Insulin Resistance Treatment: Can Cortisol Blockers and Mifepristone Improve Metabolic Health?
Updated: Aug 6
Glucocorticoid Receptor Antagonists for Insulin Resistance Treatment and Metabolic Health
Can Insulin Resistance Treatment With Cortisol Blockers Glucocorticoid Receptor Antagonists and Mifepristone Improve Metabolic Health?
Research into Insulin Resistance Treatment, Cortisol Blockers, Mifepristone and Metabolic Health has examined glucocorticoid receptor antagonists such as mifepristone for metabolic complications caused by excessive cortisol activity. These medicines may improve glucose control in selected people with endogenous Cushing’s syndrome, but they are not considered a routine treatment for general insulin resistance.
What Is Insulin Resistance?
Insulin resistance occurs when cells in the muscles, liver and other tissues do not respond effectively to insulin. The pancreas initially compensates by producing more insulin, but blood glucose levels may eventually rise.
Insulin resistance is associated with:
Prediabetes
Type 2 diabetes
Metabolic syndrome
Polycystic ovary syndrome
Fatty liver disease
Excess abdominal weight
Cardiovascular disease risk
Weight management where appropriate, regular physical activity, personalised nutrition and glucose-lowering medicines remain the main evidence-based approaches to improving insulin resistance. (1)
How Can Cortisol Contribute to Insulin Resistance?
Cortisol is a glucocorticoid hormone produced by the adrenal glands. It supports the body’s stress response and helps regulate blood glucose, blood pressure, inflammation and energy availability.
Persistently excessive cortisol activity can:
Increase glucose production by the liver
Reduce glucose uptake by muscle and fat cells
Promote abdominal fat accumulation
Increase appetite
Reduce insulin sensitivity
Contribute to high blood pressure and abnormal cholesterol levels
This is particularly evident in Cushing’s syndrome, where the body is exposed to excessive cortisol. Long-term corticosteroid medicine use can also affect blood glucose and increase the risk of insulin resistance. (2)
Everyday psychological stress does not automatically mean that a person has medically abnormal cortisol levels or requires cortisol-blocking treatment.
What Are Glucocorticoid Receptor Antagonists?
Mifepristone does not usually lower cortisol production. It blocks cortisol activity at the glucocorticoid receptor and may cause circulating cortisol and adrenocorticotropic hormone levels to rise.
Rather than necessarily reducing the amount of cortisol circulating in the blood, these medicines reduce cortisol’s effects at the receptor level. This may improve glucose metabolism when excessive cortisol activity is driving insulin resistance.
The most widely studied glucocorticoid receptor antagonist is mifepristone.
Can Mifepristone Improve Insulin Resistance?
Rather than suppressing cortisol synthesis, mifepristone prevents cortisol from acting at glucocorticoid receptors. As a result, blood concentrations of cortisol and adrenocorticotropic hormone may increase.. In the United States, a specific mifepristone product is approved to control hyperglycaemia caused by endogenous Cushing’s syndrome in certain adults with type 2 diabetes or glucose intolerance. It is not approved there as a general treatment for type 2 diabetes unrelated to Cushing’s syndrome. (3)
Research involving people with Cushing’s syndrome has found improvements in glucose control and other clinical features after treatment with mifepristone. (4)
The pilot trial mentioned in the article included only 16 participants. It was a short-term, randomised, placebo-controlled crossover study in people who were overweight or obese and had prediabetes or mild type 2 diabetes without clinical hypercortisolism. It found improvements in adipose-tissue insulin sensitivity, but it was not designed to establish long-term clinical effectiveness or safety. (5)
These findings are promising, but they are not enough to support widespread use for general insulin resistance.
Testing for Cushing’s syndrome should be based on clinical assessment and recognised diagnostic protocols. Random serum cortisol or adrenocorticotropic hormone measurements are not recommended as screening tests. Depending on the clinical situation, initial testing may include repeated late-night salivary cortisol, repeated 24-hour urinary free cortisol or an overnight dexamethasone-suppression test.
In Australia, mifepristone should not be presented as an approved treatment for general insulin resistance. Any proposed endocrine use would require specialist assessment and consideration of current Australian regulatory and medicine-access requirements.
Who Might Benefit From Cortisol-Blocking Treatment?
Mifepristone may be considered under specialist supervision for selected adults with endogenous Cushing’s syndrome who have hyperglycaemia caused by hypercortisolism, particularly when surgery has failed, is unsuitable or cannot be performed. It should not be presented as a treatment for insulin resistance where pathological cortisol excess has not been established.
Practical Ways to Improve Insulin Resistance
While research into cortisol-blocking medicines continues, established lifestyle and medical treatments remain the safest starting point.
