Background
Type 1 diabetes (T1DM) is an autoimmune disease, characterized by insulin deficiency due to pancreatic beta cell loss leading to hyperglycaemia [
1]. The introduction of intensive insulin therapy for patients with T1DM has resulted in an increased prevalence of the components of the metabolic syndrome, contributing to an amplified prevalence of cardiovascular complications [
2]. Inflammatory disturbances also contribute to cardiovascular disease [
3].
In patients with diabetes, depression is associated with increased prevalence of all diabetes-related complications [
4], and with increased cardiovascular and all-cause mortality [
5]. Depression has been linked to metabolic, autonomic and hypothalamic-pituitary-adrenal (HPA)-axis dysregulations with subsequent disturbances of cortisol secretion [
6,
7], and there is growing evidence that immuno-inflammatory changes contribute to the development of depression [
6‐
10]. Insulin deficiency, hyperglycemia as well as episodes of hypoglycemia all have impact on the brain, and might contribute to the development of depression in patients with T1DM [
7].
The tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is a transmembrane protein, which is a member of the tumour necrosis factor (TNF)-receptor super family [
11]. TWEAK is proteolytically processed by furin which leads to the release of soluble (s)TWEAK [
11]. In the reverse process, sTWEAK binds to the functional receptor of TWEAK, Fn14 [
12]. The receptor Fn14 is highly upregulated in systemic inflammatory states, which leads to increased sTWEAK binding and subsequently lower levels of sTWEAK [
12]. The TWEAK/Fn14 axis plays a beneficial role in tissue repair after acute injury. However, it has been shown that chronic TWEAK/Fn14 axis activation is implicated in the development of cardiovascular disease [
12]. High levels of sTWEAK are released by normal arteries, but are diminished in people with chronic vascular damage such as carotid stenosis, coronary artery disease and heart failure [
12,
13], resulting in an increased risk for cardiovascular mortality [
14]. Proinflammatory effects of TWEAK on astrocytes in vitro implies that TWEAK could play a significant role in brain inflammation [
15]. Low sTWEAK levels have been demonstrated in people with T1DM [
16], type 2 diabetes mellitus (T2DM) [
17], and gestational diabetes [
18]. Low sTWEAK levels have also been demonstrated in depressed people without diabetes [
19], and in people with bipolar disorder during ongoing manic episodes [
20]. Galectin-3 is a beta-galactoside-binding lectin involved in several inflammatory processes [
21]. Increased galectin-3 levels have been linked to coronary artery disease [
22,
23], heart failure [
24,
25], prolonged inflammatory responses in the brain [
26], and to cardiovascular and all-cause mortality [
25,
27]. Systemic inflammation causes decreased high-density lipoprotein (HDL)-cholesterol levels which contribute both to reduced capacity for reverse cholesterol transport, and to reduced capacity to protect low-density lipoprotein (LDL)-cholesterol from oxidation [
28]. Low HDL-cholesterol levels were previously associated with high levels of galectin-3 binding protein in these patients [
29]. Inadequate glycemic control contributes to increased cardiovascular and all-cause mortality [
30].
Systematic exploration of these T1DM patients showed that self-reported depression was associated with inadequate glycemic control [
31], midnight salivary cortisol secretion [
32], galectin-3 [
33], and inversely with HDL-cholesterol [
34]. Depression was not associated with sex, obesity, blood pressure, total cholesterol, LDL-cholesterol, triglycerides, antihypertensive drugs, lipid-lowering drugs, physical inactivity or smoking habits [
34]. Neither was depression associated with the inflammatory variables galectin-3 binding protein [
29], soluble sCD163 [
35], the soluble receptor for advanced glycation end products (sRAGE), nor the extracellular newly identified receptor for advanced glycation end products (EN-RAGE) [
36].
We hypothesised that one biological link between depression and cardiovascular complications in depressed patients with T1DM is a chronic inflammatory state due to TWEAK activation with subsequent low levels of sTWEAK. The main aim was to explore whether low levels of sTWEAK were associated with depression in T1DM patients. A secondary aim was to explore diabetes related variables associated with low sTWEAK.
