Plasma matrix metalloproteinases and tissue inhibitors of metalloproteinases explored in relation to the severity and progression of diabetic retinopathy in patients with type 1 diabetes: baseline and prospective analyses.

AIMS: To explore whether circulating matrix metalloproteinase-2 (MMP-2), MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin, MMP-9/tissue inhibitor of metalloproteinase-1 (TIMP-1), MMP-14, TIMP-2 and TIMP-3 were associated with the severity and progression of diabetic retinopathy (DR) in patients with type 1 diabetes (T1D). METHODS: Baseline and prospective analyses were conducted over a period of 10.5 person-years. In 2009, recruitment and biochemical analyses (MMPs, TIMPs, glycated haemoglobin (HbA1c), serum creatinine, macroalbuminuria) were performed. Fundus photography, performed at baseline and at follow-up in accordance with the regional screening programme, was compared after being categorised according to the International Clinical Diabetic Retinopathy Disease Severity Scale. 'DR progression at least one leve' was calculated. High MMP-2 was defined as ≥178 ng/mL (≥75th percentile) and high TIMP-2 as ≥205 ng/mL (≥75th percentile). DR was dichotomised as 'at least moderate DR' or 'no/mild DR'. RESULTS: The study included 267 participants, 57% of whom were men. At baseline, the prevalence of high MMP-2 (p=0.001) and high TIMP-2 (p=0.008) increased with the severity of DR. 'At least moderate DR' (adjusted OR (AOR) 2.4, p=0.008) and macroalbuminuria (AOR 3.6, p=0.025) were independently associated with high MMP-2. 'At least moderate DR' (AOR 2.3, p=0.009) and macroalbuminuria (3.4, p=0.031) were independently associated with high TIMP-2. DR progression occurred in 101 (46%) patients (p<0.001). HbA1c≥53 mmol/mol was associated with the progression of DR (crude OR 3.8, p=0.001). No other MMPs or TIMPs were linked to the severity or the progression of DR. CONCLUSIONS: High levels of MMP-2 and TIMP-2 indicated more severe DR or diabetic nephropathy. Only HbA1c was associated with the progression of DR in 267 patients with T1D.

Soluble CD163 and glycated haemoglobin were independently associated with the progression of diabetic retinopathy in adult patients with type 1 diabetes.

OBJECTIVE: High vitreous levels of soluble (s)CD163 have been demonstrated in severe diabetic retinopathy (DR). The aim of this study was to explore the predictive values of plasma sCD163 and glycated haemoglobin (HbA1c) for DR progression in adults with type 1 diabetes. METHODS AND ANALYSES: The study design was prospective. Fundus photography performed in 2009 and at follow-up (≤12 years later) were compared after being categorised according to the International Clinical Diabetic Retinopathy Disease Severity Scale. 'DR progression at least one level' was calculated. In 2009, data collection (sex, age, diabetes duration, metabolic variables, serum creatinine, macroalbuminuria and lifestyle factors) and biochemical analyses were performed. Plasma sCD163 and HbA1c were divided into quartiles. Logistic regression analyses were performed. RESULTS: The prevalence of DR in 2009 versus at follow-up in 270 participants (57% male) were: no apparent 28% vs 18%; mild 20% vs 13%; moderate 24% vs 26%; severe 11% vs 13%; and proliferative DR 17% vs 30% (p<0.001). DR progression occurred in 101 (45%) patients. HbA1c ≥54 mmol/mol (≥7.1%) (>1st quartile) (adjusted odds ratio (AOR) 3.8, p<0.001) and sCD163 ≥343 ng/mL (>1st quartile) (AOR 2.6, p=0.004) were independently associated with DR progression. The associations with DR progression increased significantly from the first to the fourth quartile for HbA1c (AORs: 1; 2.5; 3.6; 7.4), but not for sCD163 (AORs: 1; 2.9; 2.4; 2.4). CONCLUSION: Plasma sCD163 may constitute a valuable biomarker for DR progression in addition to and independent of the well-established biomarker HbA1c.

Galectin-3, metalloproteinase-2 and cardiovascular disease were independently associated with metalloproteinase-14 in patients with type 1 diabetes: a cross sectional study.

