Hypercortisolism in Difficult-to-Control Type 2 Diabetes: Laboratory Support for Initial Evaluation

Hypercortisolism in Difficult-to-Control Type 2 Diabetes: Laboratory Support for Initial Evaluation

This topic brief provides an overview of laboratory tests used in the initial evaluation of hypercortisolism among patients with difficult-to-control type 2 diabetes.

See also 4 related tests 5 related guides Test Guide List

TB_Hypercortisolism

Topic Brief

 

Hypercortisolism in Difficult-to-Control Type 2 Diabetes

Laboratory Support for Initial Evaluation

Clinical background

In primary care settings, many patients with type 2 diabetes (T2D) do not achieve glycemic goals despite taking multiple glucose-lowering medications.1,2 For some of these patients with “difficult-to-control” T2D, other underlying conditions may be impairing glycemic control.1,3 In particular, hypercortisolism (excessive cortisol levels) may contribute to difficult-to-control T2D but is not typically assessed during T2D management.1–3

Endogenous hypercortisolism is caused by either hypersecretion of adrenocorticotropic hormone (ACTH) or autonomous secretion of adrenal cortisol.4 Chronically elevated cortisol levels cause insulin resistance, hyperinsulinemia, and glucose intolerance and dysregulate the hypothalamic-pituitary-adrenal (HPA) axis.5 In addition to T2D, hypercortisolism is associated with hypertension, osteoporosis, and increased risk of cardiovascular disease and death.6

A large prospective study (CATALYST, ClinicalTrials.gov/Study/NCT05772169) found that 24% of patients with difficult-to-control T2D had hypercortisolism,1 and that treatment of the underlying hypercortisolism reduced hemoglobin A1c (HbA1c) levels, body weight, and use of glucose-lowering medications.2 These findings align with those of smaller studies, which together suggest that hypercortisolism may be a factor for many patients with difficult-to-control T2D.7,8

Hypercortisolism has a broad clinical spectrum and may not cause obvious signs or symptoms.4,6 Although the most severe form, overt Cushing syndrome, is characterized by features such as moon facies, striae, and “buffalo hump,” milder forms with minimal or no clinical signs are now thought to be more common.4,5 Therefore, experts suggest testing for hypercortisolism even in the absence of specific signs.5,6

Individuals suitable for testing

  • Patients with difficult-to-control T2D (eg, HbA1c >7.5% despite ≥3 glucose-lowering medications)

Test availability

Quest Diagnostics offers several tests for initial evaluation of hypercortisolism (Table).

Table. Laboratory Tests for Diagnosis of Hypercortisolism

Test code

Test name

Clinical use

29391

Dexamethasone

Aid interpretation of DST (test code 6921)

6921

Dexamethasone Suppression Test (DST), 1 Specimen

Diagnose hypercortisolism

Alternative testsa

4212

Cortisol, A.M.

Evaluate for hypercortisolism

367

Cortisol, Total

Evaluate for hypercortisolism
DST, dexamethasone suppression test.
a Direct serum cortisol test codes 4212 or 367 may be used to evaluate for hypercortisolism when ordered with 29391 and following the same protocol as for the DST. These tests are not recommended for patients taking prednisone or prednisolone, which can interfere with the assay.

Test selection

The dexamethasone suppression test (DST, test code 6921) is commonly used for initial evaluation of hypercortisolism in patients with T2D.9 The DST measures suppression of cortisol in response to an exogenous glucocorticoid. It involves administering 1 mg dexamethasone, a potent synthetic glucocorticoid, between 11:00 PM and midnight the night before serum cortisol levels are drawn (between 7:00 AM and 9:00 AM). In healthy patients, glucocorticoids suppress the HPA axis, inhibiting cortisol secretion, but in patients with hypercortisolism (in whom the HPA axis is resistant to negative feedback), cortisol levels remain elevated.4,10

To aid interpretation of DST results, simultaneously measuring dexamethasone levels (test code 29391) can help confirm they are sufficient to suppress cortisol.4,10 Low dexamethasone levels (due to nonadherence or insufficient bioavailability) can cause false-positive DST results.11,12

Although the DST’s diagnostic accuracy for hypercortisolism in the context of difficult-to-control T2D has not been determined, it has high sensitivity (98.6%) and moderate specificity (90.6%) for Cushing syndrome.13 Thus, the test is useful for ruling out hypercortisolism when clinical suspicion is low (eg, when screening patients with T2D), but other tests are needed to confirm the diagnosis (Figure1,6,12).