Results
In this study 283 patients with T1DM (56% men), 18–59 years old, diabetes duration 1–55 years were included. Baseline characteristics and laboratory results are compared between 29 patients with depression and 254 patients without depression in Table
1. All patients used either MDII (91%) or CSII (9%). The depressed patients had lower median sTWEAK (
p = 0.017) and median cholesterol (
p = 0.044); and had higher prevalence of high galectin-3 (
p = 0.005), high HbA1c (
p = 0.026), use of antidepressants (
p < 0.001), and cardiovascular complications (
p = 0.012).
Table 1
Baseline characteristics, laboratory results, and comparisons between 29 depressed and 254 non-depressed patients with T1DM
N | 283 | 29 | 254 | |
Age (years) | (18–59) | 49 (38, 53) | 42 (31, 50) | 0.036 |
Diabetes duration (years) | (1–55) | 21 (11, 35) | 20 (10, 29) | 0.45 |
Sex |
Women | 124 (44) | 13 (45) | 111 (44) | > 0.99 b |
Men | 159 (56) | 16 (55) | 143 (56) |
Depression | 29 (10) | – | – | – |
sTWEAK (ng/ml) c | (0.5–1618) | 1.5 (1.2, 2.9) | 2.7 (1.3, 13.4) | 0.017 |
Galectin-3 (ng/ml) d | (0.001–100.0) | 1.3 (0.8, 3.0) | 0.9 (0.5, 1.6) | 0.011 |
High galectin-3 (≥2.6 ng/ml) d | 41 (15) | 10 (34) | 31 (13) | 0.005 b |
HbA1c |
mmol/mol | (25–110) | 68 (55, 73) | 63 (54, 70) | 0.056 |
% | (4.4–12.2) | 8.4 (7.2, 8.8) | 7.9 (7.1, 8.5) |
High HbA1c (> 70 mmol/mol (> 8.6%)) | 75 (26) | 13 (45) | 62 (24) | 0.026 b |
Total cholesterol (mmol/l) | (2.1–10.9) | 4.3 (4.0, 4.8) | 4.6 (4.1, 5.2) | 0.044 |
LDL-cholesterol (mmol/l) | (0.6–8.3) | 2.8 (2.2, 3.2) | 2.8 (2.4, 3.3) | 0.37 |
Triglycerides (mmol/l) | (0.06–5.9) | 0.9 (0.7, 1.5) | 0.9 (0.7, 1.2) | 0.35 |
HDL-cholesterol (mmol/l) | (0.3–2.7) | 1.3 (1.2, 1.6) | 1.6 (1.3, 1.8) | 0.015 |
Triglycerides/HDL-cholesterol ratio | (0.04–5.9) | 0.6 (0.5–1.4) | 0.6 (0.4–0.9) | 0.23 |
S-Creatinine (μmol/l) e | (28–182) | 72 (63, 80) | 70 (62, 78) | 0.94 |
Abdominal obesity f | 46 (17) | 6 (21) | 40 (16) | 0.43 b |
BMI (kg/m2) g | (17.8–45.2) | 23.8 (21.8, 27.3) | 24.8 (22.8, 27.5) | 0.21 |
Systolic BP (mm Hg) | (90–160) | 120 (112, 135) | 120 (110, 130) | 0.99 |
Diastolic BP (mm Hg) | (55–100) | 70 (68, 78) | 70 (70, 75) | 0.90 |
Hypoglycemia (severe episodes) | 12 (4) | 2 (7) | 10 (4) | 0.36 b |
Smoking h | 28 (10) | 5 (18) | 23 (10) | 0.19 b |
Physical inactivity i | 29 (11) | 5 (18) | 24 (10) | 0.20 b |
Continuous subcutaneous insulin infusion | 25 (9) | 3 (10) | 22 (9) | 0.73 b |
Antidepressants | 22 (8) | 9 (31) | 13 (5) | < 0.001 b |
Lipid lowering drugs | 130 (46) | 14 (48) | 116 (46) | > 0.84 b |
Antihypertensive drugs | 89 (31) | 10 (34) | 79 (31) | 0.68 b |
Cardiovascular complications | 10 (4) | 4 (14) | 6 (2) | 0.012 b |
Associations with depression are presented for log transformed sTWEAK and four levels of low sTWEAK, representing the 60th, 65th, 70th, and 75th percentiles of sTWEAK, are presented in Table
2. sTWEAK < 7.2 ng/ml (< 70th percentile) showed the highest association with depression (adjusted odds ratio (AOR) 6.5,
p = 0.010) compared to the 60th, 65th, 75th percentiles and log transformed sTWEAK (all
p-values > 0.48 for the AORs).
