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Hypercortisolism in Difficult-To-Control Type II Diabetes

Test codes:

  • 367 (Cortisol, Total) 
  • 4212 (Cortisol, A.M.)
  • 6921 (Dexamethasone Suppression Test [DST], 1 Specimen)
  • 29391 (Dexamethasone)

Difficult-to-control type II diabetes (T2DM) is when a patient is receiving treatment for T2DM but still has elevated blood pressure, elevated serum glucose (hyperglycemia), and/or dyslipidemia. Often, patients will be on multiple medications (ie, insulin and statins) to regulate the complications of T2DM but still have HbA1c > 7.5%.

In patients with difficult-to-control T2DM, elevated cortisol may be a contributing factor in the inability to improve these conditions. Recent studies have shown that up to 25% of patients with difficult-to-control T2DM have elevated cortisol levels (hypercortisolism). 1

Both hypercortisolism and Cushing syndrome can be diagnosed with a dexamethasone suppression test. Dexamethasone is administered at 11:00 PM the night before a morning blood draw measuring cortisol. If cortisol is not suppressed (>1.8 µg/dL), then the diagnosis may be hypercortisolism or Cushing syndrome.

Although Cushing syndrome may be associated with “moon face” and other physical manifestations, these are not always present. Hypercortisolism is when a patient has elevated cortisol but no clear physical manifestations, while Cushing syndrome is high cortisol with clear physical manifestations such as abdominal obesity. 

Cortisol can induce insulin resistance.3 Cortisol administration in high doses can cause glucose intolerance, and chronic administration of cortisol can lead to the development of diabetes.2 Cortisol belongs to a family of steroids called the glucocorticoids that inhibit the cellular uptake of glucose and induce lipolysis, which increases glucose and free fatty acid levels in the serum. As elevated cortisol levels drive insulin resistance, this creates a positive feedback loop within the hypothalamic pituitary axis (HPA) that continues to disturb glucose homeostasis, which can contribute to the progression of type II diabetes mellitus and metabolic syndrome.4

While it has been appreciated for quite some time that patients with Cushing syndrome have an increased risk for cardiometabolic disorders and T2DM, it has only recently been appreciated that in patients diagnosed with T2DM, elevated cortisol may be driving pathogenesis.2

Hypercortisolism is diagnosed with a dexamethasone suppression test (TC 6921). Patients are prescribed 1 mg of dexamethasone to be taken at 11:00 PM the night before an 8:00 AM cortisol blood draw. If cortisol levels are not suppressed (>1.8 µg/dL) and dexamethasone concentrations are adequate, then conditions are consistent with hypercortisolism.5

The ability to identify hypercortisolism in patients with difficult-to-control type II diabetes is beneficial in that potential adrenal tumor sources of cortisol can be identified and removed and/or patients can be treated with glucocorticoid antagonists.6

Results from the recent Catalyst study show that mifepristone treatment lowered HbA1c values with consequent improvements in weight and reductions in the use of glucose-lowering medication in patients with difficult-to-control type II diabetes.6

References

  1. Buse JB, Kahn SE, Aroda VR, et al. Prevalence of hypercortisolism in difficult-to-control type 2 diabetes. Diabetes Care. 2025;48(12):2012-2020.
  2. DeFronzo RA, Auchus RJ. Cushing Syndrome, hypercortisolism, and glucose homeostasis: a review. Diabetes. 2025;74(12):2168-2178.
  3. Rizza RA, Mandarino LJ, Gerich JE. Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor defect of insulin action. J Clin Endocrinol Metab. 1982;54(1):131-138.
  4. Lundqvist MH, Pereira MJ, Almby K, et al. Regulation of the cortisol axis, glucagon, and growth hormone by glucose is altered in prediabetes and type 2 diabetes. J Clin Endocrinol Metab. 2024;109:e675-e688.
  5. Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing’s Syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008; 93: 1526-1540.
  6. DeFronzo RA, Fonseca V, Aroda VR, et al. Inadequately controlled type 2 diabetes and hypercortisolism: improved glycemia with mifepristone treatment. Diabetes Care. 2025;48(12):2036-2044.

 

This FAQ is provided for informational purposes only and is not intended as medical advice. Test selection and interpretation, diagnosis, and patient management decisions should be based on the clinician’s education, clinical expertise, and assessment of the patient.

 

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