Depression: aetiology

Rates of depression in people with diabetes are significantly higher than those in the general population and depression in people with diabetes is associated with greater morbidity, premature mortality and poorer quality of life. The mechanisms underlying the high rates of depression in diabetes and its adverse effects on diabetes-related outcomes are not yet well understood, but are likely to include biological and psychological processes that interact with each other. Focussing on type 2 diabetes, this chapter initially discusses the limitations of the psychological model in explaining this link, before exploring various biological and epidemiological explanations for the association between depression and metabolic dysfunction.

Limitations of the psychological model

The psychological model has been the conventional explanation for the association between depression and diabetes. This holds that the psychological burden of living with a chronic condition such as diabetes is the predisposing factor for depression. There is evidence that the risk of depression is higher in people with a diagnosis of diabetes compared to people with impaired glucose metabolism or undiagnosed diabetes, which lends some support to this model.[1] Depression moderates lifestyle behaviours, such as smoking and physical activity, and is associated with reduced diabetes self-care behaviours,[2] which would be expected to translate into poor glycaemic control and complications. However, the current evidence base suggests that treating depression alone in people with diabetes does not always improve glycaemic control as this model would suggest, even though treatments do consistently improve mood.[3] The association between depression and type 2 diabetes is bi-directional and depressive symptoms are associated with a 60% increased risk for incident diabetes.[4] This suggests that biological mechanisms could also be implicated in the diabetes-depression link. Potential biological processes include insulin resistance, activation of the hypothalamic-pituitary-adrenal (HPA) axis and the innate inflammatory response, and are discussed in detail below.

The diabetes-depression link and insulin resistance

Insulin resistance can be defined as the inability of insulin to exert its normal biological action at physiological concentrations, and several factors point to a putative biological link between insulin resistance and depression. Insulin resistance was initially considered only to occur in peripheral insulin-sensitive tissues such as liver, fat and muscle, but, as glucose and insulin cross the blood-brain barrier, the notion of central insulin resistance is emerging. The insulin receptors in the brain have a different structure and function to those in the periphery, and there is accumulating evidence that peripheral insulin resistance is associated with functional decline in the central nervous system and could be a causal link to Alzheimer’s disease and vascular dementia.[5] A meta-analysis demonstrated a small but significant cross-sectional association between depression and insulin resistance, but highlighted the need for future prospective studies to examine this link.[6]

The diabetes-depression link and the hypothalamic-pituitary-adrenal axis

The association between depression and overactivation of the hypothalamic-pituitary-adrenal (HPA) axis is well documented. The metabolic effects of hypercortisolaemia are increased gluconeogenesis, glycogenolysis and insulin resistance. Hypercortisolaemia, however, is a non-specific response to acute and chronic stress; its association with schizophrenia may reflect the non-specific stressor effects of acute psychosis and likewise in post-traumatic stress disorder. A meta-analysis of depression and HPA activation supported a link between depression and increased risk of diabetes, showing that the link was strongest among older in-patients who had melancholic or psychotic features.[7] However, the link between depression and HPA activation still requires support from large-scale observational studies.

The depression-diabetes link and the activation of the innate inflammatory response

‘The macrophage theory of depression’, first proposed in 1991, suggests that depression is associated with a cytokine-induced acute phase response.[8] This is relevant because the acute phase response is also implicated in the pathogenesis of type 2 diabetes, as first proposed by Pickup and Crook in 1998.[9] Production of pro-inflammatory cytokines is associated with pancreatic β-cell apoptosis, insulin resistance and onset of type 2 diabetes.[10]

There is growing evidence that the cytokine-mediated inflammatory response is also associated with depression. Psychological stress causes pro-inflammatory cytokine release, as noradrenaline and corticotrophin-releasing factor stimulate macrophages to release IL6- and TNF-α. A meta-analysis of the association between cytokines and major depression observed that depressed subjects had significantly higher concentrations of TNF-α and IL-6.[11] There is some evidence that some but not all antidepressants are associated with reduced levels of inflammation.[12] Whether this is an indirect effect secondary to resolution of a depressive episode leading to normalization of circulating cytokine levels or whether antidepressants directly inhibit the peripheral or central effects of inflammatory cytokines on the brain or another unknown process remains to be studied.

The diabetes-depression link and the autonomic nervous system

The sympathetic nervous system is activated by the HPA axis during stress to produce the acute anxiety response. It has been suggested that excessive or persistent activation may lead to elevated catecholamine levels and inflammatory processes, which in turn will contribute to metabolic dysfunction. Decreased heart rate variability – a proxy measure of autonomic dysfunction – has been associated with depression after myocardial infarction,[13] suggesting that acute alterations in cardiac autonomic tone may contribute to the increased risk of coronary events in people with depression. Autonomic neuropathy is a common complication of diabetes, but studies examining whether it is linked to the association between depression and type 2 diabetes are sparse. It seems plausible that, if depression is linked to reduced heart rate variability in heart disease, it may also be linked to autonomic neuropathy in diabetes, but this requires investigation in prospective cohort studies.