Figure. Initial Evaluation of Hypercortisolism in Patients With Difficult-to-Control Type 2 Diabetes

Test interpretation

DST cortisol levels <1.8 μg/dL are considered normal and strongly suggest against hypercortisolism.4,10 Assuming adequate dexamethasone levels (≥180 ng/dL), cortisol levels ≥1.8 μg/dL are consistent with hypercortisolism, and patients with these results should be referred to an endocrinologist for confirmatory testing.4 If dexamethasone levels are inadequate (<180 ng/dL), testing may need to be repeated.

The DST is not suitable for patients who are pregnant, are taking estrogen-containing oral contraceptives, or have chronic active hepatitis, as these conditions raise cortisol levels and may cause false-positive results.4,10,11 If adequate dexamethasone levels were not confirmed, false-positive or false-negative results can also be caused by conditions or medications that affect dexamethasone absorption or metabolism, including celiac disease, chronic diarrhea, and medications that act on CYP3A4 (eg, phenobarbital, fluoxetine, and cimetidine).4,10,11

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. doi:10.2337/dc24-2841
  2. 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. doi:10.2337/dc25-1055
  3. Nieman LK, Muniyappa R. Unmasking hypercortisolism in difficult-to-control type 2 diabetes: a useful paradigm shift? Diabetes Care. 2025;48(12):1994-1996. doi:10.2337/dci25-0038
  4. 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(5):1526-1540. doi:10.1210/jc.2008-0125
  5. DeFronzo RA, Auchus RJ. Cushing syndrome, hypercortisolism, and glucose homeostasis: a review. Diabetes. 2025;74(12):2168-2178. doi:10.2337/db25-0120
  6. Miller BS, Auchus RJ. Evaluation and treatment of patients with hypercortisolism. JAMA Surg. 2020;155(12):1152-1159. doi:10.1001/jamasurg.2020.3280
  7. Chiodini I, Morelli V, Salcuni AS, et al. Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism. J Clin Endocrinol Metab. 2010;95(6):2736-2745. doi:10.1210/jc.2009-2387
  8. Costa DS, Conceição FL, Leite NC, et al. Prevalence of subclinical hypercortisolism in type 2 diabetic patients from the Rio de Janeiro Type 2 Diabetes Cohort Study. J Diabetes Complicat. 2016;30(6):1032-1038. doi:10.1016/j.jdiacomp.2016.05.006
  9. Guarnotta V, Giordano C, Reimondo G. Who and how to screen for endogenous hypercortisolism in type 2 diabetes mellitus or obesity. J Endocrinol Investig. 2025;48(Suppl 1):47-59. doi:10.1007/s40618-024-02455-7
  10. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847-875. doi:10.1016/s2213-8587(21)00235-7
  11. Petersenn S. Overnight 1 mg dexamethasone suppression test and 24 h urine free cortisol—accuracy and pitfalls when screening for Cushing’s syndrome. Pituitary. 2022;25(5):693-697. doi:10.1007/s11102-022-01249-5
  12. Roper SM. Yield of serum dexamethasone measurement for reducing false-positive results of low-dose dexamethasone suppression testing. J Appl Lab Med. 2021;6(2):480-485. doi:10.1093/jalm/jfaa193
  13. Galm BP, Qiao N, Klibanski A, et al. Accuracy of laboratory tests for the diagnosis of Cushing syndrome. J Clin Endocrinol Metab. 2020;105(6):dgaa105. doi:10.1210/clinem/dgaa105

Content reviewed 2/2026

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This topic brief provides an overview of laboratory tests used in the initial evaluation of hypercortisolism among patients with difficult-to-control type 2 diabetes.

