An increased skin microvessel density is associated with neurovascular complications in type 1 diabetes mellitus.

The aim of this study was to assess the blood vessel density and maturity in the skin of adults with type 1 diabetes in relation to the presence of late neurovascular complications. We included 148 patients (87 men) with a median (interquartile range) age of 41 (31-49) and median diabetes duration of 21 (17-30) years. Microvessel (CD133, CD34, CD31 and von Willebrand factor) markers were evaluated by indirect immunohistochemistry assay in material from a skin biopsy. Diabetic retinopathy was diagnosed using direct ophthalmoscopy, and diabetic kidney disease was estimated in people with increased albuminuria and a 10-year duration of diabetes or evidence of diabetic retinopathy . Diabetic peripheral neuropathy diagnosis was based on Toronto definition, cardiac autonomic neuropathy on validated ProSciCard III program. Microvessel density, assessed by CD34 and CD133, was significantly higher in patients with cardiac autonomic neuropathy [160 (125-175) vs 121 (100-154)/1 mm2, p = 0.001 and 92 (83-104) vs 79 (63-92)/1 mm2, p = 0.007, respectively] and CD34 in patients with diabetic peripheral neuropathy [135 (106-168) vs 121 (95-145)/1 mm2, p = 0.018], as compared with subjects without complications. In multivariate logistic regression, density of CD34 and CD133 positive vessels was associated with presence of cardiac autonomic neuropathy [odds ratio 1.016 (95% confidence interval: 1.002-1.029), p = 0.019 and odds ratio 1.037 (95% confidence interval: 1.008-1.067), p = 0.011, respectively]. It was independent from age, sex, diabetes duration, smoking status, body mass index and HbA1c value. Density of CD34 positive vessels was also associated with diabetic peripheral neuropathy, independently from sex and diabetes duration [odds ratio 1.009 (95% confidence interval: 1.001-1.020), p = 0.037]. Skin microvessel density is increased in adults with clinical evidence of neurovascular complications of type 1 diabetes. This is associated with predominance of the vessels of low maturity.

Dermal microvessel density and maturity is closely associated with atherogenic dyslipidemia and accumulation of advanced glycation end products in adult patients with type 1 diabetes.

In patients with diabetes, functional changes in microcirculation and subclinical vascular pathology precede clinical manifestation of microangiopathic complications. The objective of this study was to evaluate the association between established vascular risk factors and density, maturity, and reactivity of dermal blood vessels in adults with type 1 diabetes (DM1). We included 148 DM1 patients (87 men) with a median (IQR) age of 40.5 (30.5-49) years and a median diabetes duration of 21 (17-29.5) years. The control group consisted of 13 healthy volunteers (6 men) with a median (IQR) age of 36 (31-43). Accumulation of advanced glycation end products (AGEs) was assessed using the AGE-Reader device. In the immunohistochemical (IHC) analyses, anti-CD133, anti-CD34, anti-CD31, and anti-vWF autoantibodies were used. Microvessel density (MVD) in the skin was calculated using the "hot spots technique". Microvascular function was examined by single-point laser-Doppler flowmetry (LDF). Median MVD, calculated for both papillary and reticular dermis, for CD31 antigen expression was 38 (19-56) per 1 mm2. The median CD34+ blood vessel density was 121 (100-155) per 1 mm2, CD133+ was 79 (63-92) per 1 mm2, and vWF+ was 50 (40-69) per 1 mm2. The average CD34/CD31 index was 2.78, the vWF/CD31 ratio was 1.32 and the CD133/CD31 ratio was 1.75. The CD34/CD31 index was positively associated with serum triglyceride concentration (Beta: 0.26, p = 0.012) and negatively associated with serum HDL cholesterol concentration (Beta: -0.22, p = 0.027), both independently from age, sex, diabetes duration, BMI, HbA1c value, presence of hypertension, and eGFR. We found a negative correlation between MVD assessed by CD31 and skin AF (r = -0.21, p = 0.016). In LDF, the area under the blood flow/time curve (AUC) correlated positively with CD31+ MVD (r = 0.21, p = 0.011) and negatively with CD34+ MVD (r = -0.20, p = 0.017). The MVD did not differ between participants with diabetes and healthy controls, and it did not differ according to the presence of retinopathy among the participants with diabetes. Atherogenic dyslipidemia is associated with increased formation of new blood vessels, characterized by high expression of CD34 and low reactivity in LDF. Conversely, chronic hyperglycemia and excessive formation of AGEs may result in decreased vascularity.

Higher free triiodothyronine concentration is associated with lower prevalence of microangiopathic complications and better metabolic control in adult euthyroid people with type 1 diabetes.

