Abnormal vascular thickness and stiffness in young adults with type 1 diabetes: new insights from cutting-edge ultrasound modalities.

BACKGROUND: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in patients with Type 1 Diabetes (T1D). Early markers of CVD include increased carotid intima-media thickness (CIMT) and pulse wave velocity (PWV), but these existing ultrasound technologies show limited spatial and temporal resolution in young adults. The purpose of this study is to evaluate the utility of high-resolution ultrasound modalities, including high frequency ultrasound CIMT (hfCIMT) and ultrafast ultrasound PWV (ufPWV), in young adults with Type 1 Diabetes. METHODS: This is a prospective single-center observational cohort study including 39 participants with T1D and 25 age and sex matched controls. All participants underwent hfCIMT and ufPWV measurements. hfCIMT and ufPWV measures of T1D were compared with controls and associations with age, sex, BMI, A1c, blood pressure, and lipids were studied. RESULTS: Mean age was 24.1 years old in both groups. T1D had a greater body mass index (27.7 [5.7] vs 23.1 [3.2] kg/m2), LDL Cholesterol, and estimated GFR, and had a mean A1c of 7.4 [1.0] % (57 mmol/mol) and diabetes duration of 16.1 [3.7] years with 56% using insulin pumps. In T1D, hfCIMT was significantly increased as compared to controls (0.435 ± 0.06 mm vs 0.379 ± 0.06 mm respectively, p < 0.01). ufPWV measures were significantly increased in T1D (systolic foot PWV: 5.29 ± 0.23 m/s vs 5.50 ± 0.37 m/s, p < 0.01; dicrotic notch PWV = 7.54 ± 0.46 m/s vs 7.92 ± 0.41 m/s, p < 0.01). Further, there was an impact of A1c-measured glycemia on hfCIMT, but this relationship was not seen with ufPWV. No significant statistical correlations between hfCIMT and ufPWV measures in either T1D or healthy controls were observed. CONCLUSION: Young adults with T1D present with differences in arterial thickness and stiffness when compared with controls. Use of novel high-resolution ultrasound measures describe important relationships between early structural and vascular pathophysiologic changes and are promising tools to evaluate pre-clinical CVD risk in youth with T1D. TRIAL REGISTRATION: ISRCTN91419926.

Bone health in young adults with type 1 diabetes and progressive eGFR decline.

BACKGROUND: Type 1 Diabetes (T1D) is associated with increased risk of fractures, worsened by presence of microvascular complications. This study's objective is to determine the impact of progressive decline in estimated glomerular filtration rate (eGFR) on bone biomarkers and bone microarchitecture in youth with T1D. METHODS: Slopes of eGFR were calculated using measures obtained at four timepoints from adolescence to young adulthood. Participants were identified as eGFR decliners if eGFR decreased ≥ 3ml/min/1.73m2/year. Bone health was assessed in young adulthood by high resolution peripheral quantitative computed tomography (HRpQCT Xtreme CTII) and bone biomarkers; osteocalcin, procollagen 1 intact n-terminal pro-peptide (P1NP), c-terminal telopeptide (CTX), and bone specific alkaline phosphatase. The relationship between diabetes duration, glycated hemoglobin, body mass index (BMI) and vitamin D level on bone biomarkers and microarchitecture was evaluated. Linear regression analysis was used for the statistical analysis in this study. RESULTS: Ninety-nine study participants were studied with longitudinal evaluation of eGFR over 7.4 ± 1.0 years with mean age of 14.7 ± 1.7 years at baseline. Cross sectional evaluation of bone was performed at 21.3 ± 2.1 years. 44% participants had eGFR decline and showed 5% higher cortical porosity diameter than non-decliners (p = 0.035). Greater diabetes duration was associated with higher trabecular separation (p = 0.004) and lower trabecular number (p = 0.01). Higher level of 25 hydroxy-vitamin D was associated with lower trabecular separation (p = 0.01). Elevated glycated hemoglobin (p = 0.0008) and BMI (p = 0.009), were associated with lower markers of bone formation. CONCLUSION: Mild increase in cortical porosity diameter was found in youth with T1D and eGFR decline, however, overall measures of bone microarchitecture on HR-pQCT were similar between both groups and there were no statistically significant changes in bone biomarkers. Hence, skeletal impairments were limited in youth with different eGFR trajectories near peak bone mass. Longitudinal HR-pQCT studies are needed to further understand the impact of eGFR decline on bone microarchitecture. Optimal glycemic control, normal BMI and vitamin D status were supported by this study as important markers for good bone health.

