Stress and T2DM
The first reports on a stress-diabetes link came from physicians during the 17th and 18th centuries. It was not until the early 1980s that interest in the stress-diabetes link reappeared. In spite of the well-defined pathways and candidate mechanisms, the causal relationship between stress and type 2 diabetes (T2D), has not been confirmed by empirical evidence so far. This article outlines the hypothesized mechanisms linking psychosocial stress to T2D and summarizes the evidence on this controversial topic
Acute and chronic stress during human evolution
Figure 1: Direct pathways of neuroendocrine activation leading to the fight-or-flight response (a) and how these could potentially affect type 2 diabetes risk after chronic activation (b). The acute stress response (aka, fight-or-flight response) evolved in humans as a rapid response to the challenge of external, potentially lethal, but short-termed physical threats. In such situations, the human body needs two basic things: (i) a direct and immediate boost of energy and (ii) a way as to reduce damage and prevent infection in case of injury. These physiological changes are brought about by the activation of two main axes of neuroendocrine response, the sympathetic-adrenomedullary (sympatho-adrenal) axis and the hypothalamic-pituitary-adrenocortical (HPA) axis. For an overview of the physiological changes brought about by acute activation of these axes, refer to figure 1a.
In addition to bursts of acute stress, chronic stress was also not uncommon in human evolution. In contrast to the acute stress situation, chronic stress was more closely linked with periods of extended perceived threat and insecurity, such as periods of extreme weather conditions (i.e. an ice age or severe drought) and periods of food scarcity and famine. In situations like these, the body is under a state of chronic or repeated activation of the fight-or-flight response. In addition, the body enters a ‘mode’ of energy conservation, which comprises a reduction in unnecessary energy expenditure (physical activity) and an increase in food intake in case of availability, as well as metabolic changes which lead to more efficient accumulation of body energy reserves (i.e. body fat deposition).
Acute and chronic stress in modern societies
In modern societies, people are living in an environment in which, maybe for the first time in human history, the systems described above instead of being protective, are harmful. The material and social environment has changed beyond recognition over the past 10,000 years and especially the last 200 years after the industrial revolution. The biology of modern humans, however, has remained essentially the same as it was in those early humans that dared the trip out of Africa ~60,000 years ago. In the modern day environment, physical threats are rare, but the social organization of everyday life very frequently generates psychological and social threats, which have the potential to activate the fight-or-flight response repeatedly and chronically.
Due to the fact that psychological stress is so much embedded within the social structure of modern societies, it is usually referred to as psychosocial stress, and conditions or events that have the potential to elicit such stress are termed psychosocial stressors.
The effects of psychosocial stress on the body can be broadly grouped into direct and indirect. Direct effects refer to the mechanisms through which exposure to psychosocial stressors per se leads to pathophysiological changes (the concept of embodiment).The term psychoneuroendocrine activation is commonly used to describe this process. Indirect effects refer to the mechanisms by which psychosocial stress influences health behaviours (dietary habits and physical activity, smoking and alcohol consumption), which in turn affect health.
Figure 1b displays the direct pathophysiological alterations potentially arising by chronic activation of the two stress axes. Such chronic or repeated activation of the acute stress response is thought to lead to a condition referred to as allostatic load, where the body is forced to chronically alter its normal physiology as a response of coping with an environmental stressor. In addition to the mechanisms displayed in figure 1b, increased cortisol (the major glucocorticoid of HPA activation) can interfere with the normal regulation of blood glucose by altering the body’s release and sensitivity to insulin, while adrenaline increases hepatic glucose output .
Indirect pathways could potentially link psychosocial stressors to disease through health behaviours. Chronic activation of the fight-or-flight response could potentially alter neurotransmitter balance in the brain. In particular, imbalances in brain concentrations of dopamine (neurotransmitter involved in motivation and reward) and serotonin (neurotransmitter involved in mood and appetite) could increase the salience of pleasurable or compulsive activities , such as smoking, consumption of high fat/high sugar foods, avoidance of physical activity and increased consumption of alcohol . These behaviours in turn increase the risk of T2D.
Stress and diabetes: the evidence[a]
Experimental studies in humans
Despite numerous reports of the involvement of psychosocial stress in blood glucose regulation among diabetic patients, very few studies have actually investigated the effect of psychoneuroendocrine activation on glucose metabolism in non-diabetic individuals. One such study is a recent cross-over trial among 15 overweight male Bosnian war refugees with post-traumatic stress disorder, in whom acute psychological stress induced postprandial blood glucose peaks and elevated insulin levels and a selective decrease of systemic immune markers and the proinflammatory regulator of the NF kappaB cascade, which are associated with T2D.
Interestingly, stress-induced hyperglycemia is a common problem in patients admitted to intensive care units, even when glucose homeostasis has previously been normal. This is an excellent paradigm of a ‘natural’ experiment, clearly indicating the potential of acute psychological stress to dysregulate glucose metabolism. Experimental research on the potential of stress to induce permanent metabolic deregulation is still lacking however.
Unlike experimental studies, observational epidemiological studies rely on self-reports of individuals regarding their exposure to several psychosocial stressors, including major life events, job and financial insecurity, social isolation and psychosocial stress at work and thus are able to assess the effect of chronic rather than acute stress. In some studies, objective measures of stress (i.e. biomarkers) have been used[b].
