Depression and type 2 diabetes: Inflammatory mechanisms of a psychoneuroendocrine co-morbidity

Abstract

Unipolar depression and diabetes mellitus each account for a significant proportion of the global burden of disease. Epidemiological literature suggests a bi-directional relationship between these two common disorders, and evidence from the molecular sciences supports a role for inflammation in the pathogenesis and pathophysiology of each disorder individually. Recent advances in understanding the neurobiology of depression have implicated dysfunction of the hypothalamus–pituitary–adrenal axis, neurotrophins, and inflammatory mediators in the development of this disorder. Similarly, dysregulated facets of both the innate and adaptive immune system have been implicated in the onset of insulin resistance and type 2 diabetes. This review draws upon an emerging body of epidemiological and mechanistic evidence to support the hypothesis that shared inflammatory mechanisms may represent a key biological link in this co-morbidity. Given the shared mechanisms of this co-morbidity, these patients may be excellent candidates for novel immune targeted pharmacotherapy.

Introduction

Unipolar depression and diabetes mellitus are two of the greatest challenges faced by modern healthcare systems. Both these diseases represent chronic, debilitating conditions that account for a substantial portion of the global burden of disease. The World Health Organisation (WHO) reports that unipolar depressive disorders account for 4.8% of the world's total burden of disease, and this figure increases to 5.1% and 8.2% in middle and high-income countries respectively. Similarly, the International Diabetes Federation (IDF) suggests around 6.6% of the world's population is currently living with diabetes mellitus, a figure which is expected to rise to 7.8% by 2030 (International Diabetes Federation, 2009). Significantly, projections suggest that by the year 2030 unipolar depressive disorders will become the number one contributor to morbidity worldwide and diabetes mellitus will also move into the top 10 (Mathers and Fat, 2008; pp. 28–37). The co-morbidity of these conditions increases the experience of both psychiatric and diabetic symptoms and complications (Gendelman et al., 2009, Katon et al., 2009, Koopmans et al., 2009, Lin et al., 2009, Lin et al., 2010, Maraldi et al., 2007, Molife, 2010, Musselman et al., 2003, Thaneerat et al., 2010, Winkley, 2008), amplifies spending on diabetes-related medical costs two and a half times, and increases total medical costs fourfold (Egede et al., 2002, Le et al., 2006). Additionally, the poorer glycaemic control associated with this co-morbidity is a key risk factor for cardiovascular disease, arguably the most important cause of mortality in high income nations (Richardson et al., 2008). Therefore from both altruistic and health economic points of view, this co-morbidity presents an important target for research and improvements in prevention and therapeutics.

Despite the significance of this relationship, little attention has been given to the biological pathways of this co-morbidity. The few studies that have included assessment of biomarkers found that adjustment for the markers of inflammation, C-reactive protein (CRP) and interleukin-6 (IL-6) does not attenuate the observed relationships between depression and diabetes (Carnethon et al., 2007, Golden et al., 2008, Maraldi et al., 2007). Although these few studies do not support the notion, many authors continue to speculate that inflammation may be the key biological pathway mediating this relationship. This suggestion is based upon the observation that inflammation has been implicated in the pathogenesis and pathophysiology of both depression and type 2 diabetes mellitus (T2DM) independently.

An emerging body of evidence from both human and animal studies demonstrates a reproducible sickness behaviour syndrome in response to elevations levels of cytokines and inflammatory mediators, the symptoms of which are argued to be analogous to depression (Dantzer et al., 2008). Depression is associated with dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis, neurotrophins, neurotransmitters, and inflammatory mediators. These disturbances may extend their influence peripherally through the establishment of a pro-inflammatory milieu which may have impacts on other body systems.

Similarly, several authors have discussed the existence of a pro-inflammatory state in insulin resistance and T2DM, including activation of several of the same aspects of immunity. This is frequently touted as a key link between T2DM and many conditions including those as significant as obesity and cardiovascular disease (Donath and Shoelson, 2011). Additionally, some evidence is emerging regarding the potential for these mediators to access and influence the brain.

Although it has previously been proposed that depression and T2DM may share inflammatory mechanisms, no paper has attempted to draw together the existing evidence to support this proposition. This review aims to fill that gap in the literature by undertaking a systematic review of the epidemiological, clinical, and laboratory evidence to support this hypothesis and proposing a mechanistic model of this co-morbidity.