Reduced HDL function in children and young adults with type 1 diabetes.

BACKGROUND: Patients with type 1 diabetes (T1D) are at increased risk of cardiovascular disease (CVD). Measures of high-density lipoprotein (HDL) function provide a better risk estimate for future CVD events than serum levels of HDL cholesterol. The objective of this study was to evaluate HDL function in T1D patients shortly after disease onset compared with healthy control subjects. METHODS: Participants in the atherosclerosis and childhood diabetes study were examined at baseline and after 5 years. At baseline, the cohort included 293 T1D patients with a mean age of 13.7 years and mean HbA1c of 8.4%, along with 111 healthy control subjects. Their HDL function, quantified by HDL-apoA-I exchange (HAE), was assessed at both time points. HAE is a measure of HDL's dynamic property, specifically its ability to release lipid-poor apolipoprotein A-I (apoA-I), an essential step in reverse cholesterol transport. RESULTS: The HAE-apoA-I ratio, reflecting the HDL function per concentration unit apoA-I, was significantly lower in the diabetes group both at baseline, 0.33 (SD = 0.06) versus 0.36 (SD = 0.06) %HAE/mg/dL, p < 0.001 and at follow-up, 0.34 (SD = 0.06) versus 0.36 (SD = 0.06)  %HAE/mg/dL, p = 0.003. HAE-apoA-I ratio was significantly and inversely correlated with HbA1c in the diabetes group. Over the 5 years of the study, the mean HAE-apoA-I ratio remained consistent in both groups. Individual changes were less than 15% for half of the study participants. CONCLUSIONS: This study shows reduced HDL function, quantified as HAE-apoA-I ratio, in children and young adults with T1D compared with healthy control subjects. The differences in HDL function appeared shortly after disease onset and persisted over time.

Advanced glycation end products in children with type 1 diabetes and early reduced diastolic heart function.

BACKGROUND: Reduced diastolic function is an early sign of diabetes cardiomyopathy in adults and is associated with elevated levels of HbA1c and advanced glycation end products (AGEs). OBJECTIVE: To assess the associations between early reduced diastolic function and elevated levels of HbA1c and AGEs in children and adolescents with type 1 diabetes (T1D). METHODS: One hundred fourty six T1D patients (age 8-18 years) without known diabetic complications were examined with tissue Doppler imaging and stratified into two groups according to diastolic function. A clinical examination and ultrasound of the common carotid arteries were performed. Methylglyoxal-derived hydroimidazolone-1 (MG-H1) was measured by immunoassay. RESULTS: At inclusion, 36 (25%) participants were stratified into a low diastolic function group (E'/A'-ratio < 2.0). Compared to the rest of the T1D children, these participants had higher body mass index (BMI), 22.8 (SD = 4.0) vs. 20.1 (SD = 3.4) kg/m2, p < 0.001, higher systolic blood pressure 104.2 (SD = 8.7) vs. 99.7 (SD = 9.3) mmHg, p = 0.010, and higher diastolic blood pressure, 63.6 (SD = 8.3) vs. 59.9 (SD = 7.9) mmHg, p = 0.016. The distensibility coefficient was lower, 0.035 (SD = 0.010) vs. 0.042 (SD = 0.02) kPa-1, p = 0.013, Young's modulus higher, 429 (SD = 106) vs. 365 (SD = 143), p = 0.009, and MG-H1 higher, 163.9 (SD = 39.2) vs. 150.3 (SD = 33.4) U/ml, p = 0.046. There was no difference in carotid intima-media thickness between the groups. There were no associations between reduced diastolic function and years from diagnosis, HBA1c, mean HBA1c, CRP or calculated glycemic burden. Logistic regression analysis showed that BMI was an independent risk factor for E'/A'-ratio as well as a non-significant, but relatively large effect size for MG-H1, indicating a possible role for AGEs. CONCLUSIONS: Early signs of reduced diastolic function in children and adolescents with T1D had higher BMI, but not higher HbA1c. They also had elevated serum levels of the advanced glycation end product MG-H1, higher blood pressure and increased stiffness of the common carotid artery, but these associations did not reach statistical significance when tested in a logistic regression model.

Early reduced myocardial diastolic function in children and adolescents with type 1 diabetes mellitus a population-based study.