Table 2
Elimination analyses between log transformed sTWEAK, 4 levels of dichotomized sTWEAK and depression
sTWEAK (Lg10) | – | 0.2 (0.1–0.5) | 0.4 (0.1–1.1) | 0.017 d | 0.4 (0.2–0.9) | 0.027 | 1.7 (0.4–7.6) | 0.48 |
sTWEAK < 3.9 (ng/ml) | 167 (60) | 24 (83) | 143 (57) | 0.009 | 3.6 (1.3–9.6) | 0.012 | 1.4 (0.4–5.0) | 0.61 |
sTWEAK < 6.1 (ng/ml) | 181 (65) | 25 (86) | 156 (63) | 0.013 | 3.7 (1.3–11.0) | 0.018 | 0.5 (0.04–6.2 | 0.58 |
sTWEAK < 7.2 (ng/ml) | 195 (70) | 27 (93) | 168 (68) | 0.003 | 6.5 (1.5–28.0) | 0.012 | 6.5 (1.5–28.0) | 0.012 |
sTWEAK < 11.9 (ng/ml) | 209 (75) | 27 (93) | 182 (73) | 0.021 | 5.0 (1.2–21.5) | 0.032 | 0.0 (0.0-) | > 0.99 |
In Table
3 associations with depression are presented. Age (per year) (AOR 1.05,
p = 0.027), low sTWEAK (< 7.2 ng/ml) (AOR 9.0,
p = 0.006), high galectin-3 (AOR 6.3,
p = 0.001), HDL-cholesterol (per mmol/l) (inversely) (AOR 0.1,
p = 0.006), and use of antidepressants (AOR 8.4,
p < 0.001), were associated with depression.
Table 3
Variables associated with depression in patients with T1DM
Age (per year) | 1.04 (1.00–1.07) | 0.046 | 1.05 (1.01–1.10) | 0.027 |
Diabetes duration (per year) | 1.01 (0.98–1.04) | 0.46 | – | – |
Sex (women) | 1.0 (0.5–2.3) | 0.91 | – | – |
Low sTWEAK (< 7.2 ng/ml) | 6.5 (1.5–28.0) | 0.012 | 9.0 (1.9–43.2) | 0.006 |
High galectin-3 (≥2.6 ng/ml) | 3.6 (1.5–8.5) | 0.003 | 6.3 (2.2–17.8) | 0.001 |
High HbA1c (> 70 mmol/mol (> 8.6%)) | 2.5 (1.1–5.5) | 0.021 | 2.4 (0.9–6.3) | 0.067 |
Total cholesterol (per mmol/l) | 0.6 (0.4–1.0) | 0.040 | 0.7 (0.4–1.2) | 0.19 |
LDL-cholesterol (per mmol/l) | 0.7 (0.4–1.2) | 0.23 | – | – |
Triglycerides (per mmol/l) | 1.3 (0.8–2.0) | 0.23 | – | – |
HDL-cholesterol (per mmol/l) | 0.3 (0.1–0.8) | 0.020 | 0.1 (0.03–0.6) | 0.006 |
Triglyceride/HDL-cholesterol ratio (per unit) | 1.5 (1.0–2.3) | 0.038 | 1.2 (0.6–2.4) | 0.56 |
S-Creatinine (per μmol/l) | 1.00 (0.98–1.02) | 0.72 | – | – |
Abdominal obesity | 1.4 (0.5–3.7) | 0.47 | – | – |
BMI (per kg/m2) | 1.0 (0.9–1.1) | 0.38 | – | – |
Systolic BP (per mm Hg) | 1.00 (0.96–1.03) | 0.90 | – | – |
Diastolic BP (per mm Hg) | 1.00 (0.95–1.06) | 0.98 | – | – |
Hypoglycemia (severe episodes) | 1.8 (0.4–8.6) | 0.46 | – | – |
Smoking | 2.0 (0.7–5.9) | 0.19 | – | – |
Physical inactivity | 1.9 (0.7–5.6) | 0.22 | – | – |
Continuous subcutaneous insulin infusion | 1.2 (0.3–4.3) | 0.76 | – | – |
