T2DM is a multi-factorial disease and various common chronic diseases or pathological status are closely related to initiation of T2DM. therefore, more attention should be paid to explore whether multimorbidity of diseases or pathological status could synergistically promote the occurrence of T2DM. To our best knowledge, this is the first prospective study to demonstrate the combined effect of MetS and depression on the susceptibility of T2DM from a position of multimorbidity. In this general population-based prospective study of Chinese adults, we uncovered that MetS and depression are independently associated with an increased risk of T2DM. More importantly, the combined exposure of MetS and depression was more strongly associated with the risk of T2DM when compared with exposure to single disease. It is noteworthy that a growing risk of T2DM with MetS combined with depression was more apparent in the population of age≥60 years, male, overweight.
Several cohort studies have shown that MetS was associated with an increased risk of T2DM, which was further verified among southwest China general population presented in our study. Moreover, a study showed that the MetS is associated with a 5-fold increased risk for incident T2DM[31]. The risk of DM with MetS at baseline was twice over those who with non-MetS, as evidenced by a 4-year follow-up study[32] .Based on Guizhou general population study, we determined that the presence of MetS increased 45% risk of T2DM. However, the detailed underlying mechanisms that responsible for the positive correlation between MetS and T2DM is largely unknown. But there are several potential biological mechanisms may partially explain for these founds. First, obesity and insulin resistance are commonly co-occurrence on MetS patients [31]. Insulin resistance, one of key component of MetS, is present in many metabolic disorders, such as T2DM and MetS, and is responsible for many metabolic perturbations. Second, MetS and T2DM share many common risk factors, including age, overweight or obese, nutrition and lifestyle modification [33, 34].
Similarly, previous studies have shown that depression also increases the risk of T2DM. Luo, et al found that depressive symptoms present as a risk factor for DM among elderly[35] . Moreover, a prospective study evaluated the correlation between severe depressive episode and T2DM in China[36], which is in line with our study. Pathophysiological mechanisms by which depression increases risk of T2DM also have been explained. First of all, depression was related to hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, which contributed to the increased release of counterregulatory hormones, resulting in abdominal adiposity and insulin resistance[18, 22]. Second, dysregulated immune system functions as a mediator mechanism between depression and increased risk of T2DM. Furthermore, increased C reactive protein, TNF-α, and proinflammatory cytokines are also found to be associated with both depression and T2DM[37-39]. Collectively, the above biological mechanisms may responsible for the depression-related increased risk of T2DM.
Due to the improvement of lifestyle and increasingly social stress, the probability of people simultaneously suffering from metabolic disorder and mental illness has greatly increased. We found that MetS combined with depression could synergistically associated with increased risk of T2DM, which is more higher than that MetS only or depression only, suggesting that MetS and depression may have a superimposed effect on the occurrance of T2DM. However, the underlying mechanisms for the combined effects for T2DM need further determined. It is well-established that multiple organ damage is more likely to increase the risk of various complications than single organ damage. Other plausible reason is that both MetS and depression could induce systemic proinflammatory responses which was a key feature of T2DM [40, 41]. As the action mode of mechanistic pathways underlying the relationships of depression or MetS with risk of T2DM are similar. Therefore, the multiplicative effect of both depression and MetS might contribute to the substantially stronger pro-pathogenic effect of the multimorbidity of depression and MetS on T2DM risk. Thus, the people who suffer both depression and MetS could generate more sever inflammatory reaction, which makes people with comorbidity of MetS and depression have an apparently increased risk of T2DM. Our finding imply that individuals with MetS combined with depression should be more severely targeted for preventing and screening T2DM.
In the stratified analysis, we found that patients with depression and MetS are more likely to suffer from T2DM among the population with age > 60 years, male, overweight, and the above results was consistent with previous studies[33, 34]. Our results suggested that people with BMI≥24 kg/m2 and abnormal metabolic should be taken seriously in Chinese for prevention and delay the occurrance of T2DM. Hence, adopting a healthy lifestyle pattern and weight loss is a major determinant to reach maximize effectiveness for decreasing the risk of T2DM.
The strengths of our study were its long duration of follow-up and its prospective cohort study design, which firstly prospective study the impact of depression combined with MetS on the incidence of T2DM. However, our study has several potential limitations. First of all, although we excluded patients with T2DM at baseline, we cannot conclude that whether the people of depression at baseline are not caused by T2DM, because a bidirectional relationship between T2DM and depression, which may cause some deviation. Second, some participants were loss to follow up as well as some missing information regarding confounders. However, sufficient number events and a high follow-up rate provided sufficient statistic power. Finally, the enrolled participants were only restricted in Guizhou Province, China. So, the extrapolation of the results should be cautious. Therefore, further prospective large-scale studies are needed to verify these results in other regional populations.