BACKGROUND: Reduced diastolic myocardial function is an early sign of diabetic cardiomyopathy. The aim of this study was to test the hypothesis that children and adolescents with type 1 diabetes mellitus (T1D), but without other known complications, have early reduced diastolic myocardial function diagnosed with echocardiographic color tissue Doppler imaging (cTDI). METHODS: cTDI examination was carried out in 173 T1D patients and 62 age-matched controls. The T1D-patients were 8-18 years old with (mean (SD)) diabetes duration of 5.6 (3.4) years and HbA1c of 8.4 (1.3). All were treated with either insulin pumps or 4-6 daily insulin injections. cTDI early (E') and late (A') peak diastolic velocities and systolic peak velocity were measured from the lateral, septal, anterior and posterior mitral annulus and from the lateral tricuspidal annulus. RESULTS: Myocardial diastolic function was reduced in the T1D-patients with higher peak A'-velocity and lower E'/A'-ratio in all registrations. Overall mean (SD) mitral E'/A'-ratio was 2.3 (0.5) in T1D and 2.7 (0.6) in the controls (p < 0001). The overall mitral E'/A'-ratio was negative associated with blood pressure (BP) and body mass index (BMI). Stratifying all participants into three groups according to BMI (<25, 25-75, >75 centile, respectively), the T1D had lower E'/A'-values in all stratified groups, except for in the highest BMI-group where both T1D and controls had the lowest E'/A'-ratio. Systolic function did not differ in any of the measurements. There were no associations with sex, diabetes duration, carotid artery intima-media-thickness, vessel elasticity or HbA1c. CONCLUSION: Diabetic children and adolescents using modern intensive insulin treatment had echocardiographic signs of reduced diastolic myocardial function despite short duration of disease. The reduced function was associated with higher BP and higher BMI.

Soluble RAGE and atherosclerosis in youth with type 1 diabetes: a 5-year follow-up study.

BACKGROUND: Advanced glycation end products (AGEs) play a role in the development of late complications and atherosclerosis in diabetes by engaging the receptor for advanced glycation end products, RAGE. Receptor binding leads to activation of the vascular endothelium and increased inflammation in the vessel wall. The soluble variants of the receptor, endogenous secretory RAGE (esRAGE) and the cleaved cell-surface part of RAGE, which together comprise soluble RAGE (sRAGE), are suggested to have a protective effect acting as decoys for RAGE. We aimed to test whether high levels of soluble variants of RAGE could be protective against atherosclerosis development. METHODS: Participants in the prospective atherosclerosis and childhood diabetes study were examined at baseline (aged 8-18) and at follow-up after 5 years. Both sRAGE and esRAGE were measured by immunoassay in 299 patients with type 1 diabetes and 112 healthy controls at baseline and 241 patients and 128 controls at follow-up. The AGEs methylglyoxal-derived hydroimidazolone-1 (MG-H1) and carboxymethyllysine (CML) were measured by immunoassay. The surrogate markers of atherosclerosis assessed were carotid intima-media thickness (cIMT), C-reactive protein (CRP) and Young's modulus, measures of arterial wall thickness, inflammation and arterial stiffness, respectively. RESULTS: Levels of sRAGE and esRAGE correlated strongly both at baseline and at follow-up in both diabetes patients and controls. With increasing age, mean values of both variants declined, independent of gender, diabetes or pubertal stage. In the diabetes group, multiple regression analysis showed a positive association between both variants of soluble RAGE and cIMT. There was no significant relationship with Young's modulus, but a negative association between sRAGE at baseline and CRP at follow-up. The ratios between the AGEs and the variants of soluble RAGE were increased in diabetes patients compared to controls. CONCLUSIONS: The results show a possible protective effect of high levels of sRAGE at baseline against inflammation 5 years later, but not on arterial stiffness or wall thickness, in this cohort of adolescents and young adults with T1D.

Sustained low-grade inflammation in young participants with childhood onset type 1 diabetes: The Norwegian atherosclerosis and childhood diabetes (ACD) study.

