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Depression and diabetes 2

The link between depression and diabetes: the search for
shared mechanisms
Calum D Moulton, John C Pickup, Khalida Ismail

Depression is twice as common in people with type 1 or type 2 diabetes as in the general population, and is associated Lancet Diabetes Endocrinol 2015;
with poor outcomes. Evidence is growing that depression and type 2 diabetes share biological origins, particularly 3: 461–71

overactivation of innate immunity leading to a cytokine-mediated inflammatory response, and potentially through Published Online
May 18, 2015
dysregulation of the hypothalamic-pituitary-adrenal axis. Throughout the life course, these pathways can lead to insulin
http://dx.doi.org/10.1016/
resistance, cardiovascular disease, depression, increased risk of type 2 diabetes, and increased mortality. S2213-8587(15)00134-5
Proinflammatory cytokines might directly affect the brain, causing depressive symptoms. In type 1 diabetes, mediators This is the second paper in a
of depression are not well studied, with research hindered by inconsistent definitions of depression and scarcity of Series of three papers about
observational, mechanistic, and interventional research along the life course. Despite few studies, evidence suggests depression and diabetes
that familial relationships and burden of a lifelong disorder with an onset early in personality development might Department of Psychological
contribute to increased vulnerability to depression. Overall, longitudinal research is needed to identify risk factors and Medicine, Institute of
Psychiatry
mechanisms for depression in patients with diabetes, particularly early in the life course. Ultimately, improved (C D Moulton MRCPsych,
understanding of shared origins of depression and diabetes could provide the potential to treat and improve outcomes Prof K Ismail PhD) and Diabetes
of both disorders simultaneously. These shared origins are targets for primary prevention of type 2 diabetes. and Nutritional Sciences
Division (Prof J C Pickup DPhil),
King’s College London, London,
Introduction criteria, such as the Schedules of Clinical Assessment in UK
An association between depression and diabetes was Neuropsychiatry.4 Much research into both type 1 and Correspondence to:
recognised as early as the 17th century, when British type 2 diabetes has instead used self-report Dr Calum D Moulton,
physician Thomas Willis noted that diabetes frequently questionnaires, sometimes with a cutoff to define Department of Psychological
appeared in individuals who had experienced previous depression or to describe depressive symptoms. Results Medicine, Institute of Psychiatry,
King’s College London,
life stresses or sadness.1 We now know that prevalence of of validation studies in patients with diabetes have London SE5 9RJ, UK
depression in patients with type 1 or type 2 diabetes is shown that self-report questionnaires can substantially calum.moulton@kcl.ac.uk
about twice that of the general population without overdiagnose clinical depression.5 However, whether the
diabetes.2 Both type 1 and type 2 diabetes result in phenotype of depression in diabetes differs, at least in
persistent hyperglycaemia, but show important some patients, from depression in the non-diabetic
differences in their association with depression, which population is not known. For example, biological
suggests that the association between each type might symptoms of depression (eg, fatigue, and sleep and
be driven by different underlying mechanisms. A appetite disturbance) are often reported in patients with
bidirectional relation exists between type 2 diabetes and diabetes who do not meet criteria for clinical depression
depression, and evidence is growing for biological according to a diagnostic interview.5 We therefore
correlates of depression in patients with type 2 diabetes, include papers that use both conventional diagnostic
but less research into biological mechanisms for criteria and questionnaires to define depression.
depression in patients with type 1 diabetes has been The related construct of diabetes-specific distress refers
done. The two disorders typically occur at different ages to emotional responses to diabetes, its treatment, and its
and need different management. Type 1 diabetes effects on lifestyle and the future.6 Although diabetes-
presents characteristically in childhood and early specific distress has moderate-to-strong positive
adulthood, at a time of rapid psychological and correlations with self-report measures of depression,
physiological change, whereas type 2 diabetes typically much of the variance in diabetes-specific distress is
occurs later, in mid-adulthood. Treatment of type 2 unexplained.6 Diabetes-specific emotional distress has
diabetes includes diet and lifestyle modification, and been suggested to be a separate psychological construct
oral medication or insulin injections, whereas type 1 to depression, and here we regard it as a potential
diabetes necessitates daily insulin injections or infusions mediator of the association between depression and
for life. Additionally, average age of onset of depression— diabetes self-management.
early-to-mid-20s3—suggests that important differences
exist in its relation with type 1 and type 2 diabetes. We Type 2 diabetes
therefore discuss type 1 and type 2 diabetes separately in Overview
terms of their association with depression. One interpretation for the link between depression and
The gold standard to diagnose depression is a type 2 diabetes is that the psychological burden of life
diagnostic interview based on established diagnostic with a chronic disorder predisposes patients to