BACKGROUND: Type 1 diabetes (T1D) is a major risk factor for cardiovascular disease (CVD). Matrix metalloproteinase-14 (MMP-14) is involved in the development of atherosclerosis and CVD. The main aim was to explore the associations between MMP-14 and selected inflammatory and metabolic variables, CVD, depression, physical activity, smoking and medication in patients with T1D. The secondary aim was to explore associations with CVD. METHODS: Cross-sectional design. The participants were consecutively recruited from one specialist diabetes out-patient clinic. Depression was assessed by a self-report instrument. Blood samples, anthropometrics and blood pressure were collected, supplemented with data from electronic health records. High MMP-14 was defined as ≥ 5.81 ng/mL. Non-parametric tests, Chi2 tests and multiple logistic regression analyses were performed. RESULTS: Two hundred and sixty-eighth T1D patients aged 18-59 years participated (men 58%, high MMP-14 25%, CVD 3%). Sixty-seven patients with high MMP-14, compared to 201 patients with lower MMP-14, had higher prevalence of CVD (8% versus 1%, p = 0.012), and had higher levels of galectin-3 (p < 0.001) and MMP-2 (p = 0.018). Seven patients with CVD, compared to 261 without, were older (p = 0.003), had longer diabetes duration (p = 0.027), and had higher prevalence of high MMP-14 (71% versus 24%, p = 0.012), abdominal obesity (p = 0.014), depression (p = 0.022), usage of antidepressants (p = 0.008), antihypertensive drugs (p = 0.037) and statins (p = 0.049). Galectin-3 (per ng/mL) [adjusted odds ratio (AOR) 2.19, p < 0.001], CVD (AOR 8.1, p = 0.027), and MMP-2 (per ng/mL) (AOR 1.01, p = 0.044) were associated with high MMP-14. Depression (AOR 17.4, p = 0.006), abdominal obesity (15.8, p = 0.006), high MMP-14 (AOR 14.2, p = 0.008), and diabetes duration (AOR 1.10, p = 0.012) were associated with CVD. CONCLUSIONS: The main findings of this study were that galecin-3, MMP-2, and CVD were independently associated with high levels of MMP-14 in T1D patients. The association between MMP-14 and galectin-3 is a new finding. No traditional risk factors for CVD were associated with MMP-14. Depression, abdominal obesity and MMP-14 were independently associated with CVD.

Midnight salivary cortisol secretion and the use of antidepressants were associated with abdominal obesity in women with type 1 diabetes: a cross sectional study.

BACKGROUND: Abdominal obesity is a risk factor for cardiovascular disease. The aim was to explore the influence of midnight salivary cortisol (MSC), antidepressants and sex on abdominal obesity in type 1 diabetes (T1D). We controlled for physical inactivity, smoking, depression and alexithymia. METHODS: Cross sectional study of 190 T1D patients (86 women/104 men, 18-59 years, diabetes duration 1-55 years), consecutively recruited from one specialist diabetes outpatient clinic. Anthropometrics, blood pressure, saliva and blood samples were collected, supplemented with data from electronic medical records. Depression and alexithymia were assessed by self-report instruments. MSC (nmol/l) was categorised into 3 levels: high MSC: (≥ 6.7) (n = 64); intermediate MSC: ≥ 3.7- < 6.7) (n = 64); low MSC (< 3.7) (n = 62). Abdominal obesity was defined as waist circumference (meters) ≥ 0.88 for women and as ≥ 1.02 for men. Multiple logistic regression analyses (Backward: Wald) were performed. The Hosmer and Lemeshow test for goodness-of-fit and Nagelkerke R2 were used to evaluate each multiple logistic regression analysis model. RESULTS: The prevalence of abdominal obesity was three times higher in the women than in the men (24% versus 8%) (p = 0.002). Antidepressants were used by 10% of the women and by 4% of the men (p = 0.09). The prevalence of high MSC was 1.7 times higher in the women (43% versus 26%); the prevalence of both intermediate MSC (28% versus 38%) and low MSC (29% versus 36%) were lower in the women (p = 0.048). Significant associations with abdominal obesity were for all 190 patients: female sex (adjusted odds ratio (AOR) 3.4 (confidence interval (CI) 1.4-8.2)) and the use of antidepressants (AOR 4.3 (CI 1.2-14.8)); for the 86 women: high MSC (AOR 18.4 (CI 1.9-181)) and use of antidepressants (AOR 12.2 (CI 2.0-73.6)); and for the 104 men: alexithymia (AOR 5.2 (CI 1.1-24.9)). CONCLUSIONS: Clear sex differences were demonstrated with a distinct higher prevalence of abdominal obesity, as well as a distinct higher prevalence of high midnight salivary cortisol in the women with type 1 diabetes. High midnight salivary cortisol secretion and the use of antidepressants were independent risk factors for abdominal obesity in the women.

