Cushing’s Syndrome: How Cortisol Might Be A Hidden Reason behind Excessive Blood Sugar in Diabetes

Cushing’s syndrome, often known as hypercortisolism, is the results of chronically elevated ranges of the hormone cortisol. Cushing’s syndrome results in quite a lot of problems, together with hypertension, insulin resistance, and an elevated danger of fractures and cardiovascular sickness.

That is usually regarded as a uncommon situation with curious however clearly identifiable signs, together with a spherical and puffy face and the lack of leg and arm musculature.

New proof, nevertheless, suggests {that a} milder and fewer obvious type of Cushing’s syndrome could also be extraordinarily frequent — particularly in individuals with kind 2 diabetes. As many as 2 million Individuals with diabetes may have this situation, and it could be chargeable for an excessive amount of aggravation in those that battle to fulfill their physician’s A1C objectives.

“This can be a very, very critical illness,” says Ralph DeFronzo, MD.

Dr. DeFronzo is the chief of diabetes at UT Well being San Antonio, and a large on the earth of diabetes analysis; he was instrumental within the growth of metformin and SGLT2 inhibitors as diabetes remedies. Now, DeFronzo is the lead investigator of a brand new research that has launched preliminary outcomes displaying that as many as 24 p.c of adults with difficult-to-treat kind 2 diabetes might have Cushing’s syndrome.

Cortisol and Diabetes

Cortisol is named a stress hormone. Throughout instances of acute stress — say, throughout a automotive accident or another life-threatening occasion — the physique releases massive quantities of cortisol, which act as a sort of chemical alarm system for the whole physique. Non-essential capabilities like digestion quickly decelerate, and others get boosted, comparable to the flexibility to make use of glucose for power. Cortisol counteracts the impact of insulin, inflicting blood sugar ranges to rise.

This can be a wholesome response when short-term, however elevated cortisol ranges have a wide-ranging and virtually comprehensively unfavorable impact on the well being of an individual with diabetes. 

There are lots of completely different causes of kind 2 diabetes — in a celebrated lecture, DeFronzo recognized eight, an “ominous octet” — and hypercortisolism aggravates virtually all of them. Notably, cortisol exacerbates insulin resistance and impairs insulin secretion, maybe the 2 most vital mechanisms in kind 2 diabetes growth and development.

Cortisol additionally inhibits the discharge of GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide), two intestine hormones that enhance insulin response after meals. Semaglutide (Ozempic) and tirzepatide (Mounjaro), the wildly common diabetes and weight problems medication, work by enhancing the impact of those intestine hormones.

“It shouldn’t be shocking that some individuals with difficult-to-control kind 2 diabetes have underlying hypercortisolism. If we will appropriate it, we’re going to enhance the flexibility of your tissues to reply to insulin, the flexibility of your beta cells to provide insulin, and the flexibility of your intestine cells to launch GLP-1 and GIP, and all of that’s going to enhance your glucose. Your A1C will come down properly.”

Cortisol dysfunction and sort 2 diabetes seem to have a “bidirectional relationship”, that means that every situation makes the opposite worse. A part of that is the affect that continual stress has on cortisol ranges — stress, nervousness, melancholy, and different psychological well being circumstances are extra frequent in individuals with diabetes. However DeFronzo says that it’s unlikely that emotional stress could cause the kind of hypercortisolism that defines Cushing’s syndrome.

DeFronzo speculated that hypercortisolism, and cortisol’s behavior of blocking GLP-1 and GIP manufacturing, may even be the explanation that some individuals don’t reply to medication like Ozempic and Mounjaro: “It’s not identified, and actually must be studied.”

Cortisol and Cushing’s Syndrome

Cortisol just isn’t solely launched throughout instances of emergency. The hormone performs an necessary function in glucose homeostasis, and concentrations rise and fall all through the day. Cortisol ranges enhance across the time that we get up, for instance, typically a contributor to daybreak phenomenon.

However there are a variety of ways in which the physique’s stress regulation system can get thrown out of whack:

  • The adrenal glands might develop into enlarged (hyperplasia).
  • Tumors, notably within the mind or adrenal glands, could cause dysfunctional cortisol manufacturing.
  • Steroids comparable to prednisone, used generally for bronchial asthma, arthritis, and plenty of different circumstances, artificially elevate cortisol ranges (iatrogenic Cushing’s syndrome).

The results of hypercortisolism are referred to as Cushing’s syndrome irrespective of the trigger.

Cushing’s syndrome has a basic, stereotypical presentation. Should you google the situation, you’ll see images of adults with spherical, puffy faces, stomach weight problems, and thin legs. Some have a “buffalo hump,” a fats deposit between the shoulder blades, or stretch marks on the stomach. Ladies might expertise facial hair development, and there are psychological signs too, comparable to melancholy and irritability.

Nonetheless, individuals with diabetes and Cushing’s syndrome might not match this stereotypical picture of a affected person with the situation.

“We’ve come to acknowledge that there’s a extra delicate type of Cushing’s Syndrome,” says DeFronzo. “These individuals don’t current with the classical options.” In different phrases, for these sufferers, Cushing’s could appear invisible, its signs are obscured by or misinterpreted because the signs of diabetes and different metabolic points.

It’s not at the moment identified why individuals with kind 2 diabetes might need the next prevalence of Cushing’s syndrome.

How Widespread is Cushing’s Syndrome in Diabetes?

DeFronzo’s new research, CATALYST, has evaluated 700 sufferers with “difficult-to-control” kind 2 diabetes, which the research defines as “A1C larger than 7.5 p.c regardless of receiving optimum therapies.” DeFronzo says that these sufferers are “on two or three drugs, oftentimes on insulin,” but irrespective of how a lot drugs they take, they can not appear to method glycemic management targets.