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depression, and depression in patients with type 2
diabetes is associated with poor self-care behaviours.7 To
support this interpretation, risk of depression seems to
be higher in people with a diagnosis of type 2 diabetes
than in people with impaired glucose metabolism or
undiagnosed diabetes.8 Another explanation is that
depression is coincidental with type 2 diabetes because
they share similar environmental and lifestyle factors,
such as socioeconomic deprivation, social adversity,
smoking, and reduced physical activity. For example,
childhood adversity (abuse, deprivation, and neglect)
has been shown to have effects on depression9 and self-
reported diabetes onset10 in later life. In adulthood, work
stress is associated with increased risk of type 2
diabetes11 and depression.12 Additionally, depression
typically presents in early adult life and is linked to self-
neglect and low self-esteem, which might increase risk
of unhealthy lifestyles and, in turn, increase risk of
type 2 diabetes. For example, depressive symptoms are
associated with high body-mass index (BMI), poor diet,
low levels of physical activity, and smoking, all of which
are risk factors for type 2 diabetes and cardiovascular
disease.13 The cognitive behavioural model (figure 1)
suggests that the burden of type 2 diabetes leads to low
mood and negative thoughts about diabetes, which
worsen diabetes self-care. Such negative thoughts and
behaviours can be identified and modified with cognitive
behavioural therapy (CBT) (figure 1), which slightly
improves mood and glycaemic control in patients with
type 2 diabetes.14
Although glycaemic control tends to improve when
treatment for depression is integrated with type 2
diabetes management, treatment of depression alone
does not consistently improve glycaemic control.15,16
Results of cross-sectional studies have shown a modest
association between depression and high concentrations
of haemoglobin A1c (HbA1c).17 However, prospective
studies—which are few in number—have had mixed
results,18–20 despite the more consistent finding that
depression is a strong risk factor for macrovascular
complications and dementia in patients with type 2
diabetes.21,22 Evidence suggests that diabetes-related
distress, rather than depression, is associated with
decreased glycaemic control over time.18 Moreover, the
link between depression and type 2 diabetes is
bidirectional: type 2 diabetes is associated with a roughly
20% increased risk of incident depression,23,24 and
depression is associated with a 60% increased risk of
incident type 2 diabetes.24 Collectively, these findings
suggest that the relation between depression and type 2
diabetes is complex and that, in some individuals, shared
biological mechanisms might underlie the association
between, and the course of, depression and type 2
diabetes.
Several biological mechanisms have been proposed for
the association between diabetes and depression
throughout the life course. Depression and diabetes have
462
a moderate genetic correlation of r=0·19 (albeit with a
broad CI of 0–0·46),25 whereas various type 2 diabetes-
related single nucleotide polymorphisms have been
associated with depression and type 2 diabetes
independently.26,27 Preliminary evidence suggests that
adaptations to the in-utero environment could drive so-
called metabolic ageing and predispose patients to
depression, potentially via epigenetic mechanisms such
as DNA methylation marks.28 Low birthweight followed
by accelerated weight gain in childhood has large effects
on incidence of type 2 diabetes in later life,29 and a meta-
analysis30 showed a statistically significant association
between low birthweight and later depression.
Overall, these findings suggest that depression and
type 2 diabetes could develop in parallel through shared
biological pathways. Key candidate pathways include the
innate inflammatory response, the hypothalamic-
pituitary-adrenal (HPA) axis, circadian rhythms, and
insulin resistance, which all interact with each other.
Although physiologically related and not mutually
exclusive, we discuss these pathways separately for ease.
Innate immunity and inflammation
Activated innate immunity and an acute-phase
inflammatory response are implicated in pathogenesis of
type 2 diabetes. Specifically, raised concentrations of
proinflammatory cytokines lead to pancreatic β-cell
apoptosis and insulin resistance, and predict onset of
type 2 diabetes in initially non-diabetic patients.31 The
importance of innate immunity in inflammation in type 2
diabetes has been substantiated by systematic reviews of
prospective studies.32 Additionally, anti-inflammatory
agents, such as interleukin 1 receptor antagonist and non-
steroidal anti-inflammatory drugs, improve glycaemic
control in placebo-controlled trials.33,34 Growing evidence
likewise suggests that the cytokine-mediated inflam-
matory response is associated with depression in people
without diabetes. Increased cytokine serum concentrations
activate the HPA axis, increase oxidative stress in the
brain, and might activate the tryptophan–kynurenine
pathway, resulting in reduced production of serotonin.35,36
Depressive symptoms and cognitive deficits are often
reported in patients treated with the cytokine interferon
alfa.36 A meta-analysis of the association between cytokines
and major depression reported that patients with
depression had statistically significantly higher circulating
concentrations of tumour necrosis factor (TNF) and
interleukin 6 than those without depression.37
Furthermore, a meta-analysis of four studies reported that
adjunctive therapy with the PTGS2 inhibitor celecoxib
reduced depressive symptoms.38 However, participant
numbers in these studies were low, and PTGS2 inhibitors
are likely to be more problematic in patients with type 2
diabetes because they are associated with increased risk of
thrombosis.39
Although strong evidence implicates the innate
immune system in the pathogenesis of depression in
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Core belief
“I don’t care about diabetes”

