Major depressive disorder (MDD) is a severe neuropsychiatric disorder characterized by persistent low mood, lack of interest and loss of pleasure. The number of people suffering from MDD is increasing every year, and by 2030, depression will be the second largest burden of disease worldwide (1). Depression can negatively affect the patient’s clinical parameters, especially glucose and lipid metabolism indicators (2). Despite the widespread use of antidepressants, however, only 30% of patients achieve remission with initial antidepressant therapy (3). Therefore, there must be other unrevealed mechanisms and pathologies underlying depression that need to be explored.

The relationship between MDD and disorders of glucose metabolism has been widely explored, and as early as 1931, McCowan et al. observed that patients with MDD had concomitant abnormalities in glucose tolerance that improved with remission of depressive symptoms (4). The relative risk of developing diabetes in patients with MDD is 1.2-2.6 times higher than that of the healthy population (5). Research evidence suggests that depressive symptoms can trigger disturbances in glucose metabolism in individuals (6). Patients with MDD may have varying degrees of abnormal glucose metabolism, including elevated or reduced fasting glucose, insulin and glucagon levels (7, 8). On the other hand, patients with diabetes are twice as likely to develop MDD as normal healthy people (9). High levels of HbA1c and poor glycemic control are associated with an increased incidence of MDD (10, 11). The glucose metabolic status of patients with type 2 diabetes also improves or worsens with changes in the severity of depressive symptoms (12).

The correlation between depressive symptoms and glucose metabolism is related to a variety of factors, including signaling pathways, genetic factors, and especially metabolic factors. In the last 20 years, obesity/overweight is becoming one of the causes of health impairment and a major cause of glucose metabolism disorders (13). Furthermore, MDD patients have a 58% increased risk of developing obesity (14). In addition, obese or overweight MDD patients have a lower quality of life and a poorer prognosis (15). Evidence from our recent study showed that among Chinese Han FEDN MDD patients, obese or overweight individuals have a 55% increased risk of developing MDD compared to normal healthy individuals (14).

Several studies have reported on the relationship between overweight/obesity, MDD, and glucose metabolism disorders, but the results have been inconsistent. For example, Hryhorczuk et al. found that abnormal glucose metabolism resulting from central obesity may be the main reason for the increased incidence of MDD in obese patients (16). Haleem et al. reported that fasting glucose levels were higher in obese men with depression than in non-depressed patients (17). However, a German study with 4597 participants and a Dutch study with 4747 participants both reported no association between depressive symptoms and diabetes (18, 19). Aujla et al. found that the prevalence of depressive symptoms was not higher in the diabetic population than in the normal healthy population (20).

The variables involved in these studies that led to inconsistent results may be due to differences between the subjects included in the studies, such as patients being at different stages of the disease and being of different ethnicities. Also, the methods of blood biochemistry tests used and the criteria for normal groups differed between races, regions, and hospitals. More importantly, there are more risk factors that affect the relationship between obesity/overweight, MDD, and glucose metabolism disorders. mcmartin et al. reported an inverse relationship between fruit and vegetable intake and MDD, and that poor diet can negatively affect mental health disorders (21). Second, exercise may reduce depression by distracting from depressive symptoms and promoting self-efficacy. Dietary control and exercise also moderately lower postprandial glucose and insulin, and are more effective in people with higher BMI (22). slyepchenko et al. suggested that environmental triggers, such as excessive psychological stress, sleep disturbance, poor diet, physical inactivity, and smoking, as well as medical factors, including autoimmune diseases, contribute to a greater risk of obesity/overweight and glucose metabolism disorders in people with MDD (23). Therefore, we wanted to investigate whether overweight/obese patients with MDD are more likely to develop glucose metabolism abnormalities and what factors are involved in this pathogenesis.