Antidepressants | 8.3 (3.2–21.9) | < 0.001 | 8.4 (2.7–26.1) | < 0.001 |
Lipid lowering drugs | 1.1 (0.5–2.4) | 0.79 | – | – |
Antihypertensive drugs | 1.2 (0.5–2.6) | 0.71 | – | – |
Cardiovascular complications | 6.6 (1.7–25.0) | 0.005 | 1.1 (0.2–6.3) | 0.92 |
Comparisons between patients with low sTWEAK levels (< 7.2 ng/ml), and high sTWEAK levels (≥ 7.2 ng/ml) are presented in Table
4. Fourteen percent of the patients with low sTWEAK were depressed and 2% of the patients with high sTWEAK were depressed (
p = 0.003). Patients with low sTWEAK used CSII (6%) to a lower extent than patients with high sTWEAK (17%) (
p = 0.005).
Table 4
Comparisons between 195 T1DM patients with low and 83 T1DM patients with high levels of sTWEAK
N | 195 | 83 | |
Age (years) | 42 (32, 51) | 42 (29, 51) | 0.79 |
Diabetes duration (years) | 20 (11, 30) | 18 (9, 29) | 0.58 |
Sex |
Women | 89 (46) | 30 (36) | 0.15 b |
Men | 106 (54) | 53 (64) |
Depression | 27 (14) | 2 (2) | 0.003 b |
High galectin-3 (≥2.6 ng/ml) c | 27 (14) | 14 (17) | 0.58 b |
High HbA1c (> 70 mmol/mol (> 8.6%)) | 53 (27) | 22 (26) | > 0.99 b |
Total cholesterol (mmol/l) | 4.6 (4.1, 5.2) | 4.5 (4.0, 5.0) | 0.13 |
LDL (mmol/l) | 2.9 (2.4, 3.4) | 2.8 (2.4, 3.2) | 0.34 |
Triglycerides (mmol/l) | 0.9 (0.7, 1.3) | 0.8 (0.7, 1.2) | 0.19 |
HDL (mmol/l) | 1.5 (1.3, 1.8) | 1.6 (1.3, 1.8) | 0.71 |
Triglycerides/HDL-cholesterol ratio | 0.6 (0.4–0.9) | 0.6 (0.4–0.8) | 0.23 |
S-Creatinine (μmol/l) d | 70 (62, 77) | 70 (62, 80) | 0.44 |
Abdominal obesity e | 33 (17) | 11 (13) | 0.48 b |
BMI (kg/m2) f | 24.6 (22.4, 27.9) | 24.6 (23.1, 26.1) | 0.92 |
Systolic BP (mm Hg) | 120 (110, 130) | 120 (110, 130) | 0.34 |
Diastolic BP (mm Hg) | 70 (70, 75) | 70 (65, 78) | 0.54 |
Hypoglycemia (severe episodes) | 7 (4) | 4 (5) | 0.74 b |
Smoking g | 20 (11) | 8 (10) | > 0.99 b |
Physical inactivity h | 24 (13) | 5 (6) | 0.19 b |
Continuous subcutaneous insulin infusion | 11 (6) | 14 (17) | 0.005 b |
Antidepressants | 16 (8) | 6 (7) | > 0.99 b |
Lipid lowering drugs | 92 (47) | 36 (43) | 0.60 b |
Antihypertensive drugs | 62 (32) | 26 (31) | > 0.99 b |
Cardiovascular complications | 8 (4) | 2 (2) | 0.73 b |
Associations with low sTWEAK levels are presented in Table
5. Depression (AOR 7.1,
p = 0.009) and the use of CSII (inversely) (AOR 0.3,
p = 0.003) were independently associated with low sTWEAK (< 7.2 ng/ml).