Genetics of the diabetes-depression link

Major depression and type 2 diabetes separately have genetic traits that aggregate in families, through a complex interaction between genetic risk and the environment. The Vietnam Era Twin Study of Aging is the only published twin study investigating this link, and a moderate genetic correlation of 0.19 with a broad confidence interval was reported.[14] The type 2 diabetes-depression link has not been examined at a genome wide association study significance level, but a range of type 2 diabetes-related single nucleotide polymorphisms have been suggested to be associated to depression. For example, the Pro12Ala variant of the peroxisome proliferative-activated receptor γ2 (Pro12A1a PPARG) gene has been implicated in inflammation, depression, type 1 and 2 diabetes.[15],[16] Further research into common genetic pathways of depression and type 2 diabetes is awaited. The diabetes-depression link and birth weight/early childhood adversity A systematic review found that an inverse association between birth weight and type 2 diabetes was observed in 23 populations, compared to positive associations in 8 populations.[17]However, the extent to which the ‘fetal origins’ hypothesis applies to adult depression is less certain and the evidence is contradictory.[18] Nevertheless, the hypothesis that intra-uterine environment influences the stress response phenotype is attractive, as it provides a potentially unifying model for the depression-diabetes link.

Socioeconomic deprivation is well established to be associated with increased risk of type 2 diabetes and depression, as it is for other related chronic diseases.[19] Socioeconomic status is associated with unhealthy lifestyles such as smoking, cheap high-energy goods and reduced physical activity, all of which are associated with both depression and type 2 diabetes. Although this is not a classic biological mechanism, it reminds us that social context that people live in influences lifestyles, which in turn influence psychology and biological processes.


Recent research on the pathogenesis of the depression-diabetes link has identified numerous potential mechanisms, many of which are related to each other on the same causal pathway and can be summarised in figure 1.

Fiqure 1
Fiqure 1

For example, metabolic programming a genetic level and early nutrition, environment stressors and obesogenic lifestyle collectively induce HPA overactivity. Chronic hypercortisolaemia and sympathetic nervous system activation appear to be linked to various pathophysiological processes, including activation of the innate inflammatory response, development of insulin resistance and ultimately type 2 diabetes. Depression is likely to play a role in several ways: as a coincidental result of the same environmental stressors that influence metabolic regulation; as an independent factor that influences lifestyle behaviours and nutrition; and as one of the several phenotypes for a range of stress-related disorders which have a unifying overactivation of the HPA axis and inflammatory response to stress, with other phenotypes being type 2 diabetes, cognitive impairment and cardiovascular disease. Considering the high prevalence of the diabetes-depression link, new developments in the pharmacological agents that treat both depression and diabetes are awaited.


  1. ^ Nouwen A et al. Prevalence of depression in individuals with impaired glucose metabolism or undiagnosed diabetes: a systematic review and meta-analysis of the European Depression in Diabetes (EDID) Research Consortium. Diabetes Care 2011;34(3):752-62

  2. ^ Katon W et al. The relationship between changes in depression symptoms and changes in health risk behaviors in patients with diabetes. Int J. Geriatr. Psychiatry 2010;25:466-475

  3. ^ Katon W et al. Collaborative care for patients with depression and chronic illnesses. N Engl J Med. 2010;363(27):2611-20

  4. ^ Mezuk B et al. Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 2008;31:2383-2390

  5. ^ Li L et al. Common pathological processes in Alzheimer’s disease and type 2 diabetes: a review. Brain. Res. Rev. 2007;56(2):384-402

  6. ^ Kan C et al. A systematic review and meta-analysis of the association between depression and insulin resistance. Diabetes Care 2013;36(2):480-9

  7. ^ Stetler C et al. Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom. Med. 2011;73(2):114-26

  8. ^ Smith R. The macrophage theory of depression. Med Hypotheses 1991;36:178

  9. ^ Pickup J et al. Is type II diabetes a disease of the innate immune system? Diabetologia 1998;41:1241-1248

  10. ^ Pradhan A et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2011;286:327-334

  11. ^ Dowlati Y et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 2010;67:446-457

  12. ^ Hannestad et al. The effect of antidepressants medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 2011;36:2452-2459

  13. ^ Carney R et al. Depression, heart rate variability, and acute myocardial infarction. Circulation 2011;104:2024-2028

  14. ^ Scherrer J et al. A test for common genetic and environmental vulnerability to depression and diabetes. Twin Research and Human Genetics 2011;14:169-72

  15. ^ Eftychi C et al. Analysis of the type 2 diabetes-associated single nucleotide polymorphisms in the genes IRS1, KCNJ11, and PPARG2 in type 1 diabetes. Diabetes 2004;53:870-3

  16. ^ Ji-Rong Y et al. Pro12Ala polymorphism in PPARgamma2 associated with depression in Chinese nonagenarians/centenarians. Arch Med Res 2009;40:411-5

  17. ^ Whincup P et al. Birth weight and risk of type 2 diabetes: a systematic review. JAMA 2008;300:2886-2897

  18. ^ Inskip H et al. Is birth weight associated with risk of depressive symptoms in young women? Evidence from the Southampton Women’s survey. Am. J. Epidemiol. 2008;167:164-168

  19. ^ Pollitt R et al. Evaluating the evidence for models of life course socioeconomic factors and cardiovascular outcomes: a systematic review. BMC Public Health 2005;5:7


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    Ali Merzouk added a compliment on 30 August 2013 at 08:48AM
    Very good
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