These volunteers are given a easy check for Cushing’s syndrome. Medical doctors administer a dose of a steroid named dexamethasone, which suppresses the discharge of cortisol. The following morning, medical doctors measure cortisol ranges. If cortisol ranges stay elevated it satisfies one diagnostic criterion for Cushing’s syndrome. 

To date, CATALYST has discovered {that a} exceptional 24 p.c of research individuals check optimistic for Cushing’s syndrome.

If this prevalence research is correct, the implications may very well be staggering. As we speak, the Nationwide Institute of Diabetes and Digestive and Kidney Ailments studies 40 to 70 individuals out of each a million have endogenous Cushing’s syndrome: 13,000 to 23,000 in the US right now. The CATALYST prevalence research would enhance that quantity by orders of magnitude.

“There are about 40 million individuals with kind 2 diabetes right here in the US,” says DeFronzo. “Of these, 25 p.c of them have an A1C that’s above 8.0 p.c and are on a number of drugs. That’s 10 million individuals. And what we’re studying is that on this explicit subgroup, the incidence of hypercortisolism is no less than 20 p.c. That’s 2 million individuals! It’s not a small variety of sufferers.”

“It’s much more frequent than we had appreciated.”

Cushing’s Syndrome in Diabetes — What to Look For

If individuals with Cushing’s syndrome and sort 2 diabetes don’t all the time exhibit the basic illness signs, what ought to we be on the lookout for? DeFronzo names three main components frequent to this group of sufferers:

  • Excessive A1C regardless of the usage of a number of drugs. Should you can’t get your A1C all the way down to the goal your physician has set for you regardless of utilizing increasingly more drugs, you’ll have “tough to deal with” diabetes, a possible marker of Cushing’s syndrome.
  • Hypertension regardless of the usage of a number of drugs. Cushing’s has an identical impact on blood strain because it does on blood sugar. You probably have hypertension that drugs doesn’t appear to deal with, you’ve gotten one other potential marker of the situation.
  • Lastly, some individuals with Cushing’s syndrome, particularly girls, might expertise osteoporosis or an elevated danger of bone fractures.

DeFronzo says that when physicians confront sufferers that match this image, they “actually should be fascinated with Cushing’s syndrome and hypercortisolemia.” A dexamethasone suppression check could also be referred to as for.

The Therapy of Type 2 Diabetes and Cushing’s Syndrome

When a health care provider or specialist identifies Cushing’s syndrome, the following step is to attempt to isolate its trigger.

If the situation has been induced by means of a steroid like prednisone, your medical staff might attempt to discover methods so that you can change the drug with another much less prone to provoke hyperglycemia.

If the situation is brought on by tumors on the pituitary or adrenal glands, surgical procedure is an possibility with a excessive price of success.

For individuals who will not be candidates for surgical procedure, there are a number of medication obtainable to deal with the situation. Steroidogenesis inhibitors comparable to ketoconazole and metyrapone disrupt cortisol synthesis. Cabergoline, which prompts dopamine receptors, can inhibit the discharge of a hormone that provokes cortisol manufacturing. Temozolomide, a drug used to battle mind most cancers, may gradual the expansion of noncancerous tumors on the pituitary gland.

There’s one drug at the moment indicated particularly to deal with hyperglycemia in individuals with Cushing’s syndrome and sort 2 diabetes: mifepristone (Korlym). This drug is a cortisol receptor blocker — it doesn’t scale back cortisol ranges, nevertheless it does modulate the physique’s response to cortisol, lowering the signs of Cushing’s syndrome. (Mifepristone is finest referred to as an abortion capsule — it additionally blocks receptors of progesterone, a steroidal intercourse hormone that’s essential throughout being pregnant).

Korlym was granted FDA approval after a really small non-randomized trial hinted at spectacular advantages:

  • A1C discount (7.4 p.c to six.3 p.c)
  • Fasting blood glucose discount (149 mg/dL to 105 mg/dL)
  • Weight reduction (lack of 5.7 kg), particularly across the waist

This trial, nevertheless, was not as massive or strong as a lot of the scientific trials that result in FDA approvals for main new drug indications. In its subsequent part, the CATALYST research will deal with about 130 of the newly recognized Cushing’s syndrome sufferers with Korlym, which ought to considerably enhance our understanding of the drug’s security and efficacy. Some specialists might wait to see extra convincing outcomes earlier than they agree that the drug must be prescribed extensively to individuals with diabetes who lack the overt signs of Cushing’s syndrome.

Korlym, by the way in which, doesn’t forestall the physique from releasing and utilizing excessive ranges of cortisol when vital — for instance, in case your life is at risk. DeFronzo states that your physique can overcome what is just a “partial blockade” on the cortisol receptors when vital.

Skeptical readers might want to take CATALYST’s early outcomes with a grain of salt. The trial, which may enhance the variety of potential Korlym prospects by a hundredfold, was initiated and funded by Koralym’s producer, a pharmaceutical agency named Corcept Therapeutics.


Cushing’s syndrome, a results of elevated cortisol ranges, is usually regarded as a uncommon situation, however a current research has steered that it’s exponentially extra prevalent in individuals with kind 2 diabetes than beforehand acknowledged. Cushing’s syndrome is understood to make diabetes (and hypertension) rather more tough to handle, and has a major danger of harmful long-term outcomes comparable to heart problems.

Although the connection between Cushing’s syndrome and sort 2 diabetes just isn’t but completely understood, DeFronzo encourages sufferers with difficult-to-control diabetes and hypertension to talk to their medical doctors about it.

“It’s an necessary illness to diagnose. Sufferers ought to go to their medical doctors and say, ‘Hey, do you suppose I may Cushing’s syndrome? May you’re employed me up for this?’”

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