Socioeconomic representativeness of Australian, Canadian and British cohorts from the paediatric diabetes AdDIT study: comparisons to regional and national data.

BACKGROUND: Given limited data regarding the involvement of disadvantaged groups in paediatric diabetes clinical trials, this study aimed to evaluate the socioeconomic representativeness of participants recruited into a multinational clinical trial in relation to regional and national type 1 diabetes reference populations. METHODS: Retrospective, cross-sectional evaluation of a subset of adolescent type 1 diabetes cardiorenal intervention trial (AdDIT) participants from Australia (n = 144), Canada (n = 312) and the UK (n = 173). Validated national measures of deprivation were used: the Index of Relative Socioeconomic Disadvantage (IRSD) 2016 (Australia), the Material Resources (MR) dimension of the Canadian Marginalisation index 2016 (Canada) and the Index of Multiple Deprivation (IMD) 2015 (UK). Representativeness was assessed by comparing the AdDIT cohort's distribution of deprivation quintiles with that of the local paediatric type 1 diabetes population (regional), and the broader type 1 diabetes population for which the trial's intervention was targeted (national). RESULTS: Recruited study cohorts from each country had higher proportions of participants with higher SES, and significant underrepresentation of lower SES, in relation to their national references. The socioeconomic make-up in Australia mirrored that of the regional population (p = 0.99). For Canada, the 2nd least deprived (p = 0.001) and the most deprived quintiles (p < 0.001) were over- and under-represented relative to the regional reference, while the UK featured higher regional and national SES bias with over-representation and under-representation from the least-deprived and most-deprived quintiles (p < 0.0001). CONCLUSIONS: Significant national differences in trial participation of low SES participants were observed, highlighting limitations in access to clinical research and the importance of reporting sociodemographic representation in diabetes clinical trials. TRIAL REGISTRATION: NCT01581476. Registered on 20 April 2012.

Relationship between risk factors for impaired bone health and HR-pQCT in young adults with type 1 diabetes.

Objective: In type 1 diabetes, risk factors associated with impaired bone health contribute to increased risk of fracture. The aim of this study was to (1): compare the high-resolution peripheral quantitative computed tomography (HR-pQCT) parameters of young adults with type 1 diabetes with those of healthy controls (2), identify sex differences, and (3) evaluate the association between diabetes and bone health risk factors, with HR-pQCT. Methods: This is a cross-sectional study in young Canadian adults with childhood onset type 1 diabetes. Z-scores were generated for HR-pQCT parameters using a large healthy control database. Diet, physical activity, BMI, hemoglobin A1C (A1C) and bone health measures were evaluated, and associations were analyzed using multivariate regression analysis. Results: Eighty-eight participants (age 21 ± 2.2 years; 40 males, 48 females, diabetes duration 13.9 ± 3.4 years) with type 1 diabetes were studied. Low trabecular thickness and elevated cortical geometry parameters were found suggesting impaired bone quality. There were no sex differences. Significant associations were found: Vitamin D (25(OH)D) with trabecular parameters with possible synergy with A1C, parathyroid hormone with cortical parameters, BMI with cortical bone and failure load, and diabetes duration with trabecular area. Conclusions: Our data suggests impairment of bone health as assessed by HR-pQCT in young adults with type 1 diabetes. Modifiable risk factors were associated with trabecular and cortical parameters. These findings imply that correction of vitamin D deficiency, prevention and treatment of secondary hyperparathyroidism, and optimization of metabolic control may reduce incident fractures.