Test Guide List

TB_Hypercortisolism

Topic Brief

 

Hypercortisolism in Difficult-to-Control Type 2 Diabetes

Laboratory Support for Initial Evaluation

Clinical background

In primary care settings, many patients with type 2 diabetes (T2D) do not achieve glycemic goals despite taking multiple glucose-lowering medications.1,2 For some of these patients with “difficult-to-control” T2D, other underlying conditions may be impairing glycemic control.1,3 In particular, hypercortisolism (excessive cortisol levels) may contribute to difficult-to-control T2D but is not typically assessed during T2D management.1–3

Endogenous hypercortisolism is caused by either hypersecretion of adrenocorticotropic hormone (ACTH) or autonomous secretion of adrenal cortisol.4 Chronically elevated cortisol levels cause insulin resistance, hyperinsulinemia, and glucose intolerance and dysregulate the hypothalamic-pituitary-adrenal (HPA) axis.5 In addition to T2D, hypercortisolism is associated with hypertension, osteoporosis, and increased risk of cardiovascular disease and death.6

A large prospective study (CATALYST, ClinicalTrials.gov/Study/NCT05772169) found that 24% of patients with difficult-to-control T2D had hypercortisolism,1 and that treatment of the underlying hypercortisolism reduced hemoglobin A1c (HbA1c) levels, body weight, and use of glucose-lowering medications.2 These findings align with those of smaller studies, which together suggest that hypercortisolism may be a factor for many patients with difficult-to-control T2D.7,8

Hypercortisolism has a broad clinical spectrum and may not cause obvious signs or symptoms.4,6 Although the most severe form, overt Cushing syndrome, is characterized by features such as moon facies, striae, and “buffalo hump,” milder forms with minimal or no clinical signs are now thought to be more common.4,5 Therefore, experts suggest testing for hypercortisolism even in the absence of specific signs.5,6

Individuals suitable for testing

  • Patients with difficult-to-control T2D (eg, HbA1c >7.5% despite ≥3 glucose-lowering medications)

Test availability

Quest Diagnostics offers several tests for initial evaluation of hypercortisolism (Table).

Table. Laboratory Tests for Diagnosis of Hypercortisolism

Test code

Test name

Clinical use

29391

Dexamethasone

Aid interpretation of DST (test code 6921)

6921

Dexamethasone Suppression Test (DST), 1 Specimen

Diagnose hypercortisolism

Alternative testsa

4212

Cortisol, A.M.

Evaluate for hypercortisolism

367

Cortisol, Total

Evaluate for hypercortisolism
DST, dexamethasone suppression test.
a Direct serum cortisol test codes 4212 or 367 may be used to evaluate for hypercortisolism when ordered with 29391 and following the same protocol as for the DST. These tests are not recommended for patients taking prednisone or prednisolone, which can interfere with the assay.

Test selection

The dexamethasone suppression test (DST, test code 6921) is commonly used for initial evaluation of hypercortisolism in patients with T2D.9 The DST measures suppression of cortisol in response to an exogenous glucocorticoid. It involves administering 1 mg dexamethasone, a potent synthetic glucocorticoid, between 11:00 PM and midnight the night before serum cortisol levels are drawn (between 7:00 AM and 9:00 AM). In healthy patients, glucocorticoids suppress the HPA axis, inhibiting cortisol secretion, but in patients with hypercortisolism (in whom the HPA axis is resistant to negative feedback), cortisol levels remain elevated.4,10

To aid interpretation of DST results, simultaneously measuring dexamethasone levels (test code 29391) can help confirm they are sufficient to suppress cortisol.4,10 Low dexamethasone levels (due to nonadherence or insufficient bioavailability) can cause false-positive DST results.11,12

Although the DST’s diagnostic accuracy for hypercortisolism in the context of difficult-to-control T2D has not been determined, it has high sensitivity (98.6%) and moderate specificity (90.6%) for Cushing syndrome.13 Thus, the test is useful for ruling out hypercortisolism when clinical suspicion is low (eg, when screening patients with T2D), but other tests are needed to confirm the diagnosis (Figure1,6,12).