Dysfunctional assumptions
• “If I need insulin, that’s the beginning of the end”
• “If I control my sugars, I’ll get complications anyway”

Cognitive restructuring Behavioural experiments

• “I can control the diabetes, not the diabetes control me” • Try smaller portions of food
• “It is in my power to slow complications down” • Increase amount of walking
• Check blood sugar more frequently
Situation
• Not taking medication as prescribed
• Not adhering to diet and lifestyle advice

Altered cognition
Altered emotion
• “I am a failure”
Anxiety, depression, guilt, shame
• “ I can’t do anything about this”

Physical symptoms
Fatigue, dizziness

Figure 1: Cognitive behavioural formulation for the link between depression and type 2 diabetes
A core belief (an absolute statement about diabetes) leads to development of dysfunctional assumptions (rules that guide daily actions and expectations of diabetes
management), which in turn leads to problems with management of diabetes. Problem situations in turn lead to negative emotions, physical symptoms, and
negative thoughts, which interact with each other, generating a cognitive behavioural cycle. The dashed lines represent two techniques used in cognitive behavioural
therapy that aim to break this cycle and thereby improve mood and glycaemic control: cognitive restructuring encourages patients to identify negative thoughts and
assess evidence for—and against—them, to generate an objective view; and behavioural experiments are real-life activities done in or between sessions that might
help to challenge negative thoughts, such as checking of blood glucose.

the general population, only a minority of whom have
diabetes, the role of innate immunity in development
of depression in patients with type 2 diabetes is not yet
established. In a primary-care sample of 1790 patients
with newly diagnosed type 2 diabetes, patients with
depression—defined by a Patient Health Questionnaire
9 (PHQ-9) score of 10 or more—were more overweight,
younger, had higher concentrations of C-reactive
protein (CRP) and interleukin 1-receptor antagonist,
and higher white-cell counts than people with type 2
diabetes who were not depressed, even after adjustment
for key covariates.40 In other studies, increased
concentrations of CRP and interleukin 6 predicted
increased risk of type 2 diabetes41 and depression42 after
adjustment for covariates. A large cohort study of
3573 patients with type 2 diabetes reported a statistically
significant cross-sectional association between high
CRP concentrations and depression, although after
multivariate analysis, this association was shown only
in patients with high BMI.43 In the related specialty of
cardiovascular disease, depressive symptoms predict
high white-cell counts in patients with stable coronary
heart disease,44 and depression is an independent
predictor of cardiovascular mortality after myocardial
infarction.45 Additionally, depression increases risk of
incident dementia in patients with type 2 diabetes,22
with increased concentrations of interleukin 6
associated with cognitive decline in patients with type 2
diabetes.46
In epidemiological studies, innate immunity has been
proposed as a possible mechanism by which depression
and type 2 diabetes could develop as a result of stressors
throughout the life course. In cross-sectional research,
abuse, neglect, or both before age 16 years are major
mediators of the cross-sectional relation between
increased concentrations of inflammatory cytokines and
depression in adults.47 Cumulative exposure to low
socioeconomic status from childhood to middle age is
associated with increased risk of type 2 diabetes in
adulthood, with interleukin 6 and CRP acting as
independent predictors.48
If inflammation is involved in pathogenesis of
depression in type 2 diabetes, reduction in inflammation
might be a novel treatment. However, no studies have
attempted to modify inflammation in treatment of
depression in patients with type 2 diabetes. With
the potential benefit of improvement of glycaemic
control and depressive symptoms concurrently, anti-
inflammatory approaches to treatment of depression in
patients with type 2 diabetes are awaited.

