Cortisol and Type 2 Diabetes: Testing and Talking to Your Doctor

In the fourth episode of our insights series, Cortisol and Type 2 Diabetes: What Patients Need to Know, John Buse, M.D., Ph.D., maps out the diagnostic landscape for patients and providers who suspect that cortisol is sabotaging their metabolic health. Buse establishes that the gold standard for initial screening is the overnight dexamethasone suppression test. To complete this test, a patient takes a 1mg tablet of dexamethasone at 11:00 p.m. and provides a morning blood sample the next day, generally at 8:00 a.m. and ideally before 9:00 a.m. If the resulting blood cortisol level is greater than 1.8, it indicates hypercortisolism. Buse notes that while this screening method is highly sensitive, a positive result should reflexively trigger a secondary test on that same blood sample to check actual dexamethasone levels, confirming that the patient absorbed the medication properly and isn't a rare "hyper-metabolizer" of steroid hormones.

Once hypercortisolism is confirmed, the clinical team must uncover the underlying cause, or etiology, of the hormone surge. Buse explains that on a separate day, providers will measure early morning fasting levels of ACTH and DHEA sulfate (DHEAS). If these levels are low, it points directly to autonomous cortisol secretion originating from the adrenal gland itself. Conversely, if ACTH and DHEAS are high, the root cause may be pituitary overproduction, classically known as Cushing's disease, or an extra-pituitary source. Buse acknowledges that while other tests exist, such as late-night salivary cortisol or a 24-hour urine collection, they are less sensitive and can create a frustrating diagnostic "interspace" if a patient screens positive on the initial overnight test but negative on the alternative ones.

To help resolve this clinical grey area, the episode highlights ground-breaking insights from the Catalyst study. In this trial, patients with elevated cortisol and low-ish ACTH and DHEA sulfate were randomized to receive either a placebo or mifepristone — a cortisol receptor antagonist that acts as a cortisol-directed therapy. The study demonstrated that patients taking mifepristone experienced dramatic improvements in their hemoglobin A1C and successfully lost weight, an outcome that aligns with Buse’s own anecdotal experience where patients simply feel much better. While mifepristone does come with potential adverse effects, with hypokalemia (low potassium) being the most common in practice, Buse emphasizes that using a highly sensitive overnight screening test can serve as a vital gateway to initiating a targeted therapeutic trial, ultimately helping complex type 2 diabetes patients finally achieve optimal glycemic control.