Diabetes in Cushing's disease: age, hypercortisolism, central adiposity, and β-cell stress as determinants of glycaemia.

Objective: Diabetes is a frequent complication of Cushing's disease, but metabolic differences between normal glucose tolerance, prediabetes, and diabetes remain incompletely characterised. We aimed to characterise glucose metabolism across these groups, assess abnormalities in patients with normal glucose tolerance, and identify clinical, hormonal, and body-composition factors associated with glycaemia. Design: Cross-sectional analysis of a prospective cohort with matched healthy controls. Material and methods: The study included 50 patients with Cushing's disease and 52 age- and sex-matched healthy controls who underwent detailed metabolic phenotyping, including multi-timepoint oral glucose tolerance testing with assessment of insulin sensitivity and β-cell compensatory function, and body composition analysis by dual-energy X-ray absorptiometry. Forward stepwise linear regression was performed separately in each group to identify variables independently associated with HbA1c. Results: Glucose metabolism disturbances affected 68% of patients with Cushing's disease, including prediabetes in 42% and diabetes in 26%, with most diabetes cases previously undiagnosed. Even patients with normal glucose tolerance showed lower insulin sensitivity and enhanced β-cell secretory activity compared with healthy controls. Prediabetes was characterised mainly by lower insulin sensitivity with preserved β-cell compensation, whereas diabetes was associated with a reduced insulin-to-glucose AUC ratio without significantly lower insulin sensitivity than in prediabetes. In Cushing's disease, age, morning cortisol, waist-to-hip ratio, and proinsulin were independently associated with HbA1c, explaining 59.5% of its variance; in controls, only age and BMI were associated with HbA1c. BMI was not significantly correlated with HbA1c in Cushing's disease, whereas trunk fat percentage was positively associated with HbA1c. Conclusions: In Cushing's disease, reduced insulin sensitivity with preserved β-cell compensation is detectable even in patients with normal glucose tolerance, whereas overt diabetes is characterised by impaired β-cell compensation without significantly lower insulin sensitivity than in prediabetes. Age, morning cortisol, waist-to-hip ratio, and proinsulin are independently associated with HbA1c. Central fat distribution may be more closely related to glycaemia than BMI.