Evaluation of novel glomerular filtration rate estimation equations in adolescents and young adults with type 1 diabetes.

AIMS: Individuals with type 1 diabetes (T1D) are at an increased risk of chronic kidney disease making estimation of glomerular filtration rate (eGFR) an important component of diabetes care. Which eGFR equation is most appropriate to use in patients with T1D during the transition to adult care is unclear. We, therefore, sought to evaluate the performance of five eGFR equations in adolescents and young adults with T1D. METHODS: Measured iohexol-based glomerular filtration rate was compared to the Chronic Kidney Disease and Epidemiology Collaboration (CKD-EPI) eGFR, Chronic Kidney Disease in Children (CKiD) eGFR, and three recently developed age-adjusted versions of these in 53 patients with T1D and preserved GFR using bias, precision, and accuracy. RESULTS: The best performance was found in the sex-dependent CKiD equation (bias: -0.8, accuracy: 11.8 ml/min/1.73 m2). Bias and accuracy (26.4 and 26.8 ml/min/1.73 m2) were worst in the CKD-EPI equation. Age-dependent adjustment improved performance for this equation (bias: 5.3, accuracy: 13.4 ml/min/1.73 m2), but not for the CKiD equation (bias: 15.5, accuracy: 18.8 ml/min/1.73 m2). CONCLUSION: Age-adjustment improved performance for the CKD-EPI equation, but not for the CKiD equation. The sex-adjusted CKiD equation performed best out of all equations.

Mild Idiopathic Infantile Hypercalcemia-Part 1: Biochemical and Genetic Findings.

CONTEXT: Idiopathic infantile hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D) and low parathyroid hormone (PTH) levels, may present with mild to severe hypercalcemia during the first months of life. Biallelic variants in the CYP24A1 or SLC34A1 genes are associated with severe IIH. Little is known about milder forms. OBJECTIVE: This work aims to characterize the genetic associations and biochemical profile of mild IIH. METHODS: This is a cross-sectional study including children between age 6 months and 17 years with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. Twenty children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analyzed biochemical measures including vitamin D metabolites and performed a stepwise molecular genetic analysis. Complementary biochemical assessments and renal ultrasounds were offered to first-degree family members of positive probands. RESULTS: The median age was 16 months. Median serum levels of calcium (2.69 mmol/L), urinary calcium:creatinine ratio (0.72 mmol/mmol), and 1,25(OH)2D (209 pmol/L) were elevated, whereas intact PTH was low normal (22.5 ng/L). Mean 1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven individuals (55%) had renal calcification. Genetic variants were common (65%), with the majority being heterozygous variants in SLC34A1 and SLC34A3, while a minority showed variants of CYP24A1 and other genes related to hypercalciuria. CONCLUSION: The milder form of IIH has a distinctive vitamin D metabolite profile and is primarily associated with heterozygous SLC34A1 and SLC34A3 variants.

Mild Idiopathic Infantile Hypercalcemia-Part 2: A Longitudinal Observational Study.

CONTEXT: Idiopathic infantile hypercalcemia (IIH) is an uncommon disorder with variable clinical features. The natural history and response to dietary calcium and vitamin D restriction in IIH remains unclear. OBJECTIVE: The aim of this study is to describe the clinical and biochemical response to dietary calcium and vitamin D restriction in a genetically characterized cohort of mild IIH. METHODS: This is a longitudinal, observational cohort study of 20 children with mild IIH monitored for a median of 21months. Biochemical measures, dietary assessment, and yearly renal ultrasound results, since the time of diagnosis, were obtained and assessed prospectively every 4 to 6 months. RESULTS: Median age at initial diagnosis was 4.5 months. Median levels of serum calcium (2.82 mmol/L) and 1,25 (OH)2D (192 pmol/L) were elevated, whereas serum PTH was reduced (10 ng/L). Urinary calcium:creatinine ratio was elevated for some, but not all individuals (median 1.49 mmol/mmol). All patients who were managed with a low-calcium diet showed an improvement in serum and urinary calcium measures, but the serum concentration of 1,25 dihydroxyvitamin D (1,25(OH)2D) and 1,25(OH)2D/PTH ratio remained elevated. In 2 of the 11 subjects, renal calcification worsened. There were no differences in response between individuals with CYP24A1 or SLC34A1/A3 variants. CONCLUSION: The clinical presentation of mild IIH is variable, and dietary calcium and vitamin D restriction does not consistently normalize elevated 1,25(OH)2D concentrations or prevent worsening of renal calcification in all cases. Therapeutic options should target the defect in vitamin D metabolism.