Female sex, high soluble CD163, and low HDL-cholesterol were associated with high galectin-3 binding protein in type 1 diabetes.

BACKGROUND: Galectin-3 binding protein (Gal3BP), sCD163, galectin-3, and depression have been linked to cardiovascular disease and mortality. In patients with type 1 diabetes, female sex has also been linked to cardiovascular disease and mortality. The aim was to explore whether female sex, sCD163, galectin-3, and depression were associated with Gal3BP in patients with type 1 diabetes. We adjusted for metabolic variables, creatinine, smoking, physical inactivity, and cardiovascular disease. METHODS: Cross-sectional design. Patients with type 1 diabetes (n = 285, women 44%, age18-59 years, diabetes duration 1-55 years) were consecutively recruited from one diabetes outpatient clinic. Blood samples, anthropometrics, and blood pressure were collected, supplemented with data from electronic medical records. High Gal3BP was defined as ≥3.3 mg/l (≥80th percentile). Depression was assessed by a self-report instrument. Linear and logistic regression models were elaborated for the associations and calibrated and validated for goodness of fit with the data variables. RESULTS: Median (q1, q3) Gal3BP was 2.3 (1.8, 3.1) mg/l. The prevalence of high Gal3BP for women was 30% and 14% for men (p = 0.001). Female sex (adjusted odds ratio (AOR) 3.0), sCD163 (per µg/l) (AOR 6.6), and total cholesterol (per mmol/l) (AOR 1.6) were positively associated with high Gal3BP, and HDL-cholesterol (per mmol/l) (AOR 0.2) was negatively associated with high Gal3BP. CONCLUSIONS: High Gal3BP levels were associated with female sex, increasing sCD163 and total cholesterol levels, and decreasing HDL-cholesterol levels in patients with type 1 diabetes. The prevalence of high Gal3BP was more than twice as high in the women as in the men.

Midnight salivary cortisol secretion associated with high systolic blood pressure in type 1 diabetes.

OBJECTIVE: To explore associations between high midnight salivary cortisol (MSC) secretion and high blood pressure (BP) in type 1 diabetes (T1D). METHODS: Cross-sectional study of 196 adult patients with T1D (54% men). Associations between high MSC (≥9.3 nmol/L) and high systolic BP (>130 mmHg), and high diastolic BP (>80 mmHg) were explored for all patients, users and non-users of antihypertensive drugs (AHD). Adjustments were performed for age, sex, diabetes-related variables, p-creatinine, smoking, physical inactivity, depression and medication. RESULTS: The prevalence of high MSC differed between patients with high and low systolic BP in all 196 patients: 39 vs 13% (P = 0.001); in 60 users of AHD: 37 vs 12% (P = 0.039), and in 136 non-users of AHD: 43 vs 13% (P = 0.012). Significant associations with high systolic BP were for all patients: physical inactivity (adjusted odds ratio (AOR) 6.5), high MSC (AOR 3.9), abdominal obesity (AOR 3.7), AHD (AOR 2.9), age (per year) (AOR 1.07), and p-creatinine (per µmol/L) (AOR 1.03); for 60 users of AHD: high MSC (AOR 4.1) and age (per year) (AOR 1.11); for 136 non-users of AHD: abdominal obesity (AOR 27.4), physical inactivity (AOR 14.7), male sex (AOR 9.0), smoking (AOR 7.9), and age (per year) (AOR 1.08). High MSC was not associated with high DBP. CONCLUSIONS: In adult patients with T1D, high systolic BP was associated with physical inactivity, high MSC secretion, abdominal obesity, p-creatinine, age, and AHD, the latter indicating treatment failure.