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The HPA axis
Stress is associated with activation of the HPA axis,
which affects glucocorticoid production by the adrenal
glands. Chronic stress with associated hypercortisolaemia
can lead to increased portal and peripheral free fatty
acids.49 Additionally, hypercortisolaemia impairs the
ability of insulin to translocate intracellular SLC2A4
glucose transporters to the cell surface.50 Chronic
hypercortisolaemia can therefore contribute to metabolic
syndrome, insulin resistance, and type 2 diabetes.51
Some evidence suggests that depression is associated
with chronic dysregulation of the HPA axis. Excess
cortisol hinders neurogenesis in the hippocampus,52 a
region implicated in both depression and type 2
diabetes.53 Furthermore, patients with major depression
show reduced expression of glucocorticoid-inducible
genes TSC22D3 and SGK1, associated with smaller
hippocampal volumes.54 However, studies reporting
overactivation of the HPA axis in patients with depression
have often focused on inpatients or those with severe or
melancholic subtypes,55 whereas evidence for HPA-axis
dysregulation in outpatients—arguably most relevant for
most people with depression and type 2 diabetes—has
been less convincing.56,57
Nevertheless, the suggested role of HPA-axis
dysregulation in both depression and type 2 diabetes
provides a plausible common link between the two
disorders throughout the life course. In the brain, early
stress leads to attenuated development of the
hippocampus and amygdala, areas that have a high
density of glucocorticoid receptors and persistent
postnatal neurogenesis58 and that are implicated in both
depression and type 2 diabetes.53 Additionally, women
with a history of childhood abuse have increased
pituitary–adrenal responses to stress compared with
controls.59 However, a study comparing features of the
metabolic syndrome in healthy adult controls and adults
with depression reported that depression is statistically
significantly related with fasting glucose even in the
absence of activation of the HPA axis.60
If the HPA axis is associated with depression, pharma-
cological manipulation of the axis could provide novel
treatments. Although mineralocorticoid antagonists
prevented development of glucocorticoid-induced
depressive behaviours in animals,61 results of clinical
studies have not shown improvement in depression with
mineralocorticoid agonism or antagonism.62 Moreover, the
tendency for mineralocorticoid antagonists, such as
spironolactone, to worsen glycaemic control63 emphasises
the need for clear understanding of any shared aberrations
of the HPA axis in depression and type 2 diabetes before
pharmacological manipulation of the axis can provide safe
and effective new treatments.
Insulin resistance and secretion
A positive association between depression and insulin
resistance would increase plausibility of a biological link
464
between depression and type 2 diabetes. A meta-analysis64
of 21 studies investigating the link between depression
and insulin resistance reported a small but statistically
significant cross-sectional association, but this link was
attenuated in analyses adjusted for bodyweight and other
confounders. However, interpretation is limited by a
scarcity of longitudinal data in this area; studies included
in the meta-analysis used estimates of insulin resistance
such as homoeostatic model assessment-insulin
resistance (HOMA-IR), because the gold standard (the
hyperinsulinaemic-euglycaemic clamp) is not practical
for large-scale studies. One of the few prospective studies
reported that depression was associated with high
HOMA-IR values and incident diabetes in middle-aged
women, mediated mostly through central adiposity.65 A
6-year prospective study of adults aged 50–70 years
reported that somatic-vegetative symptoms of depression
(fatigue, sleep disturbance, and appetite changes) were
associated with worsened insulin resistance over time,
partly mediated by increased BMI.66
If association with depression is clinically significant,
reduction of insulin resistance could be a potential
treatment for depression, and could slow down
development of type 2 diabetes at the same time.
Pioglitazone, which reduces insulin resistance by
stimulating the nuclear receptor PPARγ and, to a lesser
extent, PPARα, has been shown to improve depressive
symptoms in patients with bipolar depression, predicted
by increased baseline concentrations of interleukin 6,67
although this trial was uncontrolled. In a double-blind
metformin-controlled trial, pioglitazone improved
depressive symptoms compared with metformin.68
Because both drugs increase sensitivity to insulin, no
difference in HOMA-measured insulin resistance is
expected, but other biological pathways are implicated in
this effect.68 However, because the study was undertaken
in a population with polycystic ovarian syndrome, and
patients with worsened depressive symptoms (Hamilton
Depression Rating Scale >20) were excluded, these
results should be treated with caution.
Circadian rhythms
Disruption of normal circadian rhythm is implicated in
both depression69 and type 2 diabetes.70 Sleep apnoea,
which is common in patients with type 2 diabetes, is
associated with disruption of circadian rhythm.70
Extremes of sleep duration have been shown in patients
with depression71 and metabolic syndrome,72 and
increased concentrations of CRP and interleukin 6 have
been reported in long sleepers with depression.71 Patients