Comparison of Clinical and Social Characteristics of Canadian Youth Living With Type 1 and Type 2 Diabetes.

OBJECTIVES: Our aim in this study was to describe the clinical and social characteristics of 2 Canadian cohorts of adolescents with diabetes. METHODS: Participants from the Improving renal Complications in Adolescents with type 2 diabetes through REsearch (iCARE) study (n=322) and the Early Determinants of Cardio-Renal Disease in Youth With Type 1 Diabetes (n=199) study were compared. RESULTS: Adolescents were 10 to 18 years of age (mean ± standard deviation: 14.8±2.4 years). The T2DM cohort had a shorter duration of diabetes. Both groups had glycated hemoglobin levels above target. The type 2 diabetes (T2D) cohort was comprised of predominantly Indigenous youth. The type 1 diabetes (T1D) cohort was 58.3% European/Caucasian, with a high proportion (41.7%) of visible minority groups (Afro-Caribbean, Asian/Pacific Islander, Hispanic). The prevalence of obesity, hypertension, left ventricular hypertrophy, albuminuria and hyperfiltration was higher in the T2D cohort. The T1D cohort was more socially and economically advantaged in all 4 dimensions of health inequality. CONCLUSIONS: There are significant differences in clinical and social characteristics of adolescents with T2D and T1D in Canada. Both have inadequate glycemic control with evidence of onset and progression of diabetes-related complications.

Multicentric carpotarsal osteolysis syndrome (MCTO) with generalized high bone turnover and high serum RANKL: Response to denosumab.

MCTO is a rare disorder, caused by mutations in the MafB gene, a negative regulator of receptor activator of nuclear factor-кB ligand (RANKL). Manifestations include carpal and tarsal osteolysis and renal failure. Pathophysiology is poorly understood, and no effective treatment is available. In this case report we describe a patient with MCTO (MafB, mutation c.206C>T, p.Ser69Leu), diagnosed at the age of 5 years. At 7 years, skeletal survey showed diffuse osteopenia. BMD was mildly reduced, and bone turnover markers increased. He was treated with denosumab, a human monoclonal RANKL inhibitor for two years. Each injection was followed by a marked reduction in C-telopeptide (CTX). Following denosumab his BMD and bone symptoms improved and the osteolysis stabilized. At the age of 13 years, osteoporosis was diagnosed using high resolution peripheral quantitative computed tomography (HRpQCT) and serum RANKL was found to be markedly increased. This initial experience suggests that the associated osteoporosis may be ameliorated by denosumab, although further study will be needed to understand the appropriate dose, frequency, and the extent of efficacy. Monitoring of CTX and bone specific alkaline phosphatase will be especially useful in this regard. Further study in other MCTO patients is also needed to determine whether high bone turnover is specific to this mutation or more common than previously appreciated. We propose a model in which osteolysis in this condition is strongly associated with the systemic osteoporosis.

Urinary podocyte-derived microparticles in youth with type 1 and type 2 diabetes.

