance remains a healthy diet, regular physical activity, stress management, and the use of existing medications when necessary (13). GRAs may become part of future treatment strategies, but they remain experimental.

Please see your GP if you have any health concerns.

References

1. Varlamov EV, Purnell JQ, Fleseriu M. Glucocorticoid receptor antagonism as a new for insulin resistance Not there yet! J Clin Endocrinol Metab. 2021;106(6):e2447-e2449. doi: 10.1210/clinem/dgab127.

2. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BM, Colao A. Complications of Cushing’s syndrome : State of the art. Lancet Diabetes Endocrinol. 2016;4(7):611-629. doi: 10.1016/S2213-8587(16)00086-3.

3. Fleseriu M, Castinetti F. Updates on the role of glucocorticoid receptor antagonists in Cushing’s syndrome : Current and emerging indications. Endocrinol Metab Clin North Am. 2022;51(2):417-431. doi: 10.1016/j.ecl.2022.02.009.

4. Morgan SA, McCabe EL, Gathercole LL, Hassan-Smith ZK, Larner DP, Bujalska IJ, et al. 11Î²-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. Proc Natl Acad Sci U S A. 2014;111(24):E2482-2491. doi: 10.1073/pnas.1323681111.

5. Bertagna X, Guignat L, Goichot B, Chabre O. Cushing’s disease: An update. Ann Endocrinol (Paris). 2014;75(3):131-139. doi: 10.1016/j.ando.2014.04.005.

6. Fleseriu M, Biller BMK, Findling JW, Molitch ME, Schteingart DE, Gross C. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome . J Clin Endocrinol Metab. 2019;104(6):1929-1939. doi: 10.1210/jc.2018-01880.

7. Quinkler M, Sinha B, Tomlinson JW, Bujalska I, Stewart PM. Androgen receptor-mediated regulation of the 11Î²-hydroxysteroid dehydrogenase type 2 promoter. J Endocrinol. 2005;184(2):459-467. doi: 10.1677/joe.1.05983.

8. Stefan N, HÃ¤ring HU. The role of hepatokines in metabolism. Nat Rev Endocrinol. 2013;9(3):144-152. doi: 10.1038/nrendo.2012.258.

9. Oakley RH, Cidlowski JA. Glucocorticoid signaling in health and disease: Insights from tissue-specific GR knockout mice. Endocr Rev. 2013;34(6):761-799. doi: 10.1210/er.2012-1050.

10. Raff H, Carroll T. Cushing’s syndrome : Pathophysiology, diagnosis, and treatment. Endocrinol Metab Clin North Am. 2015;44(2):307-321. doi: 10.1016/j.ecl.2015.02.010.

11. Vegiopoulos A, Herzig S. Glucocorticoids, metabolism and metabolic diseases. Mol Cell Endocrinol. 2007;275(1-2):43-61. doi: 10.1016/j.mce.2007.05.015.

12. Feelders RA, Pulgar SJ, Kempel A, Pereira AM. The burden of Cushings’s disease: Clinical and health-related quality of life aspects. Eur J Endocrinol. 2012;167(3):311-326. doi: 10.1530/EJE-12-0453.

13. Reaven GM. The insulin resistance syndrome: Definition and dietary approaches to treatment. Annu Rev Nutr. 2005;25:391-406. doi: 10.1146/annurev.nutr.24.012003.132155.