Figure. Initial Evaluation of Hypercortisolism in Patients With Difficult-to-Control Type 2 Diabetes

Test interpretation

DST cortisol levels <1.8 μg/dL are considered normal and strongly suggest against hypercortisolism.4,10 Assuming adequate dexamethasone levels (≥180 ng/dL), cortisol levels ≥1.8 μg/dL are consistent with hypercortisolism, and patients with these results should be referred to an endocrinologist for confirmatory testing.4 If dexamethasone levels are inadequate (<180 ng/dL), testing may need to be repeated.

The DST is not suitable for patients who are pregnant, are taking estrogen-containing oral contraceptives, or have chronic active hepatitis, as these conditions raise cortisol levels and may cause false-positive results.4,10,11 If adequate dexamethasone levels were not confirmed, false-positive or false-negative results can also be caused by conditions or medications that affect dexamethasone absorption or metabolism, including celiac disease, chronic diarrhea, and medications that act on CYP3A4 (eg, phenobarbital, fluoxetine, and cimetidine).4,10,11

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. doi:10.2337/dc24-2841
  2. 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. doi:10.2337/dc25-1055
  3. Nieman LK, Muniyappa R. Unmasking hypercortisolism in difficult-to-control type 2 diabetes: a useful paradigm shift? Diabetes Care. 2025;48(12):1994-1996. doi:10.2337/dci25-0038
  4. 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(5):1526-1540. doi:10.1210/jc.2008-0125
  5. DeFronzo RA, Auchus RJ. Cushing syndrome, hypercortisolism, and glucose homeostasis: a review. Diabetes. 2025;74(12):2168-2178. doi:10.2337/db25-0120
  6. Miller BS, Auchus RJ. Evaluation and treatment of patients with hypercortisolism. JAMA Surg. 2020;155(12):1152-1159. doi:10.1001/jamasurg.2020.3280
  7. Chiodini I, Morelli V, Salcuni AS, et al. Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism. J Clin Endocrinol Metab. 2010;95(6):2736-2745. doi:10.1210/jc.2009-2387
  8. Costa DS, Conceição FL, Leite NC, et al. Prevalence of subclinical hypercortisolism in type 2 diabetic patients from the Rio de Janeiro Type 2 Diabetes Cohort Study. J Diabetes Complicat. 2016;30(6):1032-1038. doi:10.1016/j.jdiacomp.2016.05.006
  9. Guarnotta V, Giordano C, Reimondo G. Who and how to screen for endogenous hypercortisolism in type 2 diabetes mellitus or obesity. J Endocrinol Investig. 2025;48(Suppl 1):47-59. doi:10.1007/s40618-024-02455-7
  10. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847-875. doi:10.1016/s2213-8587(21)00235-7
  11. Petersenn S. Overnight 1 mg dexamethasone suppression test and 24 h urine free cortisol—accuracy and pitfalls when screening for Cushing’s syndrome. Pituitary. 2022;25(5):693-697. doi:10.1007/s11102-022-01249-5
  12. Roper SM. Yield of serum dexamethasone measurement for reducing false-positive results of low-dose dexamethasone suppression testing. J Appl Lab Med. 2021;6(2):480-485. doi:10.1093/jalm/jfaa193
  13. Galm BP, Qiao N, Klibanski A, et al. Accuracy of laboratory tests for the diagnosis of Cushing syndrome. J Clin Endocrinol Metab. 2020;105(6):dgaa105. doi:10.1210/clinem/dgaa105

Content reviewed 2/2026

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