The role of depression in the intergenerational transmission of type 2 diabetes

Scientific background
The scientific background should be a short introduction to the available literature and the scientific gap that the current proposal is going to fill. Type 2 diabetes (T2D) is a prevalent disease(1). The onset of T2D occurs as many as 10-15 years before the clinical diagnosis of the disease (2). Family history of T2D is a major risk factors for T2D(3). Familial aggregation studies estimate the heritability of diabetes to be approximately 25%(4-6). Genetic variants (>100) associated with T2D identified by genome-wide association studies explain 
less than 10% of the disease’s heritability(7, 8), suggesting that a substantial proportion of the 
remaining heritability comes from shared behaviours and shared environmental factors. The 
mechanisms by which parental T2D confers T2D risk to offspring are not well understood. Two large epidemiological studies(9, 10) found that offsprings’ lifestyle, metabolic factors, and genetic factors explained only a small proportion of the excess risk of T2D associated with T2D family history, thereby highlighting that important familial influences on T2D risk remain undiscovered. Depression might play an important role in the intergenerational transmission of T2D, though it has not yet been explored. There is evidence that offspring of parents with depression are diagnosed with more health conditions than offspring of parents without depression(11, 12). There are several ways that parental depression history (PDH) could increase the risk of T2D in offspring. For example, PDH increases the risk of intergenerational transmission of overweight and obesity in children and adolescents through parenting practices related to child diet, screen behaviours, and physical 
activity, which, in turn, increases the risk of obesity in adulthood and the risk of developing T2D(13). PDH has also been associated with a 13 times higher risk of depression in the offspring(14-17); separate research indicates that depression increases the risk of T2D(18-20). Children of depressed mothers show patterns of stress generation, which contribute to chronic stress or the failure to resolve difficulties and may lower threshold for depressive reactions to stress, which also increases the risk of T2D(21). The combination of parental T2D and PDH might increase the risk of T2D in offspring in a synergistic way.
Although the intergenerational transmission of T2D risk factors from parents to children has 
consistently been demonstrated, there are individual differences in vulnerability, with some offspring developing T2D and others maintaining healthy functioning. Thus, a key endeavor is to identify protective characteristics in offspring that decrease vulnerability to the effects of parental T2D. 
Stress resilience, the ability to adapt successfully to stress and adversity(22), is recognised as a determinant of both mental(23) and somatic health(24, 25). There is evidence that high stress resilience may play an important role in the prevention of T2D(25). Flourishing(26, 27) is a broader concept than resilience and has received increasing attention recently. It is goes beyond psychological assets and is defined as the combination of social, emotional, physical and psychological well-being(28). Flourishing has been associated with a decreased risk of chronic conditions, including T2D(29-31). Resilience and flourishing are separate but related entities that might decrease the risk of T2D onset in individuals with parental T2D and PDH. 

What is known from the literature?
Intergenerational transmission of T2D: Meigs et al.(32) evaluated the parental transmission of T2D in the Framingham study in the USA. They found that 24% of participants with T2D had one parent with T2D and 2% had two parents with T2D. Similar results were reported in a large Dutch cohort study (33). A Swedish study using administrative data(34) found that 28% of participants with T2D had one parent with T2D and 1% had two parents with T2D. 
Modifiable risk factors for T2D: Metabolic abnormalities, often summarized as the metabolic 
syndrome, have been promoted as a method of identifying individuals at increased risk of T2D(35). The metabolic syndrome is associated with a five times higher risk for incidence of T2D(36). Physical activity helps preventing T2D both directly, by improving insulin action, and indirectly, by reducing overall obesity and reducing the proportion of body fat in the central abdominal region, while physical inactivity is a risk factor for T2D(37). Smoking and alcohol abuse have been associated with an increased risk of T2D(38, 39). Low socioeconomic status might have an indirect effect on T2D incidence due to its association with obesity and physical inactivity(40). Non-modifiable risk factors for T2D: Age, non-white race or ethnicity(41, 42), history of gestational diabetes, and low birth weight(43) are associated with T2D incidence. Recent genome-wide association studies suggest that the genetic architecture of T2D is determined by common risk variants in multiple gene loci, but the effect sizes are very small(44). According to the results of a European case-control study, only approximately 10% of the T2D variability can be explained by T2Dsusceptible loci(45, 46).