BACKGROUND AND AIMS: Persons with type 1 diabetes (T1D) have increased mortality from cardiovascular disease. Early inflammation is important in the development of atherosclerosis. We aimed to evaluate the extent of inflammation and difference in mean over a five-year period in young persons with T1D compared to healthy controls. METHODS: The Norwegian Atherosclerosis and Childhood Diabetes (ACD) study is a prospective population-based cohort study on atherosclerosis development in childhood-onset T1D compared to healthy controls, with follow-ups every fifth year. The original study cohort consisted of 314 children with T1D on intensive insulin treatment and 120 healthy controls of similar age. Circulating levels of VCAM-1, TNA-α, P-selectin, E-selectin, CRP, IL-6, IL-18, MCP-1, MMP-9 and TIMP-1 were measured by ELISAs at baseline and at the five-year follow-up. RESULTS: The group with T1D had mean age 13.7 (SD = 2.8) years, disease duration 5.6 (SD = 3.4) years and HbA1c 68 (SD = 13.1) mmol/mol at baseline. Levels of almost all inflammatory markers were significantly increased in the group with T1D compared to controls, and significant mean-difference between the two groups over the five-year period was observed in four markers: IL-18, P-selectin, E-selectin and TIMP-1. CONCLUSIONS: The early low-grade inflammation present in young individuals with T1D five years after diagnosis is sustained at ten-year disease duration, with moderate changes for most markers of inflammation over time. The evolving inflammatory profile indicates an accelerated chain of events in the progression of early atheromatosis in T1D.

Increased arterial stiffness in childhood onset diabetes: a cardiovascular magnetic resonance study.

Aims: Arterial stiffness is a strong predictor of cardiovascular events. We aimed to assess the impact of type 1 diabetes (T1D) on arterial stiffness and cardiac function in young adults. Methods and results: Aortic pulse wave velocity (PWV), distensibility, left ventricular (LV) function and LV mass were measured by cardiovascular magnetic resonance imaging (CMR) in 47 T1D patients and 33 healthy controls. All were participants in the Atherosclerosis and Childhood Diabetes study, with baseline values registered 5 years previously. The patients had a mean age of 20.8 years and a median duration of diabetes of 10.0 years. PWV was significantly higher in the diabetes group compared with controls, mean 4.10 (SD = 4.58) vs. 3.90 (SD = 4.04) m/s, P = 0.045. In the diabetes group, insulin pump users at baseline had lower PWV than multiple injection users, mean 3.94 (SD = 0.38) vs. 4.23 (SD = 0.48) m/s, P = 0.028. Also in the diabetes group, multiple regression analysis identified C-reactive protein (CRP), female gender and insulin pump use as independent baseline risk factors for PWV 5 years later. There was no difference in cardiac function or LV mass between the diabetes and control groups. Conclusion: In this prospective study, we found increased PWV assessed by CMR in young adults with T1D compared with controls. Also, CRP, female gender and insulin pump use emerged as independent baseline risk factors for PWV 5 years later.

Preserved endothelial function in young adults with type 1 diabetes.

BACKGROUND AND AIM: Endothelial dysfunction is involved in the pathogenesis of atherosclerosis and is typically present in older adults with type 1 diabetes (T1D). In young adults, we aimed to assess the impact of T1D on endothelial function as detected by digital peripheral arterial tonometry (PAT) and its relationship with cardiovascular risk factors and long term glycemic control. MATERIALS AND METHODS: Reactive hyperemia index (RHI) as a measure of endothelial function was assessed by PAT in 46 T1D patients and 32 healthy controls. All were participants in the "Atherosclerosis and Childhood Diabetes" study, with baseline values registered five years previously. Annual measurements of HbA1c for assessment of glycemic burden were provided by the Norwegian Childhood Diabetes Registry. RESULTS: The diabetes patients had a mean age of 20.8 years, a median duration of diabetes of 10.0 years and a mean HbA1c of 8.7%. RHI was not significantly decreased in the diabetes group, mean 2.00 (SD = 0.59) vs. 2.21 (SD = 0.56), p = .116. There was no gender difference or any associations with traditional risk factors. Furthermore, there was no significant association between RHI and either HbA1c or long term glycemic burden. CONCLUSIONS: RHI as a measure of endothelial function was preserved in young adults with T1D compared with healthy controls.

Inflammation in childhood type 1 diabetes; influence of glycemic control.

