Improvements in peripheral vascular function with vitamin D treatment in deficient adolescents with type 1 diabetes.

BACKGROUND: Vitamin D (VitD) deficiency is prevalent in adolescents with type 1 diabetes (T1D) and is associated with diabetes-related vascular complications in adulthood. The objective of this clinical trial was to assess VitD treatment on endothelial function (EF) and markers of renal inflammation, in this patient group. METHODS: Adolescents with T1D with suboptimal levels of VitD (<37.5 nmol/L) were treated for 12 to 24 weeks with a VitD analog (VitD3 ) at doses of 1000 or 2000 IU daily. The primary end-point assessed the change in reactive hyperemia index (lnRHI), a measure of EF. Secondary end-points included changes in blood pressure, lipid profile, HbA1c and albumin creatinine ratio (ACR). Urinary cytokine/chemokine inflammatory profile was also assessed in a subset of subjects posttreatment. RESULTS: Two hundred and seventy-one subjects were screened for VitD status and 31 VitD deficient subjects with a mean age of 15.7 ± 1.4 years were enrolled and completed the study. Mean 25-OH-VitD levels significantly increased (33.0 ± 12.8 vs 67.0 ± 23.2 nmol/L, P < .01) with a significant improvement in EF following VitD supplementation (lnRHI 0.58 ± 0.20 vs 0.68 ± 0.21, P = .03). VitD supplementation did not significantly impact systolic blood pressure/diastolic blood pressure (SBP/DBP), lipids, HbA1c and ACR and no adverse effects were seen. Several urinary inflammatory cytokines/chemokines: MCP-3 (P < .01), epidermal growth factor (EGF) (P < .01) tumor necrosis factor ß (TNFß) (P = .01), interleukin-10 (IL-10) (P = .01), also significantly decreased post-VitD-treatment. CONCLUSIONS: Treatment with VitD was associated with an improvement in EF and reduced expression of urinary inflammatory markers in adolescents with T1D. This data is suggestive of an additional benefit of VitD supplementation on early markers of microvascular complications.

The relationship between urinary renin-angiotensin system markers, renal function, and blood pressure in adolescents with type 1 diabetes.

The relationship between the renal renin-angiotensin aldosterone system (RAAS) and cardiorenal pathophysiology is unclear. Our aims were to assess 1) levels of urinary RAAS components and 2) the association between RAAS components and HbA1c, the urine albumin/creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and blood pressure (BP) in otherwise healthy adolescents with type 1 diabetes mellitus (TID) vs. healthy controls (HC). Urinary angiotensinogen and angtionsin-converting enzyme (ACE) 2 levels, activity of ACE and ACE2, BP, HbA1c, ACR, and eGFR were measured in 65 HC and 194 T1D from the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT). Urinary levels of all RAAS components were higher in T1D vs. HC (P < 0.0001). Higher HbA1c was associated with higher urinary angiotensinogen, ACE2, and higher activity of ACE and ACE2 (P < 0.0001, P = 0.0003, P = 0.003, and P = 0.007 respectively) in T1D. Higher ACR (within the normal range) was associated with higher urinary angiotensinogen (P < 0.0001) and ACE activity (P = 0.007), but not with urinary ACE2 activity or ACE2 levels. These observations were absent in HC. Urinary RAAS components were not associated with BP or eGFR in T1D or HC. Otherwise healthy adolescents with T1D exhibit higher levels of urinary RAAS components compared with HC. While levels of all urinary RAAS components correlate with HbA1c in T1D, only urinary angiotensinogen and ACE activity correlate with ACR, suggesting that these factors reflect an intermediary pathogenic link between hyperglycemia and albuminuria within the normal range.

Early changes in cardiovascular structure and function in adolescents with type 1 diabetes.