The first meta-analysis on the stress-diabetes association was by Chida & Hamer (2008) and concluded that adverse psychosocial factors were significantly associated with poor glucose regulation among diabetic patients but found no evidence for an association with incident T2D. In contrast, a more recent systematic review by Pouwer et al (2010) concluded that there was evidence that emotional stress, anxiety, anger and hostility increased T2D risk in prospective epidemiological studies, while evidence was conflicting for adverse life events and work stressors. Two meta-analyses concentrating on the role of work stress on T2D found conflicting evidence, with the one reporting no evidence for an association and the other showing evidence for an association between job strain and T2D among cross-sectional.
Figure 2: Hazard Ratio (95% Confidence Intervals) for the association between different categories of stress and obesity (cross-classification) and incident type 2 diabetes in the Whitehall II study.One of the reasons for the inconsistent findings observed is the fact that psychosocial stress appears to affect risk of T2D differentially according to other factors, such as gender and body weight status. Analyzing data from the Whitehall II study, it was found that psychosocial stress at work doubles the risk of T2D among women but does not increase risk among men. Interestingly, this adverse effect of stress among women was further exacerbated in the presence of obesity(figure 2).
^ Brunner E. Stress and the biology of inequality. BMJ 1997; 314 (7092):1472-1476.
^ Krieger N. Embodiment: a conceptual glossary for epidemiology. J.Epidemiol.Community Health 2005; 59(5): 350-55.
^ McEwen BS. Stress, adaptation, and disease. Allostasis and allostatic load. Ann.N.Y.Acad.Sci., 1998; 840:33-44.
^ Dallman M.F, Akana SF, Strack AM, Scribner KS, Pecoraro N, et al. Chronic stress-induced effects of corticosterone on brain: direct and indirect. Ann.N.Y.Acad.Sci. 2004; 1018: 141-150.
^ Ismail K, Winkley K, Rabe-Hesketh S. Systematic review and meta-analysis of randomised controlled trials of psychological interventions to improve glycaemic control in patients with type 2 diabetes. Lancet. 2004; 363(9421):1589-97.
^ Nowotny B, Cavka M, Herder C, Löffler H, Poschen U, et al. Effects of acute psychological stress on glucose metabolism and subclinical inflammation in patients with post-traumatic stress disorder..Horm Metab Res. 2010; 42(10): 746-53.
^ McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin. 2001; 17(1):107-24.
^ Chida Y, Hamer M. An association of adverse psychosocial factors with diabetes mellitus: a meta-analytic review of longitudinal cohort studies.Diabetologia. 2008; 51(12): 2168-78.
^ Pouwer F, Kupper N, Adriaanse MC. Does emotional stress cause type 2 diabetes mellitus? A review from the European Depression in Diabetes (EDID) Research Consortium. Discov Med. 2010; 9(45):112-8.
^ Cosgrove MP, Sargeant LA, Caleyachetty R, Griffin SJ. Work-related stress and Type 2 diabetes: systematic review and meta-analysis. Occup Med (Lond), 2012; 62(3):167-173.
^ Nyberg ST, Fransson EI, Heikkilä K, Alfredsson L, Casini A, et al. Job strain and cardiovascular disease risk factors: meta-analysis of individual-participant data from 47,000 men and women. PLoS One. 2013; 8(6):e67323.
^ Heraclides A, Chandola T, Witte DR, Brunner EJ. Psychosocial stress at work doubles the risk of type 2 diabetes in middle-aged women: evidence from the Whitehall II study. Diabetes Care. 2009; 32(12):2230-5
^ Heraclides AM, Chandola T, Witte DR, Brunner EJ. Work stress, obesity and the risk of type 2 diabetes: gender-specific bidirectional effect in the Whitehall II study. Obesity (Silver Spring). 2012; 20(2):428-33.
^ Smith PM, Glazier RH, Lu H, Mustard CA. The psychosocial work environment and incident diabetes in Ontario, Canada. Occup Med (Lond). 2012; 62(6):413-9
^ Djindjic N, Jovanovic J, Djindjic B, Jovanovic M, Jovanovic JJ. Associations between the occupational stress index and hypertension, type 2 diabetes mellitus, and lipid disorders in middle-aged men and women. Ann Occup Hyg. 2012; 56(9):1051-62
^ Eriksson AK, van den Donk M, Hilding A, Östenson CG. Work stress, sense of coherence, and risk of type 2 diabetes in a prospective study of middle-aged Swedish men and women.Diabetes Care. 2013; 36(9):2683-9.
^ Williams ED, Magliano DJ, Tapp RJ, Oldenburg BF, Shaw JE. Psychosocial stress predicts abnormal glucose metabolism: the Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Ann Behav Med. 2013; 46(1):62-72.
^ Even though numerous high quality animal studies support the notion that both acute and chronic stress cause a dysregulation of glucose metabolism, this article will focus mainly on evidence among humans.
^ For a detailed overview of biomarkers of psychosocial stress, refer to Chida & Hammer (2008) and Chandola et al (2010) and for their association with T2D-related outcomes refer to Brunner et al (2002), Steptoe & Wardle (2005), Licht et al (2010) and DeSantis et al (2011)