ABSTRACT: Hypercortisolism is associated with insulin resistance (IR) and diabetes mellitus (DM); however, to our knowledge prior studies have not examined the association of diurnal cortisol curve features with measures of glycemia or IR in a population-based setting. Using log-transformed salivary cortisol data on 850 ethnically diverse men and women from the Multi-Ethnic Study of Atherosclerosis, we investigated the cross-sectional association of cortisol curve features with (1) glycemia in those with and without DM and (2) IR, in non-diabetic subjects. The log-transformed salivary cortisol curve features included wake-up cortisol, cortisol awakening response (CAR), early decline slope (30min to 2h post-awakening), late decline slope (2h post-awakening to bedtime), overall decline slope (0min to bedtime, excluding 30min cortisol), bedtime cortisol and total area under the curve (AUC). Overall, following multivariable adjustment, among those with diabetes mellitus (DM), early decline slope, overall decline slope, bedtime cortisol, and AUC were significantly and positively associated with a 5.4% (95% CI: 1.3, 9.7), 54.7% (95% CI: 12.4, 112.9), 4.0% (95% CI: 1.6,6.4), and 6.8% (95% CI: 3.3,10.4) higher HbA1c per 1 unit increase in log cortisol feature, respectively. Cortisol curve features were not associated with HbA1c among non-diabetic participants; however, wake-up cortisol and AUC were associated with a 8.2% lower (95% CI: -13.3,-2.7) and 7.9% lower (95% CI: -14.6, -0.6) log HOMA-IR, respectively. This was attenuated by adjustment for waist circumference. Among participants with DM, cortisol curve parameters suggestive of higher hypothalamic-pituitary-adrenal (HPA) axis activity and dysfunction were associated with higher HbA1c. In non-diabetic participants, greater HPA activity was paradoxically associated with lower insulin resistance.