BACKGROUND: Children with type 1 diabetes (T1D) are at higher risk of early adult-onset cardiovascular disease. We assessed cardiovascular structure and function in adolescents with T1D compared with healthy controls and the relationships between peripheral vascular function and myocardial parameters. METHODS AND RESULTS: 199 T1D [14.4 ± 1.6 years, diabetes duration 6.2 (2.0-12.8) years] and 178 controls (14.4 ± 2.1 years) completed endothelial function by flow mediated vasodilatation (FMD), arterial stiffness using pulse wave velocity (PWV) along with M-mode, pulse wave and tissue Doppler, and myocardial deformation echocardiographic imaging. Systolic (113 ± 10 vs. 110 ± 9 mmHg; p = 0.0005) and diastolic (62 ± 7 vs. 58 ± 7 mmHg; p < 0.0001) blood pressures, carotid femoral PWV and endothelial dysfunction measurements were increased in T1D compared with controls. Systolic and diastolic left ventricular dimensions and function by M-mode and pulse wave Doppler assessment were not significantly different. Mitral valve lateral e' (17.6 ± 2.6 vs. 18.6 ± 2.6 cm/s; p < 0.001) and a' (5.4 ± 1.1 vs. 5.9 ± 1.1 cm/s; p < 0.001) myocardial velocities were decreased and E/e' (7.3 ± 1.2 vs. 6.7 ± 1.3; p = 0.0003) increased in T1D. Left ventricular mid circumferential strain (-20.4 ± 2.3 vs. -19.5 ± 1.7 %; p < 0.001) was higher, whereas global longitudinal strain was lower (-19.0 ± 1.9 vs. -19.8 ± 1.5 % p < 0.001) in T1D. CONCLUSIONS: Adolescents with T1D exhibit early changes in blood pressure, peripheral vascular function and left ventricular myocardial deformation indices with a shift from longitudinal to circumferential shortening. Longitudinal follow-up of these changes in ongoing prospective trials may allow detection of those most at risk for cardiovascular abnormalities including hypertension that could preferentially benefit from early therapeutic interventions.

Physiological changes in blood pressure impact peripheral endothelial function during adolescence.

Reactive hyperemia index is a measure of endothelial function used to assess subclinical atherosclerosis. When evaluated in healthy adolescents, significant changes in endothelial function were correlated with advancing age, pubertal status, and blood pressure. Blood pressure was the principal contributor to reactive hyperemia index variability independent of age, lipid profile, body mass index, and/or pubertal status. Interpretation of this peripheral vascular marker should include age and maturational changes in paediatric patients.

The urinary inflammatory profile in gluten free diet-adherent adolescents with type 1 diabetes and celiac disease.

AIMS: Our objective was to characterize urinary cytokine/chemokine excretion in adolescents with type 1 diabetes (T1D) and celiac disease (CD) adhering to gluten free diet (GFD) compared to matched T1D patients and healthy control (HC) group from an existing cohort. METHODS: Eighteen T1D+CD+GFD patients aged 10-16years were identified and matched 2:1 for age, sex, diabetes duration and glycated hemoglobin to 36 T1D subjects and 36 HC. T1D+CD+GFD patients were adherent with a GFD. Urine and serum levels of cytokines/chemokines as well as baseline clinical and laboratory variables were assessed. RESULTS: T1D+CD+GFD patients exhibited lower levels of urinary IL-1B, IL-4, IL-5 (p<0.05) and IFN-γ, IL-8 and G-CSF levels (p<0.07) compared with T1D patients. Urinary biomarker levels between T1D+CD+GFD and HC were mostly similar. In contrast, urinary FGF-2, Flt-3, IL-1B, IL-1RA, IL-4, IL-5, IL-9, IL-10, IL-12p40, IL-15, MIP-1ß, and TNF-ß (p<0.05) were higher in T1D patients compared to HC. Similar levels of inflammatory markers were seen in the serum for all 3 groups. CONCLUSIONS: T1D+CD+GFD patients demonstrated decreased urinary inflammatory cytokine/chemokines compared to T1D and some similar to HC, which is suggestive of a potential modulatory role of treated CD on urinary markers.

Association Between Plasma Uric Acid Levels and Cardiorenal Function in Adolescents With Type 1 Diabetes.