with depression and patients with type 2 diabetes have
common variations in sleep architecture, such as
decreased slow-wave sleep and increased rapid eye
movement density, associated with increased
concentrations of proinflammatory cytokines, such as
interleukin 6 and TNF.73 Such sleep architecture
variations can be seen before onset of depressive
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symptoms,74 suggesting that a subpopulation might be at
increased risk of depressive symptoms and metabolic
disturbances.
At the cellular level, clock genes are associated with
regulation of circadian rhythm, and their expression is
controlled by environmental cues such as light–dark
cycles, food, and social cues.75 In patients with type 2
diabetes, clock gene expression has been directly
associated with fasting glucose concentrations.76 In
patients with depression, the rapid antidepressant
actions of low-dose ketamine and sleep deprivation
therapy might be due to resetting of abnormal clock
genes and subsequent restoration of circadian rhythms.77
This finding highlights the translational potential of
these emerging biological pathways, and studies
investigating the role of clock genes in depression in
patients with type 2 diabetes are awaited.
An alternative explanation: antidepressants rather than
depression?
Prescription of antidepressant medication, independently
of depression itself, has been suggested as a possible link
between depression and type 2 diabetes. One study78
reported that a medication history of more than 200
defined daily doses of conventional antidepressants
increased risk of diabetes in patients with moderate or
severe depression by 93–165% compared with the general
population. However, subsequent analysis by the same
authors79 suggested that the link was not causal. Selective
serotonin reuptake inhibitors (SSRIs) improve glucose
regulation in the short term in the general population,80
and use of SSRIs for 1 year in patients with established
type 2 diabetes is not associated with reduction of
Environmental threats and toxins
Obesity, sedentary lifestyle, smoking, and chronic social adversity
Macrophages
Pro-inflammatory cytokines (interleukin 6, interleukin 1, and TNF)
causing sickness behaviours
Acute-phase response
Blood proteins (C-reactive protein; serum amyloid A) and triglycerides
Cell damage
Pancreatic β cells, insulin resistance, endothelial cells (arterial),
and neuroglia (brain cells)
Disease
Type 2 diabetes, atherosclerosis, depression, and cognitive impairment
Figure 2: Flow diagram showing the effects of the innate immune response
after activation by toxins throughout the life course
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glycaemic control.81 Because SSRIs are the most frequently
prescribed antidepressants with known anorexigenic
properties,39 this finding suggests that they have no causal
role in type 2 diabetes. Future research should identify
clearly the prospective relation between baseline
antidepressant use and development of prediabetes
stages, and the extent to which antidepressant use has
direct effects on diabetogenic metabolic pathways, rather
than being a proxy marker of depression itself.
Summary: depression and type 2 diabetes share
biological origins
Despite limitations in methodological quality of many
studies, evidence of shared psychological and,
increasingly, biological mechanisms for depression and
type 2 diabetes is consistent. In some individuals, these
shared mechanisms might lead to development of both
disorders in parallel. Fetal or maternal stress in utero,
cumulative exposure to low socioeconomic status, and
poor health behaviours in people with a genetic
predisposition might promote dysregulation of the HPA
axis, promote disturbance of circadian rhythms, and act
as toxins to activate the innate inflammatory response
(figure 2). Dysregulation of these biological pathways
might lead, in parallel, to insulin resistance and type 2
diabetes, depression, dementia, and cardiovascular
disease. Depressive symptoms or depression might arise
in patients with diabetes when excess proinflammatory
cytokines in the brain lead to increased breakdown of
tryptophan to neuroactive metabolites such as
kynurenine, and reduced concentrations of serotonin
(figure 3). Reasons why depression typically presents at a
younger age than type 2 diabetes are not known. Possible
hypotheses are that the brain is more sensitive to the
end-effects of these biological pathways, or that the effect
of environmental stress on the brain is the first event,
which, in turn, affects central regulation of metabolism.
Type 1 diabetes
Overview
Patients with type 1 diabetes need a complex management
regimen, including regular and frequent monitoring and
recording of blood glucose concentrations and calculation
and administration of insulin doses in the context of
carbohydrate intake and physical activity. People with
type 1 diabetes might struggle to accept and adjust to this
monitoring to different extents, posing a practical and
psychological burden. The cognitive behavioural model
is often used to explain the link between depression and
type 1 diabetes (figure 4). In type 1 diabetes, CBT has
been used to help patients to identify and reframe
negative beliefs about their disease, which might
otherwise result in overwhelming frustration and
abandonment of self-care activities, such as self-
monitoring of blood glucose.82 A systematic review83 of
