Cushing’s Syndrome: How Cortisol May Be A Hidden Cause of High Blood Sugar in Diabetes

Cushing’s syndrome, also known as hypercortisolism, is the result of chronically elevated levels of the hormone cortisol. Cushing’s syndrome leads to a variety of complications, including high blood pressure, insulin resistance, and an increased risk of fractures and cardiovascular illness.

This is generally thought to be a rare condition with curious but clearly identifiable symptoms, including a round and puffy face and the loss of leg and arm musculature.

New evidence, however, suggests that a milder and less apparent form of Cushing’s syndrome may be extremely common — especially in people with type 2 diabetes. As many as 2 million Americans with diabetes could have this condition, and it may be responsible for a great deal of aggravation in those who struggle to meet their doctor’s A1C goals.

“This is a very, very serious disease,” says Ralph DeFronzo, MD.

Dr. DeFronzo is the chief of diabetes at UT Health San Antonio, and a giant in the world of diabetes research; he was instrumental in the development of metformin and SGLT2 inhibitors as diabetes treatments. Now, DeFronzo is the lead investigator of a new study that has released preliminary results showing that as many as 24 percent of adults with difficult-to-treat type 2 diabetes may have Cushing’s syndrome.

Cortisol and Diabetes

Cortisol is known as a stress hormone. During times of acute stress — say, during a car accident or some other life-threatening event — the body releases large amounts of cortisol, which act as a kind of chemical alarm system for the entire body. Non-essential functions like digestion rapidly slow down, and others get boosted, such as the ability to use glucose for energy. Cortisol counteracts the effect of insulin, causing blood sugar levels to rise.

This is a healthy response when temporary, but elevated cortisol levels have a wide-ranging and almost comprehensively negative effect on the health of a person with diabetes. 

There are many different causes of type 2 diabetes — in a celebrated lecture, DeFronzo identified eight, an “ominous octet” — and hypercortisolism aggravates almost all of them. Notably, cortisol exacerbates insulin resistance and impairs insulin secretion, perhaps the two most significant mechanisms in type 2 diabetes development and progression.

Cortisol also inhibits the release of GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide), two gut hormones that improve insulin response after meals. Semaglutide (Ozempic) and tirzepatide (Mounjaro), the wildly popular diabetes and obesity drugs, work by enhancing the effect of these gut hormones.

“It shouldn’t be surprising that some people with difficult-to-control type 2 diabetes have underlying hypercortisolism. If we can correct it, we are going to improve the ability of your tissues to respond to insulin, the ability of your beta cells to produce insulin, and the ability of your gut cells to release GLP-1 and GIP, and all of that is going to improve your glucose. Your A1C will come down nicely.”

Cortisol dysfunction and type 2 diabetes appear to have a “bidirectional relationship”, meaning that each condition makes the other worse. Part of this is the influence that chronic stress has on cortisol levels — stress, anxiety, depression, and other mental health conditions are more common in people with diabetes. But DeFronzo says that it is unlikely that emotional stress can cause the type of hypercortisolism that defines Cushing’s syndrome.

DeFronzo speculated that hypercortisolism, and cortisol’s habit of blocking GLP-1 and GIP production, could even be the reason that some people do not respond to drugs like Ozempic and Mounjaro: “It’s not known, and really needs to be studied.”

Cortisol and Cushing’s Syndrome

Cortisol is not only released during times of emergency. The hormone plays an important role in glucose homeostasis, and concentrations rise and fall throughout the day. Cortisol levels increase around the time that we wake up, for example, sometimes a contributor to dawn phenomenon.

But there are a number of ways that the body’s stress regulation system can get thrown out of whack:

The adrenal glands may become enlarged (hyperplasia).
Tumors, particularly in the brain or adrenal glands, can cause dysfunctional cortisol production.
Steroids such as prednisone, used commonly for asthma, arthritis, and many other conditions, artificially elevate cortisol levels (iatrogenic Cushing’s syndrome).

The effects of hypercortisolism are known as Cushing’s syndrome no matter the cause.

Cushing’s syndrome has a classic, stereotypical presentation. If you google the condition, you’ll see photos of adults with round, puffy faces, abdominal obesity, and skinny legs. Some have a “buffalo hump,” a fat deposit between the shoulder blades, or stretch marks on the abdomen. Women may experience facial hair growth, and there are psychological symptoms too, such as depression and irritability.

However, people with diabetes and Cushing’s syndrome may not match this stereotypical image of a patient with the condition.

“We’ve come to recognize that there is a more subtle form of Cushing’s Syndrome,” says DeFronzo. “These people don’t present with the classical features.” In other words, for these patients, Cushing’s may seem invisible, its symptoms are obscured by or misinterpreted as the symptoms of diabetes and other metabolic issues.

It’s not currently known why people with type 2 diabetes might have a higher prevalence of Cushing’s syndrome.

How Common is Cushing’s Syndrome in Diabetes?

DeFronzo’s new study, CATALYST, has evaluated 700 patients with “difficult-to-control” type 2 diabetes, which the study defines as “A1C greater than 7.5 percent despite receiving optimal therapies.” DeFronzo says that these patients are “on two or three medications, oftentimes on insulin,” yet no matter how much medicine they take, they cannot seem to approach glycemic control targets.

These volunteers are given a simple test for Cushing’s syndrome. Doctors administer a dose of a steroid named dexamethasone, which suppresses the release of cortisol. The next morning, doctors measure cortisol levels. If cortisol levels remain elevated it satisfies one diagnostic criterion for Cushing’s syndrome. 