OBJECTIVE: The relationship between plasma uric acid (PUA) and renal and cardiovascular parameters in adolescents with type 1 diabetes (T1D) is not well understood. Our aims in this exploratory analysis were to study the association between PUA and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (ACR), blood pressure, endothelial function, and arterial stiffness in T1D adolescents. These associations were also studied in healthy control (HC) subjects. RESEARCH DESIGN AND METHODS: We studied 188 T1D subjects recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) and 65 HC subjects. Baseline PUA, eGFRcystatin C, ACR, blood pressure, flow-mediated dilation (FMD), and carotid-femoral pulse wave velocity (PWV) were measured. RESULTS: PUA was lower in T1D vs. HC subjects (242 ± 55 vs. 306 ± 74 µmol/L, respectively; P < 0.0001). Higher PUA was inversely associated with eGFR in T1D subjects (r = -0.48, P < 0.0001) even after correction for baseline clinical demographic characteristics. PUA was not associated with ACR in T1D after adjustment for potential confounders such as eGFR. For cardiovascular parameters, PUA levels did not associate with systolic blood pressure, FMD, or PWV in T1D or HC subjects. CONCLUSIONS: Even within the physiological range, PUA levels were significantly lower in T1D adolescent patients compared with HC subjects. There was an inverse relationship between PUA and eGFR in T1D, likely reflecting an increase in clearance. There were no associations observed with ACR, blood pressure, arterial stiffness, or endothelial function. Thus, in contrast with adults, PUA may not yet be associated with cardiorenal abnormalities in adolescents with T1D.

Assessment of habitual physical activity in adolescents with type 1 diabetes.

OBJECTIVE: To evaluate habitual physical activity in a cohort of adolescents with type 1 diabetes in relation to similarly aged control subjects. METHODS: A cross-sectional case control study of 54 healthy adolescents and 66 patients with type 1 diabetes, 14 to 18 years of age, was conducted. Subjects were surveyed using the Habitual Activity Estimation Scale, a validated self-report instrument to assess activity levels in teens. Subjects' time was classified into categories ranging from inactive (lying down, resting) to very active (increased heart rate and diaphoresis). Active time, described in relative (%) and absolute hours per day was determined for each individual. Age, sex, weight, height and body mass index were recorded for all participants, and the charts of subjects with type 1 diabetes were reviewed for most recent levels of glycated hemoglobin, low-density lipoproteins, high-density lipoproteins, total cholesterol, triglycerides and blood pressure. A regression analysis was performed to determine factors associated with hours spent being active. RESULTS: Subjects with type 1 diabetes spent similar hours being very active (3.4 hours vs. 3.5 hours, p=0.49) but reported more time being inactive than controls (2.0 hours vs. 1.3 hours, p=0.002). In both groups, female gender was associated with more hours spent being active. Metabolic control as assessed by glycated hemoglobin worsened with activity. In the group with type 1 diabetes, more hours spent being active were associated with lower systolic blood pressure, lower serum triglyceride levels, lower total cholesterol and higher high-density lipoproteins, whereas inactivity correlated with higher low-density lipoproteins and total cholesterol. CONCLUSIONS: Adolescents with type 1 diabetes reported significantly more time being inactive than did healthy controls. In patients with type 1 diabetes, activity was associated with improved cardiovascular risk profile.

The urinary cytokine/chemokine signature of renal hyperfiltration in adolescents with type 1 diabetes.

OBJECTIVE: Urinary cytokine/chemokine levels are elevated in adults with type 1 diabetes (T1D) exhibiting renal hyperfiltration. Whether this observation extends to adolescents with T1D remains unknown. Our first objective was to determine the relationship between hyperfiltration and urinary cytokines/chemokines in normotensive, normoalbuminuric adolescents with T1D using GFR(cystatin). Our second aim was to determine the relationship between urine and plasma levels of inflammatory biomarkers, to clarify the origin of these factors. METHODS: Urine and serum cytokines/chemokines (Luminex platform) and GFR(cystatin) were measured in normofiltering (n = 111, T1D-N, GFR<135 ml/min/1.73 m(2)) and hyperfiltering (n = 31, T1D-H, GFR ≥ 135 ml/min/1.73 m(2)) adolescents with T1D (ages 10-16), and in age and sex matched healthy control subjects (HC, n = 59). RESULTS: We noted significant step-wise increases in urinary cytokine/chemokine excretion according to filtration status with highest levels in T1D-H, with parallel trends in serum analyte concentrations. After adjusting for serum glucose at the time of sampling, differences in urinary cytokine excretion were not statistically significant. Only serum IL-2 significantly differed between HC and T1D (p = 0.0076). CONCLUSIONS: Hyperfiltration is associated with increased urinary cytokine/chemokine excretion in T1D adolescents, and parallel trends in serum cytokine concentration. The GFR-associated trends in cytokine excretion may be driven by the effects of ambient hyperglycemia. The relationship between hyperfiltration, glycemia, and variations in serum and urine cytokine expression and their impact on future renal and systemic vascular complications requires further study.