Chronic Inflammation Mediates the Association between Cortisol and Hyperglycemia: Findings from the Cross-Sectional Population-Based KORA Age Study.

Hamimatunnisa Johar,Wolfgang Koenig,Karl-Heinz Ladwig,Johannes Kruse,Derek Spieler,Christian Herder,Martin Bidlingmaier,Wolfgang Rathmann,Annette Peters

doi:10.3390/jcm10132751

Abstract

(1) Background: The study aimed to investigate the role of subclinical inflammation on the association between diurnal cortisol patterns and glycaemia in an aged population. (2) Methods: Salivary cortisol, interleukin-6 (IL-6) and glycated haemoglobin (HbA1c) were analysed in a sample of 394 men and 364 women (mean age = 5 ± 6.3, 65–90 years). The ratio of morning after awakening and late-night cortisol was calculated as an indication of diurnal cortisol slope (DCS). Multivariable regression models were run to examine whether IL-6 mediates the relationship between the DCS and glycaemia. The Sobel test and bootstrapping methods were used to quantify the mediation analyses. (3) Results: In comparison to normoglycaemic counterparts (n = 676, 89.2%), an increase in IL-6 concentrations, in individuals with hyperglycaemia (HbA1c ≥ 6.5%) (n = 82, 10.8%) (p = 0.04), was significantly associated with a flatter DCS. The link between flatter DCS and elevated HbA1c level was significant mediated by a heightened IL-6 level. Our results do not suggest reverse-directionality, whereby cortisol did not mediate the association of IL-6 with HbA1c. (4) Conclusions: In our sample, the relation between flatter DCS and hyperglycaemia was partly explained by IL-6 levels. The paradigm of subclinical inflammation-mediated cortisol response on glucose metabolism could have widespread implications for improving our understanding of the pathophysiology of type 2 diabetes mellitus.

Highlights

The role of psychological stress factors in the pathogenesis of type 2 diabetes is increasingly acknowledged [1,2], the exact mechanisms through which psychosocial stress act on hyperglycaemia are not well understood
There were no significant differences between glycaemic groups in sociodemographic and psychological factors, overall cortisol output (AUC), serum cortisol levels, smoking status, and physical activity
We found that a flatter diurnal cortisol slope (DCS) was significantly associated with elevated IL-6 levels in the total population (p = 0.008) and the effect was strongest in individuals with hyperglycaemia, even after adjusting for age and sex p = 0.004)

Summary

Introduction

The role of psychological stress factors in the pathogenesis of type 2 diabetes is increasingly acknowledged [1,2], the exact mechanisms through which psychosocial stress act on hyperglycaemia are not well understood. There is little doubt that impairments of the hypothalamic-pituitary-adrenal (HPA) axis plays a major role in the crosstalk between psychosocial stress and the metabolic disruption. Stress-induced disruption of the HPA axis can result either in glucocorticoid excess, presumably based on altered feedback regulation of cortisol, or, in a blunted glucocorticoid secretion, most likely due to an impaired glucocorticoid receptor sensitivity or decreased responsiveness to glucocorticoids, a phenomenon known as glucocorticoid resistance [4]. A mismatch between the level of the cortisol awakening reaction (CAR) in the morning and the nadir in the evening, leading to a flatter diurnal cortisol slope (DCS), is a valid indicator of impaired HPA axis functioning [5]. A meta-analysis of 80 studies recently evidenced that a flatter DCS was associated with poorer general health outcomes [6]

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