Build Balanced Meals
Aim to combine:
High-fibre vegetables
Wholegrain or lower-GI carbohydrate foods
Lean protein
Legumes
Nuts and seeds
Healthy fats
Minimally processed foods
Regularly consuming sugary drinks, highly refined carbohydrates and large portions of energy-dense foods may make blood glucose and weight management more difficult.
There is no single diet that is suitable for every person with insulin resistance. The best eating pattern should account for your glucose levels, medical conditions, medications, food preferences, culture and daily routine. (6)
Exercise Regularly
Physical activity helps muscles use glucose more effectively and can improve insulin sensitivity.
Where medically appropriate, aim for at least 150 minutes of moderate-to-vigorous aerobic activity each week, spread across at least 3 days, together with resistance exercise on 2–3 non-consecutive days. Include resistance or strength-based activity around twice a week where medically appropriate. (7)
Work Towards Sustainable Weight Management
For people carrying excess weight, even modest weight loss may improve insulin sensitivity and blood glucose control.
Weight loss is not required or appropriate for everyone. Advice should be individualised rather than based only on body weight or BMI.
Prioritise Sleep and Stress Management
Poor sleep and ongoing stress can affect appetite, food choices, activity levels and blood glucose management.
Helpful strategies may include:
Maintaining a regular sleep routine
Allowing adequate recovery time
Using relaxation or breathing techniques
Seeking psychological support when needed
Addressing sleep apnoea or persistent sleep problems with a GP
Review Your Medicines
Some medicines, particularly long-term corticosteroids, can raise blood glucose levels.
Do not stop prescribed corticosteroids or change the dose without medical guidance. Suddenly stopping these medicines can be dangerous. Ask your GP or specialist whether your medicines could be affecting your glucose levels.
What are limitations of Glucocorticoid Receptor Antagonists?
Most Insulin Resistance Is Not Caused by Excess Cortisol
Insulin resistance has many possible causes. Blocking cortisol receptors may provide little benefit when abnormal glucocorticoid activity is not a major contributing factor.
Human Evidence Remains Limited
Most evidence for mifepristone’s metabolic benefits comes from people with Cushing’s syndrome. Studies involving people without Cushing’s syndrome have generally been small and experimental.
Large clinical trials are still needed to establish:
Which patients may benefit
The most appropriate dose
Long-term effectiveness
Long-term safety
Whether the benefits outweigh the risks
Cortisol Levels May Increase
Blocking glucocorticoid receptors can activate feedback mechanisms that increase cortisol and adrenocorticotropic hormone levels. This makes treatment response and excessive receptor blockade more difficult to monitor using cortisol measurements alone. (8)
These Medicines Affect More Than Blood Glucose
Glucocorticoid receptors are involved in immune regulation, blood pressure, stress responses and many other essential functions. Blocking them can have significant effects throughout the body.
Safety Considerations
Mifepristone can cause significant adverse effects and requires close medical supervision. Possible risks include:
Low potassium levels
Nausea and vomiting
Fatigue
Headache
Dizziness
Swelling
High blood pressure
Symptoms caused by excessive glucocorticoid receptor blockade
Endometrial thickening or vaginal bleeding
Changes in heart rhythm, including QT-interval prolongation
Significant interactions with other medicines
Increased risk of hypoglycaemia when used with certain diabetes medicines
Mifepristone must not be used during an ongoing pregnancy when prescribed for hypercortisolism. It can also interact with medicines metabolised through the CYP3A pathway, so all medicines and supplements should be reviewed before treatment begins. (10)
Mifepristone may cause cortisol and adrenocorticotropic hormone levels to remain elevated or increase. Therefore, cortisol measurements alone cannot be used to assess treatment response or excessive glucocorticoid receptor blockade. Monitoring should instead include symptoms, blood pressure, potassium levels, blood glucose and possible medicine interactions. (10)
Glucocorticoid receptor antagonists should never be purchased or used as a self-directed treatment for insulin resistance.
When Should You Consult a GP?
Speak with your GP if you:
Have repeatedly elevated blood glucose results
Have symptoms of diabetes, including excessive thirst, frequent urination or unexplained fatigue
Have been diagnosed with prediabetes, PCOS or metabolic syndrome
Have a strong family history of type 2 diabetes
Take long-term corticosteroid medicines
Have unexplained high blood pressure or rapid abdominal weight gain
Develop easy bruising, muscle weakness or wide purple stretch marks
Are concerned that a medical condition or medicine is affecting your cortisol or glucose levels
A GP can assess your risk and determine whether tests such as fasting glucose, HbA1c, cholesterol, liver function or other investigations are appropriate.
Testing for Cushing’s syndrome should be based on a clinical assessment. A single cortisol measurement or commercial home cortisol test cannot reliably determine whether cortisol is causing insulin resistance.