Lower HDL-cholesterol, a known marker of cardiovascular risk, was associated with depression in type 1 diabetes: a cross sectional study.

BACKGROUND: Depression, metabolic disturbances and inflammation have been linked to cardiovascular disease and mortality. Low levels of high-density lipoprotein cholesterol (HDL-cholesterol), a known marker of cardiovascular risk, have been observed in patients with major depression in psychiatric populations. Our main aim was to explore associations between depression, antidepressants, and metabolic and inflammatory variables in patients with type 1 diabetes (T1D). A secondary aim was to explore variables associated with HDL-cholesterol. METHODS: Cross-sectional design. T1D patients (n = 292, men 55%, age18-59 years, diabetes duration ≥1 year) were consecutively recruited from one specialist diabetes clinic. Depression was defined as ≥8 points for Hospital Anxiety and Depression Scale-Depression sub scale. Blood samples, anthropometrics, blood pressure, and data regarding medication and life style were collected from electronic health records. Non-parametric tests, multiple logistic and linear regression analyses were performed. RESULTS: The depression prevalence was 10 and 8% used antidepressants. Median (q1, q3) HDL-cholesterol (mmol/l) was for the depressed 1.3 (1.2, 1.5) and for the non-depressed 1.6 (1.3, 1.8), p = 0.001. HDL-cholesterol levels (per mmol/l) were negatively associated with depression (Adjusted odds ratio (AOR) 0.2, p = 0.007), and the use of antidepressants was positively associated with depression (AOR 8.1, p <  0.001). No other metabolic or inflammatory variables, or life style factors, were associated with depression when adjusted for antidepressants. Abdominal obesity was associated with antidepressants in women (AOR 4.6, p = 0.029). Decreasing HDL-cholesterol levels were associated with increasing triglyceride levels (p <  0.001), increasing high-sensitive C-reactive protein (hs-CRP) levels (p = 0.021), younger age (p <  0.001), male sex (p <  0.001), and depression (p = 0.045). CONCLUSIONS: Lower HDL-cholesterol levels, known predictors of cardiovascular disease, were associated with depression in patients with T1D. The use of antidepressants was associated with abdominal obesity in women. Depression, low-grade inflammation measured as hs-CRP, higher triglycerides, male sex, and lower age were independently associated with lower HDL-cholesterol levels.

Depression in type 1 diabetes was associated with high levels of circulating galectin-3.

OBJECTIVE: Neuroinflammatory responses are implicated in depression. The aim was to explore whether depression in patients with type 1 diabetes (T1D) was associated with high circulating galectin-3, controlling for metabolic variables, s-creatinine, life style factors, medication and cardiovascular complications. DESIGN: Cross-sectional. METHODS: Participants were T1D patients (n = 283, 56% men, age 18-59 years, diabetes duration ≥1 year). Depression was assessed by Hospital Anxiety and Depression Scale-depression subscale. Blood samples, anthropometrics and blood pressure were collected, and supplemented with data from medical records and the Swedish National Diabetes Registry. Galectin-3 ≥2.562 µg/l, corresponding to the 85th percentile, was defined as high galectin-3. RESULTS: Median (quartile1, quartile3) galectin-3 (µg/l) was 1.3 (0.8, 2.9) for the 30 depressed patients, and 0.9 (0.5, 1.6) for the 253 non-depressed, P = 0.009. Depression was associated with high galectin-3 in all the 283 patients (adjusted odds ratio (AOR) 3.5), in the 161 men (AOR 3.4), and in the 122 women (AOR 3.9). HbA1c, s-lipids, s-creatinine, blood pressure, obesity, smoking, physical inactivity, cardiovascular complications and drugs (antihypertensive, lipid lowering, oral antidiabetic drugs and antidepressants) were not associated with high galectin-3. CONCLUSIONS: This is the first study to show an association between depression and galectin-3. Depression was the only explored parameter associated with high circulating galectin-3 levels in 283 T1D patients. High galectin-3 levels might contribute to the increased risk for Alzheimer's disease, cardiovascular and all-cause mortality observed in persons with depression. Potentially, in the future, treatment targeting galactin-3 might improve the prognosis for patients with high galectin-3 levels.