OBJECTIVE: Patients with type 1 diabetes have increased mortality from cardiovascular disease, and inflammation is important in the development of atherosclerosis. Our aim was to evaluate the extent of inflammation and the influence of glycemic control in the early phases of atherosclerosis in childhood type 1 diabetes. MATERIALS AND METHODS: A population based cohort representative of all children with type 1 diabetes in Norway was studied. Diabetes patients (n = 314) were compared to healthy controls (n = 120), aged 8-18 years. Circulating levels of VCAM-1, ICAM-1, E-selectin, P-selectin, TNFα, IL-6, CRP, MCP-1, IL-18, MMP-9 and TIMP-1 were measured by immunoassays. RESULTS: The diabetes patients had a mean age of 13.7 (SD = 2.8) years, disease duration of 5.5 (SD = 3.4) years and HbA1c of 8.4 (SD = 1.2) % (68 mmol/mol, SD = 13.1). The levels of most of the measured markers were significantly increased in the diabetes group compared to controls. In the diabetes group, all except MCP-1 and MMP-9 were significantly correlated to HbA1c, albeit the relation to VCAM-1 was inverse. There were no significant correlations in the control group. The measured markers were only to a limited degree associated with traditional risk factors. CRP showed the most pronounced difference between diabetes patients and controls and the strongest correlation with HbA1c. The use of oral contraceptives profoundly increased CRP levels, independent of the presence of diabetes. CONCLUSIONS: Our results indicate that inflammation may play an important role in the accelerated atherosclerosis in early type 1 diabetes, and that this process seems primarily driven by hyperglycemia.

The advanced glycation end product methylglyoxal-derived hydroimidazolone-1 and early signs of atherosclerosis in childhood diabetes.

BACKGROUND: Advanced protein glycation is an important mechanism for the development of late diabetic complications including atherosclerosis. Methylglyoxal-derived hydroimidazolone-1 is the most abundant advanced glycation end product in human plasma. AIM: To investigate the relationship between methylglyoxal-derived hydroimidazolone-1 and early signs of atherosclerosis in children and adolescents with type 1 diabetes and healthy controls. METHODS: A total of 314 diabetes patients aged 8-18 years were compared with 120 healthy controls. Serum methylglyoxal-derived hydroimidazolone-1 was measured by immunoassay. Atherosclerosis was evaluated by assessing carotid intima-media thickness by ultrasound, arterial stiffness by Young's modulus and inflammation by C-reactive protein. RESULTS: Methylglyoxal-derived hydroimidazolone-1 was significantly increased in the diabetes group compared with controls, 155.3 (standard deviation (SD) = 41.0) versus 143.0 (SD = 35.1) U/mL, p = 0.003, as was C-reactive protein, median 0.51 (0.27, 1.83) versus 0.31 (0.19, 0.67) mg/L, p < 0.001. There was no significant difference between the groups regarding carotid intima-media thickness or Young's modulus. Multiple regression analysis showed a significant positive association between methylglyoxal-derived hydroimidazolone-1 and C-reactive protein in the diabetes group. CONCLUSION: Serum levels of methylglyoxal-derived hydroimidazolone-1 in diabetes patients are increased and associated with low-grade inflammation, but not yet arterial stiffness or wall thickness. This indicates that methylglyoxal-derived hydroimidazolone-1 may be important in the early phase of the accelerated atherosclerotic process in diabetes.

Early signs of atherosclerosis in diabetic children on intensive insulin treatment: a population-based study.

OBJECTIVE: To evaluate early stages of atherosclerosis and predisposing factors in type 1 diabetic children and adolescents compared with age- and sex-matched healthy control subjects. RESEARCH DESIGN AND METHODS: All children and adolescents with type 1 diabetes, aged 8-18 years in Health Region South-East in Norway were invited to participate in the study (n = 800). A total of 40% (n = 314) agreed to participate and were compared with 118 age-matched healthy control subjects. Carotid artery intima-media thickness (cIMT) and elasticity were measured using standardized methods. RESULTS: Mean age of the diabetic patients was 13.7 years, mean diabetes duration was 5.5 years, and mean A1C was 8.4%; 97% were using intensive insulin treatment, and 60% were using insulin pumps. Diabetic patients had more frequently elevated cIMT than healthy control subjects: 19.5% were above the 90th centile of healthy control subjects, and 13.1% were above the 95th centile (P < 0.001). Mean cIMT was higher in diabetic boys than in healthy control subjects (0.46 +/- 0.06 vs. 0.44 +/- 0.05 mm, P = 0.04) but not significantly so in girls. There was no significant difference between the groups regarding carotid distensibility, compliance, or wall stress. None of the subjects had atherosclerotic plaque formation. Although within the normal range, the mean values of systolic blood pressure, total cholesterol, LDL cholesterol, and apolipoprotein B were significantly higher in the diabetic patients than in the healthy control subjects. CONCLUSIONS: Despite short disease duration, intensive insulin treatment, fair glycemic control, and no signs of microvascular complications, children and adolescents with type 1 diabetes had slightly increased cIMT compared with healthy control subjects, and the differences were more prominent in boys.