patients with and without depression identified that
psychological treatments, predominantly CBT, slightly
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Childhood Adulthood
Genetic factors
adversity adversity
Insulin resistance
Innate immunity and inflammation β-cell apoptosis
Hippocampal atrophy
Endothelial dysfunction
HPA axis dysregulation Circadian rhythm
disturbance
In-utero stress Unhealthy
and nutrition lifestyles
Figure 3: Summary of shared biological pathways contributing to pathogenesis of depression and type 2
diabetes throughout the life course
HPA=hypothalamic-pituitary-adrenal.
improved glycaemic control in patients with type 1
diabetes. However, results of an uncontrolled study of
group CBT for depression showed reduced depression in
the subgroup with type 1 diabetes, but no improvement
in glycaemic control.84
In addition to psychological mechanisms, biological
mechanisms, such as inflammation and cerebral
damage, might have a role in mediation of the link
between depression and type 1 diabetes.85 The role of
biological pathways might be a barrier to conventional
treatments for depression in patients with type 1 diabetes
and, conversely, could be a new modifiable target for
intervention. However, in a large-scale cohort study of
children diagnosed with diabetes before age 20 years,
only high concentrations of apolipoprotein B were
associated with worsened depressive symptoms in
patients with type 1 diabetes after adjustment for
confounders.86 Some authors have highlighted parallels
in cerebral correlates for depression and type 1 diabetes.85
However, although changes typical of depression, such
as hippocampal atrophy, are consistently noted in
patients with type 2 diabetes, the cerebral correlates of
type 1 diabetes seem to be different, and only thalamic
atrophy is a consistent finding.53
Type 1 diabetes is characterised by a much earlier age
of onset than type 2 diabetes, and has the potential to
cause substantial disruption to normal developmental
processes.
Childhood
Depression can be difficult to diagnose in childhood, and
few studies have investigated the association between
depression and type 1 diabetes during this period.
Although some aspects of diabetes management might
be done by the children themselves, such as self-
administration of insulin, the adult caregiver is mostly
responsible for the complex decision making associated
with these tasks, such as dosing insulin on the basis of
466
blood glucose readings and diet. Therefore, the relation
between depression and type 1 diabetes in childhood take
into account both the child and their familial
Depression relationships.
Some evidence suggests that children with type 1
diabetes who grow up in an environment of high
Type 2 diabetes
expressed emotion have poor glycaemic control.87 The
burden of parental responsibility during childhood is a
Cardiovascular
disease
prominent theme of qualitative studies in patients with
type 1 diabetes.88 In children with type 1 diabetes,
Dementia
evidence suggests that critical parenting behaviours
increase depressive symptoms, with associated reduction
of self-care behaviours.89 Clinically, addition of structured
behavioural group training has been shown to reduce
parental stress and, possibly, maintain improved
glycaemic control over time.90
Quality of attachment between child and parents or
guardians is a plausible mediator of the child’s adjustment
to type 1 diabetes and subsequent psychological sequelae.
Attachment theory proposes that past experiences with
caregivers are incorporated psychologically to form
cognitive models that inform future interpersonal
relationships, and these patterns of attachment continue
into later life.91 Individual differences exist in the way that
people regulate their attachment behaviour in response to
threats, such as illness. In adults with type 1 diabetes,
dismissing attachment style—characterised by low trust of
others and excessive self-reliance—is associated with
increased risk of poor glycaemic control.92 However,
studies examining attachment behaviour, psychological
adjustment, and glycaemic control in children with type 1
diabetes are awaited.
Adolescence
The transition from childhood into adolescence
necessitates increased independence and diabetes self-
management, such as self-monitoring of blood glucose,
dietary intake, and insulin dosing,93 behaviours with
which depression has been shown to interact adversely.94
This increased independence coincides with emergence
of risk-taking behaviours, such as experimentation with
tobacco and alcohol, and desire for peer approval.
Additionally, onset of puberty results in decreased glucose
uptake, owing in part to increased activity of the growth
hormone axis.95 In view of these rapid psychological and
physiological changes, diabetes-specific distress is well
characterised in adolescents with type 1 diabetes, and is
associated with poor glycaemic control, prominent
negative beliefs about diabetes, and reduced self-efficacy.96
Fear of hypoglycaemia might result in increased anxiety,
guilt, and avoidant behaviour.97 Coping skills training in
adolescents results in decreased HbA1c concentrations and
improved diabetes self-care and quality of life.98 However,
a meta-analysis of psychoeducational interventions
reported that no programme has proven effective in
randomised studies for patients with poor glycaemic
control.99
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Core belief
“I hate having diabetes”

