Hypercortisolism: A Hidden Culprit in Difficult-To-Manage Cases of Type 2 Diabetes?

Today, people with type 2 diabetes have many options when it comes to blood sugar-lowering medications. But some people may still struggle to meet their glycemic goals, even if they closely follow plans mapped out with their healthcare providers. 

However, recent research offers a new explanation – and a potential solution – for at least some of these difficult-to-manage cases. 

Scientists now think that hypercortisolism (excess levels of the hormone cortisol) may be more common than previously realized, and that this issue may be especially prevalent among people with type 2 diabetes whose blood sugar doesn’t respond as well to the typical medications. In these cases, using treatments that target cortisol signaling may be key to achieving blood sugar goals.

What is cortisol, and why do cortisol levels vary?

Cortisol is one of the hormones that help the body respond to stress. When the brain perceives a threat, it sends a message to the adrenal glands, which sit on top of either kidney. In response, the adrenal glands pump cortisol into the bloodstream.

As it circulates through the body, cortisol prepares various organs to switch from “rest and digest” to “fight or flight” mode. The digestive system slows down, fat metabolism turns on, and the amount of sugar in the blood rises. 

Ideally, once the source of stress is dealt with, the brain will send a signal to reduce cortisol output, and the body can get back to resting and digesting. However, chronic stress may keep cortisol levels high for long periods of time.

Cortisol also shuts off the immune system so that energy can be redirected away from healing injuries and fighting infections. In other words, cortisol can reduce inflammation for a limited amount of time. Certain medications may also affect overall cortisol levels – for example, corticosteroid drugs such as prednisone are designed to mimic this effect.

While corticosteroids can provide short-term relief, healthcare providers try to limit how long people use them because having high cortisol levels for too long can cause health problems.

What is hypercortisolism? How is it linked to diabetes?

Sometimes structural or chemical changes in the body cause it to produce too much cortisol. Hypercortisolism is a condition that occurs when the body experiences prolonged exposure to excessive amounts of cortisol. 

Historically, endocrinologists reserved a diagnosis of hypercortisolism for people with the most extreme version of the condition, Cushing’s disease. This condition usually occurs in people who have a benign tumor on their pituitary gland (near the brain) or one of their adrenal glands.

Although Cushing’s disease is fairly rare, it is usually obvious to experienced providers because people with Cushing’s disease have very stereotypical physical symptoms, such as lumps of fat on the upper back and stretch marks on the abdomen.

The excess cortisol not only causes a person to gain weight, but it also weakens bones, increases blood pressure, and raises cholesterol and blood sugar. When type 2 diabetes and Cushing’s disease occur together, it can be difficult to lower a person’s blood sugar without first lowering their cortisol levels.

How common is hypercortisolism? 

More recently, researchers have found evidence linking additional cases of difficult-to-manage type 2 diabetes to hidden hypercortisolism, which refers to people who have elevated levels of cortisol but do not present with typical symptoms of Cushing’s disease. 

According to a 2025 study, nearly 25% of people who cannot manage their blood sugar with medication have hidden hypercortisolism. Another 25% have elevated levels of cortisol, but do not quite rise to the level of a hypercortisolism diagnosis.

“We always knew it was a potential problem, but we thought it was rare,” said Dr. John Buse, an endocrinologist at the University of North Carolina at Chapel Hill who led the study. “Now, we know it’s pretty common.”

At the very least, Buse said he would like to see more people who are trying to manage their type 2 diabetes but not seeing results discuss the possibility of hypercortisolism with their healthcare provider.

Diagnosing hypercortisolism

Widespread hidden hypercortisolism is still a fairly new idea for endocrinologists, let alone the broader medical community. But according to Buse, most healthcare providers already have the capacity to test for it with what’s called a dexamethasone suppression test (DST).

Dexamethasone is a corticosteroid medication. Healthy adrenal glands are expected to limit the amount of cortisol they make when the drug is in a person’s system. 

The specifics of the test vary from clinic to clinic, but the basic idea of the DST is that a person takes some amount of dexamethasone and then (hours or days later) provides a blood or urine sample. If their blood cortisol levels are greater than 1.8 μg/dL, they may have hypercortisolism. 

How to treat hypercortisolism

Treating hypercortisolism depends on the underlying cause. An obvious growth on the pituitary gland or one of the adrenal glands may be removed surgically. Buse said that treating an adrenal tumor in particular can be fairly straightforward because a person only needs one of these glands.

However, many people with hypercortisolism do not have obvious growths. In these cases, or in cases where a person cannot have surgery, mifepristone (Korlym) offers a pharmaceutical alternative. Although the drug is more commonly used to induce medical abortion during early pregnancy, mifepristone is also used to treat people with excess cortisol levels.

The drug does not actively lower cortisol levels. Instead, it prevents cortisol from affecting the body. For it to be effective, a person with hypercortisolism would need to take mifepristone as long as their body continues to produce excess cortisol. For some, that may mean taking the drug for the rest of their lives.

Still, the benefits could be tremendous. Many people with hidden hypercortisolism not only struggle to manage type 2 diabetes, but also live with high blood pressure and are more likely to experience bone fractures.

In another recent study, Buse and his colleagues showed that mifepristone could help people with difficult-to-manage type 2 diabetes and hidden hypercortisolism lower their blood sugar.

While the drug was effective, Buse also noted that 40% of people didn’t finish the study, as mifepristone can be difficult to take. In some cases, mifepristone can lower a person’s potassium levels, causing weakness, nausea, and fatigue. For these people, Buse expressed optimism that future cortisol-blocking medications – at least one of which is currently in development – may be less likely to cause this side effect.

More commonly, people did not finish the study because they experienced what’s called glucocorticoid withdrawal syndrome. When cortisol levels are first lowered, a person can experience nausea, headaches, and fatigue, but these side effects usually improve over time.

“The idea is that the body gets used to these high cortisol levels,” Buse explained. “People generally feel better, but they feel worse for two to four weeks.” 

Buse added that he was not experienced with mifepristone prior to his work on the study. In the future, he hopes to get better at counseling patients on the medication. After all, GLP-1 medications cause many people to experience nausea, but he said he manages to keep most of his patients on them because he can tell them exactly what to expect.

The bottom line

Medications like metformin, SGLT-2 inhibitors, and GLP-1 drugs do not work for everyone who has type 2 diabetes. For at least some of these people, excessive cortisol may be contributing to high blood sugar levels. 

Although healthcare providers have not typically considered hypercortisolism as a diagnosis for someone who does not have the classic symptoms of Cushing’s disease, the tools to diagnose and treat excess cortisol are already readily available. People who are struggling to manage their blood sugar despite sticking to their treatment plans may consider asking their healthcare team about testing for excess cortisol.

Learn more about what can affect blood sugar management here:

• 42 Factors That Affect Blood Glucose
• Diabetes and Arthritis: Decoding the Link
• The Biggest Myth About Starting Type 2 Diabetes Drugs