When Should You Consult a Dietitian?
An Accredited Practising Dietitian can help if you:
Have insulin resistance, prediabetes or type 2 diabetes
Have PCOS or metabolic syndrome
Experience large changes in blood glucose after meals
Feel unsure about carbohydrates, portion sizes or meal timing
Want to improve your diet without following an unnecessarily restrictive plan
Need nutrition advice that considers medications, allergies or other health conditions
Have tried multiple diets without achieving sustainable results
A dietitian can assess your usual intake and create a practical eating plan that supports blood glucose management while meeting your nutritional needs.
The Bottom Line
Glucocorticoid receptor antagonists are an interesting area of metabolic research, particularly for insulin resistance caused by excessive cortisol activity.
Mifepristone has demonstrated benefits for hyperglycaemia associated with Cushing’s syndrome, and early studies suggest it may influence insulin sensitivity in other groups. However, it remains an experimental approach for insulin resistance that is not caused by Cushing’s syndrome.
For most people, the priority remains personalised nutrition, regular physical activity, appropriate weight management, adequate sleep, medical monitoring and established glucose-lowering treatments when required.
Get Personalised Support for Insulin Resistance
Managing insulin resistance does not require a highly restrictive or one-size-fits-all diet.
FerFit Dietetics & Nutrition provides personalised nutrition support for people living with insulin resistance, prediabetes, type 2 diabetes, PCOS and metabolic health concerns.
Book an appointment with a FerFit dietitian to receive a practical eating plan tailored to your health, blood glucose results, lifestyle and food preferences.
FerFit Dietetics & Nutrition provides personalised dietitian support in Elwood Glen Huntly Mentone and Upwey, helping people manage insulin resistance diabetes PCOS and other metabolic health concerns.
Watch the video below for a simple, practical explanation and helpful tips you can start using today.
References
Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98(4):2133–2223. doi:10.1152/physrev.00063.2017.
Teede HJ, Tay CT, Laven JJE, et al. Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome. J Clin Endocrinol Metab. 2023;108(10):2447–2469. doi:10.1210/clinem/dgad463.
American Diabetes Association Professional Practice Committee. Prevention or delay of diabetes and associated comorbidities: Standards of Care in Diabetes—2026. Diabetes Care. 2026;49(Suppl 1):S50–S60. doi:10.2337/dc26-S003.
American Diabetes Association Professional Practice Committee. Facilitating positive health behaviors and well-being to improve health outcomes: Standards of Care in Diabetes—2026. Diabetes Care. 2026;49(Suppl 1):S89–S131. doi:10.2337/dc26-S005.
American Diabetes Association Professional Practice Committee. Obesity and weight management for the prevention and treatment of diabetes: Standards of Care in Diabetes—2026. Diabetes Care. 2026;49(Suppl 1):S166–S182. doi:10.2337/dc26-S008.
Chang M, Wang JC. Hepatic glucocorticoid receptor action and glucose homeostasis. Endocr Rev. 2026;47(1):52–74. doi:10.1210/endrev/bnaf030.
Beuschlein F, Else T, Bancos I, et al. European Society of Endocrinology and Endocrine Society joint clinical guideline: diagnosis and therapy of glucocorticoid-induced adrenal insufficiency. J Clin Endocrinol Metab. 2024;109(7):1657–1683. doi:10.1210/clinem/dgae250.
Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(5):1526–1540. doi:10.1210/jc.2008-0125.
Nieman LK, Biller BMK, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(8):2807–2831. doi:10.1210/jc.2015-1818.
National Library of Medicine. DailyMed: KORLYM—mifepristone tablet prescribing information. Revised September 2024; updated September 25, 2025. Accessed August 6, 2026.
Fleseriu M, Biller BMK, Findling JW, Molitch ME, Schteingart DE, Gross C; SEISMIC Study Investigators. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab. 2012;97(6):2039–2049. doi:10.1210/jc.2011-3350.
Gubbi S, Muniyappa R, Sharma ST, Grewal S, McGlotten R, Nieman LK. Mifepristone improves adipose tissue insulin sensitivity in insulin-resistant individuals. J Clin Endocrinol Metab. 2021;106(5):1501–1515. doi:10.1210/clinem/dgab046.
Therapeutic Goods Administration. Australian Public Assessment Report for Mifepristone Linepharma and Australian Public Assessment Report for mifepristone/misoprostol. Commonwealth of Australia. Accessed August 6, 20
Author and Clinical Review
Written by: Julia Haimovich, FerFit Dietitian APD & CEDC
Reviewed date: August 2026
Review date: August 2027
This article provides general educational information and is not a substitute for individual medical care. Do not stop or alter cholesterol medication without consulting your prescribing doctor.
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