PURPOSE: Type 1 diabetes mellitus (T1DM) is a disorder of insulin deficiency but with a wide range of hormones simultaneously disturbed. The study was performed to explore relation of free triiodothyronine (FT3) with metabolic control and occurrence of microangiopathic complications. METHODS: A total of 266 adult T1DM participants [56% men; 32 (interquartile range, IQR: 25-39) years and disease duration 13 (IQR: 8-19) years] in euthyroid state with negative history for hypothyroidism were included to the study. Participants were screened for thyroid-stimulating hormone (TSH), free thyroxine (FT4) and FT3. Moreover, microangiopathic complications (retinopathy, diabetic kidney disease, peripheral and autonomic neuropathy), markers of metabolic control such as glycated hemoglobin (HbA1c) were evaluated. RESULTS: A total of 114 (42.9%) people had diagnosed at least one microangiopathic complication. In multivariable linear regression higher HbA1c was statistically significant independent predictor of lower FT3 (ß = -0.25; p < 0.0001) after adjustment for sex, T1DM duration, HbA1c, waist-to-hip ratio (WHR) (R2 = 0.15, p < 0.0001). Higher FT3 was simultaneously a predictor of lower prevalence of microangiopathy in multivariate logistic regression analysis (odds ratio, 0.51; 95% confidence interval, 0.27-0.98; p = 0.04) after an adjustment for: age, hypertension, HbA1c, WHR and total cholesterol (TC). CONCLUSIONS: FT3 as tissue active hormone plays a clinically important role in T1DM people. The higher FT3 concentration is related to the lower prevalence of microangiopathy and better metabolic control of the disease in adult euthyroid people with T1DM.

Higher concentrations of osteoprotegerin in type 1 diabetic patients are related to retinopathy: Results from the Poznan Prospective Study.

BACKGROUND: Osteoprotegerin (OPG) is an arterial calcification marker which has been associated with vascular damage. Elevated OPG concentrations associated with low-grade inflammatory processes are found in diabetic subjects. OBJECTIVES: The aim of the study was to assess concentrations of OPG in relation to the presence of diabetic complications in patients with diabetes type 1 (DM 1) participating in the Poznan Prospective Study (PoProStu). MATERIAL AND METHODS: The study included 74 patients with DM1 (48 men) with a median age of 39 years (interquartile range [IQR]: 34-43) and a median 15-year history (IQR: 14-16) of diabetes, who were participants in the PoProStu. Serum OPG concentration was measured using the ELISA method, and serum concentration of C-reactive protein was measured with a high sensitivity test (hsCRP). The visceral adipose index (VAI) was used to determine indirect markers of insulin resistance (IR). The prevalence of microangiopathic diabetes complications was assessed. RESULTS: Retinopathy was diagnosed in 28 patients (38%), diabetic kidney disease (DKD) in 28 (38%) patients, and neuropathy in 17 (23%) patients. The median OPG level was 43.8 (28.0-74.0) pg/mL. Patients with retinopathy had higher levels of OPG than those without retinopathy: 47.5 (35.0-88.0) vs 35.4 (24.7-69.4) pg/mL (p = 0.04). Positive correlations were observed between OPG concentration and hsCRP (Rs = 0.53; p < 0.001), HbA1c level (Rs = 0.36; p = 0.002), VAI (Rs = 0.23; p = 0.04) and waist circumference (Rs = 0.24; p = 0.04). CONCLUSIONS: Higher concentrations of osteoprotegerin in DM1 patients are related to the presence of retinopathy. The study results indicate that OPG might play a role in the pathogenesis of vascular complications in association with hyperglycemia and low-grade inflammatory processes.

Prevalence of anti-thyroid peroxidase in adults with type 1 diabetes participating in Poznan Prospective Study.