Table 5
Variables associated with low sTWEAK levels
Age (per year) | 1.00 (0.98–1.03) | 0.73 | – | – |
Diabetes duration (per year) | 1.00 (0.98–1.02) | 0.71 | – | – |
Sex (women) | 1.5 (0.9–2.5) | 0.14 | – | – |
Depression | 6.5 (1.5–28.0) | 0.012 | 7.1 (1.6–31.4) | 0.009 |
High galectin-3 (≥2.6 ng/ml) | 0.8 (0.4–1.6) | 0.49 | – | – |
High HbA1c (> 70 mmol/mol (> 8.6%)) | 1.0 (0.6–1.8) | 0.91 | – | – |
Total cholesterol (mmol/l) | 1.2 (0.9–1.6) | 0.19 | – | – |
LDL (mmol/l) | 1.2 (0.9–1.7) | 0.29 | – | – |
Triglycerides (mmol/l) | 1.3 (0.9–2.0) | 0.18 | – | – |
HDL (mmol/l) | 0.8 (0.4–1.7) | 0.60 | – | – |
Triglycerides/HDL-cholesterol ratio | 1.5 (0.9–2.6) | 0.11 | – | – |
S-Creatinine (μmol/l) | 1.00 (0.98–1.01) | 0.63 | – | – |
Abdominal obesity | 1.4 (0.6–2.8) | 0.42 | – | – |
BMI (per kg/m2) | 0.7 (0.4–1.3) | 0.26 | – | – |
Systolic BP (mm Hg) | 1.01 (0.99–1.03) | 0.33 | – | – |
Diastolic BP (mm Hg) | 1.00 (0.96–1.03) | 0.63 | – | – |
Hypoglycemia (severe episodes) | 0.7 (0.2–2.6) | 0.64 | – | – |
Smoking | 1.0 (0.4–2.5) | 0.92 | – | – |
Physical inactivity | 2.1 (0.8–5.9) | 0.14 | – | – |
Continuous subcutaneous insulin infusion | 0.3 (0.1–0.7) | 0.004 | 0.3 (0.1–0.6) | 0.003 |
Antidepressants users | 1.1 (0.4–3.0) | 0.78 | – | – |
Lipid lowering drugs | 1.2 (0.7–2.0) | 0.56 | – | – |
Antihypertensive drugs | 1.0 (0.6–1.8) | 0.94 | – | – |
Cardiovascular complications | 1.7 (0.4–8.3) | 0.49 | – | – |
Discussion
The main finding of this study of adult patients with T1DM was that the depressed patients had lower levels of sTWEAK than the non-depressed patients. Lower levels of sTWEAK and HDL-cholesterol, higher levels of galectin-3, the use of antidepressants, and age were independently associated with depression. The depressed patients had also higher levels of HbA1c, but the association between high HbA1c and depression was not independent in this context. The use of CSII was inversely associated with low sTWEAK.
Depression is a serious disease with somatic implications, including cardiovascular disease and all-cause mortality [
4‐
7]. Three independent risk factors or risk markers for cardiovascular disease were demonstrated in these depressed patients with T1DM. Low sTWEAK levels [
12‐
14] and high galectin-3 levels [
22‐
25,
27] have previously been linked to the development of cardiovascular disease and increased mortality. HDL-cholesterol levels decrease in inflammatory states [
28,
29]. HDL-cholesterol is an established risk marker for cardiovascular disease, but the role of HDL-cholesterol as a causal factor in cardiovascular disease is disputed [
44]. In previous research, we have not demonstrated any higher prevalence of metabolic disturbances in the depressed than in the non-depressed, except for increased HbA1c and lower HDL-cholesterol in the depressed patients [
31,
34]. In this study we added a proxy for insulin resistance [
41], which was not associated with depression. Increased HbA1c levels without associated obesity or signs of insulin resistance in the depressed patients could be due to inadequate insulin supply. Insulin deficiency has been suggested as one reason for the development of depression in patients with T1DM [
7,
45]. Users of MDII compared to users of CSII had more often low levels of sTWEAK. We haven’t found any previous research exploring the associations between sTWEAK and CSII.