AIMS/HYPOTHESIS: The release of podocyte-derived microparticles into the urine may reflect early kidney injury in diabetes. We measured the urinary excretion of podocyte-derived microparticles in youth with type 1 and type 2 diabetes, and related the values to blood pressure, renal function and blood glucose levels. METHODS: Cross-sectional, exploratory analysis of urine samples and clinical data from youth with type 1 (n = 53) and type 2 (n = 50) diabetes was carried out. Urinary podocyte-derived microparticle numbers, measured by flow cytometry, were assessed in relation to measures of blood glucose levels and renal function. RESULTS: Podocyte-derived microparticle excretion (MPE) normalised to urinary creatinine (MP/UCr) was higher in type 1 vs type 2 diabetes (median [IQR] MP/UCr: 7.88 [8.97] vs 1.84 [8.62]; p < 0.0001), despite the type 2 diabetes group having higher blood pressure (systolic blood pressure, median [range]: 124 [110-154] vs 114 [94-143] mmHg) and higher proportions of microalbuminuria (44.0% vs 13.2%), but shorter time since diabetes diagnosis (median [range]: 1.2 [0.0-7.0] vs 6.4 [2.0-13.9] years), than the type 1 diabetes cohort. MPE in youth with type 1 diabetes was associated with blood glucose (p = 0.01) and eGFR (p = 0.03) but not HbA1c, systolic or diastolic blood pressure or urine albumin/creatinine ratio. After adjustment for age at baseline, duration of diabetes, sex and BMI, the association with eGFR remained significant (p = 0.04). No associations were found between MPE and these clinical variables in youth with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Significant associations between podocyte MPE, blood glucose levels and eGFR were observed in youth with type 1 diabetes but not in those with type 2 diabetes, notwithstanding increased renal pathology in the type 2 diabetes cohort. These findings suggest that podocyte injury differs in the two diabetes cohorts. Graphical abstract.

Urinary proteomics links keratan sulfate degradation and lysosomal enzymes to early type 1 diabetes.

Diabetes is the leading cause of end-stage renal disease worldwide. Our understanding of the early kidney response to chronic hyperglycemia remains incomplete. To address this, we first investigated the urinary proteomes of otherwise healthy youths with and without type 1 diabetes and subsequently examined the enriched pathways that might be dysregulated in early disease using systems biology approaches. This cross-sectional study included two separate cohorts for the discovery (N = 30) and internal validation (N = 30) of differentially excreted proteins. Discovery proteomics was performed on a Q Exactive Plus hybrid quadrupole-orbitrap mass spectrometer. We then searched the pathDIP, KEGG, and Reactome databases to identify enriched pathways in early diabetes; the Integrated Interactions Database to retrieve protein-protein interaction data; and the PubMed database to compare fold changes of our signature proteins with those published in similarly designed studies. Proteins were selected for internal validation based on pathway enrichment and availability of commercial enzyme-linked immunosorbent assay kits. Of the 2451 proteins identified, 576 were quantified in all samples from the discovery cohort; 34 comprised the urinary signature for early diabetes after Benjamini-Hochberg adjustment (Q < 0.05). The top pathways associated with this signature included lysosome, glycosaminoglycan degradation, and innate immune system (Q < 0.01). Notably, all enzymes involved in keratan sulfate degradation were significantly elevated in urines from youths with diabetes (|fold change| > 1.6). Increased urinary excretion of monocyte differentiation antigen CD14, hexosaminidase A, and lumican was also observed in the validation cohort (P < 0.05). Twenty-one proteins from our signature have been reported elsewhere as potential mediators of early diabetes. In this study, we identified a urinary proteomic signature for early type 1 diabetes, of which lysosomal enzymes were major constituents. Our findings highlight novel pathways such as keratan sulfate degradation in the early kidney response to hyperglycemia.

Peptidomic Analysis of Urine from Youths with Early Type 1 Diabetes Reveals Novel Bioactivity of Uromodulin Peptides In Vitro.