Depression as a risk factor for T2D: Two meta-analyses(18, 47) and additional recent prospective studies(48-53) suggest an association between depressive symptoms and incidence of T2D. Several diabetes risk factors are associated with depressive symptoms: depressed individuals are less likely to comply with dietary and weight loss recommendations(54) and are more likely to be physically inactive(55). There is evidence that depressed individuals have higher caloric intake(56), and are 
more likely to be smokers(56). Additionally, depressive symptoms are associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis, dysregulation of the sympathoadrenal systems(57)
and increased inflammation(58), which can induce insulin resistance and contribute to T2D risk(58). Furthermore, some antidepressant medications are associated with an increased risk of T2D(59), partly because they can cause weight gain and obesity(59). 
Intergenerational transmission of depression: Parental depression is one of the most robustly 
established risk factors of child and adolescent psychopathology. A meta-analysis found a correlation of 0.23 for maternal depression and offspring internalizing problems(60). A recent study from Finland, using a 20% random sample of Finns born between 1986 and 1996, found that exposure to maternal depressive symptoms posed an equal risk for girls and boys, whereas the effect of paternal depressive symptoms was weaker for girls than for boys(61). The mechanisms explaining how parental depression compromises healthy child development are complex and multifaceted, including various biological and psychosocial mechanisms (e.g., impaired parenting and interparental conflict(62, 63)). 
According to the original formulation of the stress generation hypothesis(64), individuals with a history of depression, relative to their never-depressed counterparts, encounter a higher rate of stressful life events that are dependent, at least in part, on their own actions. Specifically, the stress generation model hypothesizes that depressed individuals behave in ways that contribute to the occurrence of additional stressors (i.e., they generate dependent life events), which in turn maintain depression or increase the risk of relapse(65). Maternal depression is also associated with social disadvantage, marital conflict and risk of overt maltreatment(66, 67), all of which predict depression in adolescence and adulthood. 
Chronic stress as a risk factor for T2D: Perceived chronic stress has been associated with the
development of T2D(68-70). Exposure to chronic stress may contribute to unhealthy lifestyle 
behaviours that are known risk factors for T2D (68, 71). Chronic stress also activates the 
hypothalamic–pituitary–adrenal (HPA) axis, resulting in increased cortisol levels that may contribute to abdominal obesity(72) and mobilizes biological responses implicated in T2D, including the release of glucose and lipids into the circulation, inflammatory cytokine expression and increased blood pressure(73). T2D and Depression: The prevalence of depression in adults with T2D is approximately twice as high as the prevalence of depression in adults without T2D(74, 75). The risk of incident depression is also approximately 24% higher in those with T2D compared to those without T2D(76). Stress resilience as a protective factor for T2D: Psychological stress arises from an imbalance between exposure to potentially stressful conditions and an individual’s capacity to cope(77). When coping resources are stretched beyond their limits by long-term exposure to severe stress, the result 
is a state of chronic allostatic load that involves dysregulation of multiple neuroendocrine, 
cardiovascular, metabolic and inflammatory pathways(78). Resilience refers to the ability to be 
flexible and adaptive in response to challenges(79). This includes the ability to endure difficult 
experiences, including change, personal problems, illness, pressure, failure, and painful feelings. 
Empirical evidence suggests that resilience is grounded in a diverse array of genetic(80), 
biological(81), psychological(82), and environmental(83) factors. A large prospective study in Sweden found that low stress resilience in young men was associated with an increased risk of developing T2D after adjusting for BMI, family history of diabetes, and individual and socioeconomic factors(25). Flourishing as a protective factor for T2D: The term flourishing has been used for a long time and literally means “to grow” or “to prosper”. It represents an important powerful way to view health in its fullest sense(26, 84). Increasingly rigorous research has demonstrated that a range of positive psychological, social, and environmental factors (including wellbeing) powerfully affect physical and mental health, often with effect sizes of comparable magnitude to what is observed with conventional risk factors(27). For example, increasing evidence has demonstrated that life satisfaction or having a sense of optimism are prospectively associated with lower T2D incidence(31, 85-87). Potential mechanisms include biological alterations (e.g., healthy lipid profiles)(88, 89) and better health behaviors (e.g., physical activity)(29, 90). Flourishing is not limited to psychological well-being; it also includes physical and social well-being(84).