High Evening Cortisol Levels Linked to Increased Risk for Type 2 Diabetes

Commentary by Ruth Hackett MSc and Valentina Vicennati, MD

Diabetes kit containing various itemsHigh evening cortisol levels were predictive of new-onset type 2 diabetes in a prospective cohort study published in the February the Journal of Clinical Endocrinology and Metabolism.

“While cross-sectional evidence has shown that cortisol patterning differs between healthy individuals and those with diabetes, this study shows for the first time that dysregulation of cortisol in daily life can predispose people to new-onset diabetes later in life independently of traditional risk factors,” said lead author Ruth Hackett MSc, Department of Epidemiology and Public Health, University College London.

“This is an interesting paper, underlying the importance of the HPA axis activity and rhythmicity on metabolic alterations,” commented Valentina Vicennati, MD, Specialist in Endocrinology in the Department of Medical and Surgical Sciences at Alma Mater Studiorum-University of Bologna. “HPA axis activity (ie, cortisol) should be considered a marker of type 2 diabetes development; a biorhythm of cortisol should be included in the screening of metabolic alterations,” Dr. Vicennati said.

Data From the Whitehall II Study
The study involved 3,270 people (75.1% men) enrolled in the Whitehall II study. The participants underwent salivary cortisol measurement at six intervals throughout a single day between 2002-2004. After 9 years of follow-up, 210 participants (6.4%) had new-onset diabetes and 518 individuals (15.8%)  had impaired fasting glucose (IFG).

Increased evening cortisol level collected in 2002-2004 was predictive of new-onset T2D in 2012-2013 (odds ratio [OR], 1.18; P=0.035) after adjusting for age, sex, smoking, grade of employment, body mass index >23, cardiovascular medication, history of coronary heart disease, and IFG. In addition, participants with new-onset type 2 diabetes showed a trend toward a flatter cortisol slope (OR, 1.15; P=0.075), which may be caused by low waking or high evening cortisol levels, the authors noted in the study.

When the analysis was broadened to include development of type 2 diabetes or IFG, patients with either endpoint were significantly more likely to have had a higher evening cortisol level (OR, 1.10; P=0.044) and a flatter cortisol slope (OR, 1.12, P=0.015) 9 years previously.

Potential Mechanism Underlying the Link Between Cortisol Dysregulation and Development of Type 2 Diabetes
Several proposed mechanisms underlying the link between cortisol dysregulation and future problems with glucose metabolism were proposed by the authors including cortisol’s ability to raise glucose through gluconeogenesis. “Cortisol can directly act on the β cells of the pancreas and in this way can directly reduce insulin sensitivity and insulin secretion,” Ms. Hackett explained.

“Another potential mechanism is through obesity—obesity is highly predictive of diabetes and prediabetes (as measured using impaired fasting glucose in this study) and fat tissue is a source of glucocorticoid receptors,” Ms. Hackett noted. “However, we controlled for body mass index in this study, so this suggests that there is a link between cortisol and future diabetes independently of this pathway.”

“Inflammation is another potential pathway that could be involved as cortisol is involved in regulating inflammation, and we know that inflammation plays a role in diabetes,” Ms. Hackett said.

In addition, stress may underlie the relationship. “Psychosocial stress factors increase the risk of type 2 diabetes and these factors are associated with poorer outcomes in diabetes patients,” Dr. Hackett said. “It is plausible that our results could be due to long-term changes in circadian process as a result of chronic stress that predisposed these individuals to developing prediabetes or diabetes later in life.”

Interestingly, “the same dysregulation (heightened evening cortisol levels and flattened slope) has previously been shown to have predictive value for other conditions such as cardiovascular disease,” she said.

Dr. Vicennati added that “a well-preserved cortisol biorhythm might avoid metabolic alterations. On the contrary, if the HPA axis activity is altered (ie, subclinical Cushing’s syndrome, Cushing’s syndrome) we should have metabolic disorders.”1

“As mentioned in the study, glucocorticoid-overtreated patients with adrenal insufficiency, especially in the evening, develop insulin resistance and type 2 diabetes," Dr. Vicennati said. “The same findings have been found in people with misalignment of the HPA axis (ie, taxi drivers, nocturnal jobs).”

March 11, 2016

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