Dysfunctional assumptions
• “If I check my sugars in public, people will think I am taking drugs”
• “If I have a hypo, it will be humiliating and no one will help me”

Cognitive restructuring Behavioural experiments

• “I guess many people check their blood sugars” • Checking blood sugar more frequently in private or public
• “I can control my sugars without necessarily having a hypo” • Gradually increasing insulin dose

Situation
• Not checking blood sugar
• Omitting insulin

Altered cognition
Altered emotion
• “I am a failure”
Anxiety, depression, guilt, shame
• “I don’t want to think about this”

Physical symptoms
Fatigue, dizziness

Figure 4: Cognitive behavioural formulation for the link between depression and type 1 diabetes
As with type 2 diabetes, a core belief about type 1 diabetes leads to development of dysfunctional assumptions, which in turn lead to problems with management of
type 1 diabetes. In this example, frequent difficulties with insulin management provide opportunities for therapeutic intervention (behavioural experiments and
cognitive restructuring), thereby improving both mood and diabetes management.

Additionally, type 1 diabetes in adolescence can lead to
negative communication and difficulties within the wider
family. Family stress is associated with poor glycaemic
control in adolescents with type 1 diabetes,100 and parental
stress is a possible mediator of both adolescent depression
and poor glycaemic control.101
Adolescence is a key period for development of eating
disorders, which are likewise associated with depression
and the desire for peer approval.102 Some prospective
studies have investigated the association of eating
disorders with depression and type 1 diabetes
concomitantly, but the interaction is complex. In a case-
control study comparing patients with both type 1
diabetes and an eating disorder with those with an eating
disorder alone, the group with type 1 diabetes had
statistically significantly lower scores on the Beck
Depression Inventory—an unexpected outcome.103
Adolescents with type 1 diabetes and disturbed eating
behaviour—a generic term for subthreshold eating
disorder symptoms—are far more likely to report
depressive symptoms than those with type 1 diabetes
alone, but do not consistently have poorer glycaemic
control prospectively.104
Clinically, if adolescents with depression and type 1
diabetes develop poor diabetes outcomes or have high
comorbidity, routine depression screening in patients
with type 1 diabetes could improve outcomes. Results of a
study of 528 adolescents with type 1 diabetes showed that
high scores on the Children’s Depression Inventory (CDI)
were associated with decreased blood glucose monitoring
frequency and increased HbA1c concentrations.105 However,
in another study, prevalence of depressive symptoms—as
measured by the CDI—in patients with poor glycaemic
control was similar to prevalence in those with good
glycaemic control.106 These apparently conflicting findings
might be due to differences in methods, since correlation
between depression score and HbA1c concentration105 is
more sensitive than bivariate comparison of high and low
HbA1c concentration in relation to depression score.106
However, these findings highlight the need for
longitudinal assessment of potential benefits of depression
screening on type 1 diabetes outcomes, and emphasise the
apparent vulnerability of all adolescents, irrespective of
HbA1c concentration, to development of depression.
Adulthood
Relative to the many studies of prevalence of depression
in patients with type 1 diabetes in adulthood, mechanistic
studies of depression have been sparse. A systematic
review reported inconclusive evidence that prevalence of
depressive symptoms is increased in young adults with
type 1 diabetes, but showed that those who are most
depressed have poorest glycaemic control.107 However,
cross-sectional evidence suggests that diabetes-specific
emotional distress, rather than depression, is associated
with poor glycaemic control in adults with type 1