First-episode and drug-naïve (FEDN) MDD patients may provide an exceptional opportunity to examine which risk factors are associated with glucose metabolism disorders occurring in overweight/obese MDD patients, while minimizing the impact of confounding factors, including disease duration, comorbidities, and medications. To our knowledge, no studies have been reported in the Chinese Han population about glucose metabolism disorders in overweight/obese FEDN MDD patients. Therefore, this is the first study to examine the incidence of elevated fasting glucose and clinically relevant factors in Chinese Han overweight/obese FEDN MDD patients.

It is hoped that the results of this study will help to identify biomarkers of glucose metabolism disorders in overweight/obese MDD patients. Therefore, it is hoped that the results of this study will help clinical staff to improve daily screening and early prevention to prevent patients from developing complications such as diabetes mellitus.

To our knowledge, this is the first cross-sectional study with a large sample size to explore the prevalence and clinical correlates of elevated fasting glucose in overweight/obese FEDN MDD patients. The main findings of this study were: (1) elevated fasting glucose in overweight/obese MDD patients was associated with TSH, TgAb, TPOAb, and TG; (2) TSH had the potential to differentiate the MDD patients with elevated fasting glucose from those with normal fasting glucose; and (3) TSH, TG, and LDL-C were independently associated with elevated fasting glucose in overweight/obese MDD patients.

Our study showed that TSH, TG and LDL-C were factors associated with elevated fasting glucose in overweight/obese FEDN MDD patients, with the elevated fasting glucose group being significantly higher than the normoglycemic group. The reasons and mechanisms for this phenomenon may be as follows: First, the concentration of 5-hydroxytryptamine in the brain is reduced in patients with major depression, leading to an increase in the concentration of thyrotropin-releasing hormone (TRH), which accelerates the secretion of TSH (28). Increased serum TSH can then act on TSH receptors in adipocytes to inhibit adipose triglyceride lipase, which in turn causes increased storage of triglycerides and an increase in adipocyte size, ultimately leading to overweight or obesity (29). Excess adipose tissue, especially large abdominal accumulations of dysfunctional fat, in turn increases triglyceride and LDL-C production, ultimately triggering insulin resistance and glucose dysregulation (30, 31); thus, elevated TSH, TG, and LDL-C may trigger elevated fasting glucose in overweight/obese FEDN MDD patients. However, some details are unknown and more large sample investigations and animal experiments are needed to prove this.

Our study found that overweight/obese MDD patients were more likely to have elevated fasting glucose levels compared to patients with normal BMI, indicating an increased risk of developing diabetes, and the results of some previous studies are consistent with ours. For example, Haleem et al. reported that obese MDD patients had higher fasting glucose levels than non-depressed obese patients and that depression severity was positively associated with elevated serum glucose (18). Zhang et al. found that overweight MDD patients had higher fasting glucose levels than non-overweight MDD patients at different ages of onset (32). Our results also showed that MDD patients with elevated fasting glucose also had significantly higher TSH, TPOAb, TC, TG, LDL-C, and systolic and diastolic blood pressure compared to patients with normal fasting glucose. These differences suggest that the overall severity of metabolic disorders is also increased in MDD patients with abnormal fasting glucose.

The association of depressive symptoms with dysregulated glucose metabolism in never-treated MDD patients involves an imbalance in the neuro-endocrine network and, as a result, increasing attention has been paid to neuroendocrine mechanisms. First, one of the main triggers of glucose metabolism disorders due to overweight/obesity has been reported to be insulin resistance. Patients with MDD are at particularly high risk of developing overweight or obesity (33), and abdominal fat accumulation induces insulin resistance, meaning that overweight or obese MDD patients are more likely to develop glucose metabolism abnormalities (34). Furthermore, the reduction of depressive symptoms was positively correlated with the remission of insulin resistance (35). The insulin sensitizer pioglitazone alone significantly improved depressive symptoms in MDD patients with abdominal obesity after 12 weeks of treatment (35). Insulin also produces antidepressant effects by reducing visceral fat (36). However, it has also been reported that there is little association between insulin resistance and depression (37–39). Second, one of the endocrine signs of MDD is an abnormally increased activity of the hypothalamic-pituitary-adrenal system (HPA axis), followed by cortisolism. Cortisol is a well-known anti-insulin hormone. Sustained high levels of cortisol increase the intake of high-calorie foods and drive the accumulation of visceral fat. The endocrine sequelae of hypercortisolism are mainly hyperglycemia and hyperinsulinemia (40). Third, elevated glucocorticoid concentrations, also a common endocrine marker in MDD, are closely associated with dyslipidemia, impaired glucose homeostasis, hypertension, and abdominal obesity (41). Taken together, multiple risk factors such as insulin resistance, hypercortisolism, and elevated glucocorticoid concentrations may be mechanisms underlying abnormal glucose metabolism in overweight/obese MDD patients, but the exact mechanisms are inconclusive and require subsequent in-depth studies.