BACKGROUND: Type 1 diabetes (DM 1) is frequently associated with autoimmune thyroid diseases (AITD). Screening for AITD in adults is rarely performed. The aim of this study was to evaluate the prevalence of anti-thyroid peroxidase (anti-TPO) and thyroid function and their association with metabolic control in adults participating in Poznan Prospective Study (PoProStu). MATERIAL AND METHODS: The analysis included 74 patients (26 women and 48 men) aged 38.5 (IQR: 34.5-42.5), who have had diabetes for 15.0 (14-16) years. All patients have been treated with intensive functional insulin therapy (IFIT) from the onset of the disease. Anti-TPO and thyroid-stimulating hormone (TSH) were determined. The concentration of anti-TPO ≥ 5.61 IU/mL was considered positive. Based on the levels of anti-TPO the patients were divided into two groups: anti-TPO positive and anti-TPO negative. Metabolic control was assessed by the level of glycated hemoglobin (HbA 1c). RESULTS: Anti-TPO was positive in 32 (43.2%) patients. Prevalence of autoantibodies was significantly higher in women (53% vs 21%; p = 0.009). There was no significant difference in HbA 1c levels [median (IQR): 7.6% (7.1-8.6) vs 7.6% (7.1-8.8); p = 0.82] and TSH levels [median (IQR): 2.05 µIU/mL (1.23-3.15) vs 1.62 µIU/mL (1.00-2.10); p = 0.06] between anti-TPO positive and negative patients. After excluding patients with a thyroid dysfunction, a significant difference in TSH levels between anti-TPO positive and negative group was found [median (IQR): 2.11 µIU/mL (1.29-3.31) vs 1.66 µIU/mL (1.29-3.31); p = 0.04]. CONCLUSIONS: High anti-TPO prevalence is found in adult patients with long-standing DM 1, and autoantibodies occur more often in women. Therefore, screening for asymptomatic thyroid dysfunction should be performed in this group, as already recommended by the joint statement of Polish Society of Endocrinology and Diabetes Poland.

Skin autofluorescence is associated with carotid intima-media thickness, diabetic microangiopathy, and long-lasting metabolic control in type 1 diabetic patients. Results from Poznan Prospective Study.

AIMS: Our aim was to assess the association between skin autofluorescence (AF) related to advanced glycation end products (AGEs) accumulation and long-term metabolic control, microvascular complications and carotid intima-media thickness (IMT) in an observational cohort of type 1 diabetes (DM1). METHODS: The analysis included 77 patients with DM1 (28 women and 49 men) aged 38 (IQR: 34-41), diabetes duration 15 (14-17), participating in Poznan Prospective Study (PoProStu). Skin AF was measured with AGE Reader (DiagnOptics). RESULTS: We found 50% of any microvascular complication; 37% of retinopathy, 37% of diabetic kidney disease and 22% of distal symmetrical neuropathy. Median carotid IMT was 0.57 (0.52-0.67) mm and skin AF 2.2 (IQR: 1.9-2.6). We found positive correlation between skin AF and patients' age (r=0.31, p=0.006), mean HbA1c from the observation time (r=0.35, p=0.001) and IMT (r=0.39, p<0.001). In multivariate logistic regression presence of microvascular complications was independently associated with skin AF: for retinopathy (OR 3.49; 95% CI: 1.08-11.28, p=0.03), for diabetic kidney disease (OR 3.62; 95% CI: 1.16-11.28, p=0.02), for neuropathy (OR 5.01; 95% CI: 1.21-20.77, p=0.02) and for any microangiopathy (OR 3.13; 95% CI: 1.06-9.18, p=0.03). CONCLUSION: Skin AF is a reliable marker of past glycemic control of diabetes. Increased accumulation of AGEs is related to the presence of diabetic microangiopathy as well as subclinical macroangiopathy in patients with type 1.

Clinical characteristics and autoantibody pattern in newly diagnosed adult-onset autoimmune diabetes.

INTRODUCTION: Autoimmune diabetes in adults comprises a broad spectrum of clinical phenotypes. OBJECTIVES: The aim of the study was to investigate clinical and biochemical features and anti-islet autoantibody pattern in adult patients with newly diagnosed autoimmune diabetes with regard to age and the number of autoantibodies detected at diagnosis. PATIENTS AND METHODS: We retrospectively evaluated 344 patients (aged ≥18 years) with newly diagnosed diabetes and a positive anti-islet antibody titer. Patients were divided based on age (<35 and ≥35 years of age) or the number of detected autoantibodies (1, 2, or 3). RESULTS: The studied age groups did not differ with respect to the majority of clinical and laboratory features (e.g., clinical presentation, metabolic status, or degree of insulin deficiency). Autoantibodies to islet cell cytoplasm and to glutamic acid decarboxylase 65 occurred more frequently in younger patients, while the prevalence of autoantibodies to intracytoplasmatic domain of the tyrosine phosphatase-like protein (IA-2A) was similar in both age groups. Single autoantibody positivity was observed more often in older patients. The most common isolated autoantibody in this group was IA-2A. The presence of multiple autoantibodies was associated with younger age, lower fasting and stimulated C-peptide levels, and shorter duration of symptoms. CONCLUSIONS: The patient's age at diabetes onset does not determine clinical and biochemical characteristics at diagnosis but is associated with different autoantibody status. IA-2A antibodies may be useful in diagnosing autoimmune diabetes in adult patients. The assessment of the immune profile at diagnosis may help identify patients at a higher risk of significant insulin deficiency.