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 Series
Search strategy and selection criteria
We searched PubMed from Jan 1, 1900, to Dec 18, 2014,
for peer-reviewed articles only, with the keywords:
“diabetes”, “diabetic”, “depression”, “depressive”, and
“distress”. For different sections, these keywords were
combined with the following: “childhood”, “parent”,
“parenting”, “attachment”, “adolescence”, “adolescent”,
“adult”, “adulthood”, “adult-onset, “inflammation”,
“inflammatory”, “immune”, “HPA”, “cortisol”,
“hypothalamic-pituitary-adrenal”, “genetic”, “genetics”, “in
utero”, “uterine”, “birth”, “childhood”, “trauma”, “stress”,
“anti-depressant”, “anti-depressants”, “insulin resistance”,
“insulin sensitivity”, “insulin secretion”, “HOMA-IR”,
“antidepressant”, “antidepressants”, “clock genes”, “clock
gene”, “circadian”, and “sleep”. We limited the searches to
English languages articles and excluded case reports,
commentaries, and letters. We also screened reference lists
of included papers. Because of space constraints, we could
not cite every paper of potential relevance. Of
interventional studies, randomised trials were prioritised
where possible. Of observational studies, meta-analyses
and prospective studies received priority where possible.
diabetes.108 In a cross-sectional study of 6712 adults with
type 1 diabetes, patients with depression were more likely
to be of non-white ethnicity, to be of low socioeconomic
status, to have poor glycaemic control, and to have
increased numbers of diabetic complications, suggesting
that social factors are neglected but relevant risk factors
for poor diabetes control.109 Little direct evidence exists for
the cognitive behavioural model for depression in type 1
diabetes, but most psychological treatments to improve
glycaemic control apply cognitive behavioural techniques
with small but clinically significant effects.84
Summary: link between depression and type 1 diabetes
The consensus suggests that worsened depressive
symptoms are noted in patients with type 1 diabetes, but
whether these symptoms consistently correlate with
poor glycaemic control is unclear, and understanding of
mechanisms of depression in patients with type 1
diabetes is limited. The close chronological relation
between type 1 diabetes and onset of depression is
striking, with ongoing adjustment to diagnosis of type 1
diabetes and its treatment burden occurring at a time of
increasing vulnerability to depression. Further research
is needed to identify factors predicting depression,
comparing biological (inflammation), psychological
(family and individual), and environmental (schooling
and social adversity) risk factors for depression in large
population-based prospective cohorts of patients with
type 1 diabetes, comparing them with healthy controls,
with patients with other long-term disorders, or both,
across the life course. Additionally, studies are needed to
develop sophisticated psychological models of diabetes—
468
looking beyond CBT—such as whether attachment
theory might help to explain depression in patients with
type 1 diabetes.
Future directions
In both type 1 and type 2 diabetes, greater understanding
is needed of the similarities and differences between
correlates of depressive symptoms, depression, and
diabetes-specific distress. In type 1 diabetes, further
research is needed to identify risk factors for depression,
taking developmental stage into account, by use of
systematic models of family dynamics, CBT, attachment
theory, and key transition points in adolescence. Further
research should investigate potential biological and
cerebral correlates of depression in patients with type 1
diabetes, to elucidate potentially modifiable factors for
treatment of depression in these patients. In type 2
diabetes, further basic science research, such as studies
in animals, could identify clearly the concurrent effects
of biological processes, both peripherally and centrally.
Although consistent neuroimaging correlates of both
type 2 diabetes and depression have been reported
separately, almost no studies have investigated the two
disorders together. Large, well characterised cohorts are
needed to test whether shared origins of depression and
type 2 diabetes exist at a genome-wide association
significance level. At the same time, future research
should examine the longitudinal relation between
depression and prediabetes stages, which might provide
opportunities for timely interventions to slow down or
stop the course of diabetes, depression, or both.
More research is needed to investigate depression and
type 2 diabetes concurrently across the life course, and to
identify clearly their temporal relation and biological
correlates. Because most patients with depression do not
develop type 2 diabetes, and vice versa, future research
should identify biological characteristics of individuals at
high risk of these disorders and associated complications.
The further upstream that interventions target these
shared biological pathways, the greater the clinical
benefit will be. In established type 2 diabetes, for
example, identification of biomarkers predicting
macrovascular complications could delay or prevent their
onset. Characterisation of biomarkers of depression in
patients with type 2 diabetes could identify patients who
might benefit from anti-inflammatory medications or
other immune-modifying therapies. Most excitingly,
identification and modification of upstream biomarkers
of both depression and type 2 diabetes could, in some
cases, wholly prevent development of these two chronic
and debilitating disorders.
Contributors
CDM did the literature search and wrote the first draft. KI wrote the
outline for the paper. JCP and KI revised the manuscript. All authors
approved the final draft.
Declaration of interests
We declare no competing interests.
www.thelancet.com/diabetes-endocrinology Vol 3 June 2015

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