So far, CATALYST has found that a remarkable 24 percent of study participants test positive for Cushing’s syndrome.

If this prevalence study is accurate, the consequences could be staggering. Today, the National Institute of Diabetes and Digestive and Kidney Diseases reports 40 to 70 people out of every one million have endogenous Cushing’s syndrome: 13,000 to 23,000 in the United States today. The CATALYST prevalence study would increase that number by orders of magnitude.

“There are about 40 million people with type 2 diabetes here in the United States,” says DeFronzo. “Of those, 25 percent of them have an A1C that’s above 8.0 percent and are on multiple medications. That’s 10 million people. And what we’re learning is that in this particular subgroup, the incidence of hypercortisolism is at least 20 percent. That’s 2 million people! It’s not a small number of patients.”

“It’s a lot more common than we had appreciated.”

Cushing’s Syndrome in Diabetes — What to Look For

If people with Cushing’s syndrome and type 2 diabetes don’t always exhibit the classic disease symptoms, what should we be looking for? DeFronzo names three major factors common to this group of patients:

High A1C despite the use of multiple medications. If you can’t get your A1C down to the target your doctor has set for you despite using more and more medicine, you may have “difficult to treat” diabetes, a potential marker of Cushing’s syndrome.
High blood pressure despite the use of multiple medications. Cushing’s has a similar effect on blood pressure as it does on blood sugar. If you have hypertension that medicine doesn’t seem to address, you have another potential marker of the condition.
Finally, some people with Cushing’s syndrome, especially women, may experience osteoporosis or an increased risk of bone fractures.

DeFronzo says that when physicians confront patients that fit this picture, they “really ought to be thinking about Cushing’s syndrome and hypercortisolemia.” A dexamethasone suppression test may be called for.

The Treatment of Type 2 Diabetes and Cushing’s Syndrome

When a doctor or specialist identifies Cushing’s syndrome, the next step is to try and isolate its cause.

If the condition has been caused by the use of a steroid like prednisone, your medical team may try to find ways for you to replace the drug with an alternative less likely to provoke hyperglycemia.

If the condition is caused by tumors on the pituitary or adrenal glands, surgery is an option with a high rate of success.

For those who are not candidates for surgery, there are several drugs available to treat the condition. Steroidogenesis inhibitors such as ketoconazole and metyrapone disrupt cortisol synthesis. Cabergoline, which activates dopamine receptors, can inhibit the release of a hormone that provokes cortisol production. Temozolomide, a drug used to fight brain cancer, can also slow the growth of noncancerous tumors on the pituitary gland.

There is one drug currently indicated specifically to treat hyperglycemia in people with Cushing’s syndrome and type 2 diabetes: mifepristone (Korlym). This drug is a cortisol receptor blocker — it does not reduce cortisol levels, but it does modulate the body’s response to cortisol, reducing the symptoms of Cushing’s syndrome. (Mifepristone is best known as an abortion pill — it also blocks receptors of progesterone, a steroidal sex hormone that is critical during pregnancy).

Korlym was granted FDA approval after a very small non-randomized trial hinted at impressive benefits:

A1C reduction (7.4 percent to 6.3 percent)
Fasting blood glucose reduction (149 mg/dL to 105 mg/dL)
Weight loss (loss of 5.7 kg), especially around the waist

This trial, however, was not as large or robust as most of the clinical trials that lead to FDA approvals for major new drug indications. In its next phase, the CATALYST study will treat about 130 of the newly identified Cushing’s syndrome patients with Korlym, which should significantly improve our understanding of the drug’s safety and efficacy. Some experts may wait to see more convincing results before they agree that the drug should be prescribed widely to people with diabetes who lack the overt symptoms of Cushing’s syndrome.

Korlym, by the way, doesn’t prevent the body from releasing and using high levels of cortisol when necessary — for example, if your life is in danger. DeFronzo states that your body can overcome what is only a “partial blockade” at the cortisol receptors when necessary.

Skeptical readers may wish to take CATALYST’s early results with a grain of salt. The trial, which could increase the number of potential Korlym customers by a hundredfold, was initiated and funded by Koralym’s manufacturer, a pharmaceutical firm named Corcept Therapeutics.

Takeaways

Cushing’s syndrome, a result of elevated cortisol levels, is generally thought to be a rare condition, but a recent study has suggested that it is exponentially more prevalent in people with type 2 diabetes than previously acknowledged. Cushing’s syndrome is known to make diabetes (and hypertension) much more difficult to manage, and has a significant risk of dangerous long-term outcomes such as cardiovascular disease.

Though the relationship between Cushing’s syndrome and type 2 diabetes is not yet perfectly understood, DeFronzo encourages patients with difficult-to-control diabetes and hypertension to speak to their doctors about it.

“It’s an important disease to diagnose. Patients should go to their doctors and say, ‘Hey, do you think I could Cushing’s syndrome? Could you work me up for this?’”

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Joseph J and Golden S. Cortisol Dysregulation: The Bidirectional Link Between Stress, Depression, and Type 2 Diabetes Mellitus. Annals of the New York Academy of Sciences. March 2017.

Cushing’s Syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. May 2018.

Fleserui M et al. Mifepristone, a Glucocorticoid Receptor Antagonist, Produces Clinical and Metabolic Benefits in Patients with Cushing’s Syndrome. The Journal of Clinical Endocrinology and Metabolism. June 2012.

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