In addition, this study showed that higher HAMA score was positively associated with elevated fasting glucose in overweight/obese MDD patients. Several studies have reported a relationship between anxiety symptoms and glucose metabolism, but the results are not entirely consistent. For example, Simon et al. found a causal relationship between anxiety symptoms and weight gain or obesity (42), which in turn was associated with elevated glucose and insulin concentrations (43, 44). Abnormally elevated glucose can further interfere with an individual’s mood (45). However, Jaremka et al. reported no change in glucose levels in individuals with significant anxiety symptoms in those with larger waist circumference (46).

The present study has some limitations. First, the present study used a cross-sectional design, so the results did not explain the causal relationship between elevated fasting glucose and BMI in patients with MDD. Future studies should focus on longitudinal studies with the aim of further exploring the relationship between BMI and glucose metabolism in MDD. Second, studies have shown that fasting glucose alone is not sufficient to diagnose abnormal glucose metabolism. Moreover, HbA1c and oral glucose tolerance test (OGTT) are more sensitive measures of abnormal glucose metabolism than fasting glucose (47). However, unfortunately, in the present study, we did not collect data on HbA1c and OGTT and therefore could not fully elucidate further conclusions on impaired glucose metabolism in MDD patients. Third, unhealthy lifestyles, especially high-calorie diet and sedentary lifestyles, may make patients more susceptible to metabolic disorders such as hyperlipidemia, hypertension, and metabolic syndrome (48, 49). Unfortunately, we did not collect data in this area, which should be included in future studies. Fourth, a healthy control group was not set up in this study. In addition, the prevalence of metabolic disorders was higher among the immediate family members of MDD patients compared to healthy controls, and unfortunately (50), we did not investigate the family history of diabetes in the participants in this study, which should be corrected in future studies. Fifth, the sample included in this study consisted of patients with FEDN MDD, so the conclusions drawn cannot be extended to MDD patients with a history of recurrent episodes and medication use.

Identification of accurate risk factors is a promising approach to effectively prevent elevated fasting glucose in overweight/obese MDD patients. Our findings show that the prevalence of elevated fasting glucose is much higher in overweight/obese FEDN MDD patients than in MDD patients with normal BMI. Age, disease duration, TSH, TgAb, TPOAb and TG were related factors for elevated fasting glucose in overweight/obese FEDN MDD patients. These results are important for clinical practice because changes in metabolic markers might be a biomarker of elevated fasting glucose. Second, the prevalence of elevated fasting glucose was higher in overweight/obese FEDN MDD patients with high TSH, TG, and LDL-C levels.

In conclusion, our results showed that the prevalence of elevated fasting glucose in overweight/obese FEDN MDD patients was much higher than that in MDD patients with normal BMI. Second, TSH, TgAb, TPOAb, and TG are related factors for elevated blood glucose in overweight/obese FEDN MDD patients.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the ethics committee of the First Hospital of Shanxi Medical University. The patients/participants provided their written informed consent to participate in this study.

WG wrote the original manuscript. ZD, XC, and DZ analyzed the data. HX and XZ supervised the project and revised the manuscript. All authors contributed to the article and approved the submitted version.