One difficulty we had to address was that there is no established consensus regarding normal sTWEAK levels. Therefore, we explored and compared the associations between log transformed sTWEAK, four different definitions of low sTWEAK levels and depression. Low sTWEAK levels, defined as levels below the 70th percentile (< 7.2 ng/ml), showed the highest association with depression, and this cut-off level was therefore chosen in the further analyses.
To our knowledge, a potential association between sTWEAK and depression hasn’t previously been explored in patients with T1DM. Neither has it been explored whether low sTWEAK, high galectin-3, high HbA1c and low HDL-cholesterol were independently associated with depression. We only found one previous study exploring the association between sTWEAK and depression, and that study was performed in a population without diabetes [
19]. Their findings of an association between low sTWEAK levels and depression is in accordance with our findings. Another study showed that manic episodes were linked to low levels of sTWEAK levels [
20]. Both depressive states and manic episodes may be symptoms of brain inflammation. Our findings of low sTWEAK levels in the depressed patients imply activation of TWEAK, which has proinflammatory effects on the astrocytes in the brain, which have been demonstrated in vitro [
15]. According to previous research, galectin-3 may contribute to microglia activation with sustained inflammatory responses in the brain [
26]. These findings are potentially very important as it has been demonstrated in previous research that both astrocytes and microglia are involved in the development of depression [
46,
47].
There are several subjects for further research. As this is a cross-sectional study, we can’t clarify whether the depressed state leads to immunological disturbances, or if these immunological disturbances lead to a depressed state. To answer this question, it will be necessary to perform longitudinal studies. We will perform a follow-up exploring the impact of sTWEAK and galectin-3 on cardiovascular complications, comparing with conventional diabetes related risk factors. According to previous research, some antidepressants attenuate immuno-inflammatory changes [
9]. Whether antidepressants may have impact on the levels of sTWEAK and galectin-3 is a subject for further exploration. As immuno-inflammatory changes and the activation of the hypothalamic pituitary axis are part of the stress response, which is involved in depression, it would also be interesting to explore associations between sTWEAK, galectin-3 and cortisol secretion [
9]. To compare TWEAK levels between users of MDII and users of CSII in a future larger study would be very interesting. If our findings would be confirmed in a larger study, it would be a very important finding supporting the choice of CSII over MDII. Finally, development of novel therapeutics against the TWEAK/Fn14 axis may be of value both for the treatment or prevention of depression and cardiovascular disease.
Strengths of the study are that inclusion and exclusion criteria were well defined. No patients using systemic corticosteroids, or specific drugs for psychotic or bipolar disorders were included. The findings of this study are new as exploration of the association between sTWEAK and depression has not previously been performed in a clinically well-defined setting of T1DM. Neither has the mode of insulin distribution been explored against sTWEAK. The results were controlled for relevant variables which in previous research have been linked to either depression or cardiovascular complications, or to both. The logistic regression models were elaborated for the associations, and calibrated and validated for goodness of fit with the data variables. Precise ELISA techniques were used, and the assays showed low intra-assay coefficients of variation for both sTWEAK and galectin-3. One weakness was that there was no control group with persons without diabetes. Another weakness was that there were very few patients with cardiovascular complications, so no further explorations of associations with cardiovascular complications could be performed. A third weakness was that depression was not assessed by a clinical interview. However, the association between the use of antidepressants and self-reported depression in this study was high, indicating that depression assessed by HADS-D had clinical significance.
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