Chronic hyperglycemia is known to disrupt the proteolytic milieu, initiating compensatory and maladaptive pathways in the diabetic kidney. Such changes in intrarenal proteolysis are captured by the urinary peptidome. To elucidate the early kidney response to chronic hyperglycemia, we conducted a peptidomic investigation into urines from otherwise healthy youths with type 1 diabetes and their non-diabetic peers using unbiased and targeted mass spectrometry-based techniques. This cross-sectional study included two separate cohorts for the discovery (n = 30) and internal validation (n = 30) of differential peptide excretion. Peptide bioactivity was predicted using PeptideRanker and subsequently verified in vitro Proteasix and the Nephroseq database were used to identify putative proteases responsible for peptide generation and examine their expression in diabetic nephropathy. A total of 6550 urinary peptides were identified in the discovery analysis. We further examined the subset of 162 peptides, which were quantified across all thirty samples. Of the 15 differentially excreted peptides (p < 0.05), seven derived from a C-terminal region (589SGSVIDQSRVLNLGPITRK607) of uromodulin, a kidney-specific protein. Increased excretion of five uromodulin peptides was replicated in the validation cohort using parallel reaction monitoring (p < 0.05). One of the validated peptides (SGSVIDQSRVLNLGPI) activated NFκB and AP-1 signaling, stimulated cytokine release, and enhanced neutrophil migration in vitro. In silico analyses highlighted several potential proteases such as hepsin, meprin A, and cathepsin B to be responsible for generating these peptides. In summary, we identified a urinary signature of uromodulin peptides associated with early type 1 diabetes before clinical manifestations of kidney disease and discovered novel bioactivity of uromodulin peptides in vitro Our present findings lay the groundwork for future studies to validate peptide excretion in larger and broader populations, to investigate the role of bioactive uromodulin peptides in high glucose conditions, and to examine proteases that cleave uromodulin.

Elevated high-density lipoprotein in adolescents with Type 1 diabetes is associated with endothelial dysfunction in the presence of systemic inflammation.

AIMS: High-density lipoprotein (HDL) function may be altered in patients with chronic disease, transforming the particle from a beneficial vasoprotective molecule to a noxious pro-inflammatory equivalent. Adolescents with Type 1 diabetes often have elevated HDL, but its vasoprotective properties and relationship to endothelial function have not been assessed. METHODS AND RESULTS: Seventy adolescents with Type 1 diabetes (age 10-17 years) and 30 age-matched healthy controls supplied urine samples for the measurement of early renal dysfunction (albumin:creatinine ratio; ACR), blood samples for the assessment of cardiovascular risk factors (lipid profiles, HDL functionality, glycaemic control, and inflammatory risk score), and had their conduit artery endothelial function tested using flow-mediated dilation (FMD). HDL-c levels (1.69 ± 0.41 vs. 1.44 ± 0.29mmol/L; P < 0.001), and glycated haemoglobin (HbA1c) (8.4 ± 1.2 vs. 5.4 ± 0.2%; P < 0.001) were increased in all patients compared with controls. However, increased inflammation and HDL dysfunction were evident only in patients who also had evidence of early renal dysfunction (mean ± standard deviation for high-ACR vs. low-ACR and healthy controls: inflammatory risk score 11.3 ± 2.5 vs. 9.5 ± 2.4 and 9.2 ± 2.4, P < 0.01; HDL-mediated nitric-oxide bioavailability 38.0 ± 8.9 vs. 33.3 ± 7.3 and 25.0 ± 7.7%, P < 0.001; HDL-mediated superoxide production 3.71 ± 3.57 vs. 2.11 ± 3.49 and 1.91 ± 2.47nmol O2 per 250 000 cells, P < 0.05). Endothelial function (FMD) was impaired only in those who had both a high inflammatory risk score and high levels of HDL-c (P < 0.05). CONCLUSION: Increased levels of HDL-c commonly observed in individuals with Type 1 diabetes may be detrimental to endothelial function when accompanied by renal dysfunction and chronic inflammation.

Relationship between serum inflammatory markers and vascular function in a cohort of adolescents with type 1 diabetes.

OBJECTIVE: The contribution of inflammation to endothelial/vascular dysfunction in early Type I Diabetes (T1D) is not well understood. The objective of this study was to examine the interaction between systemic inflammation and vascular function in adolescent's with and without-T1D. METHODS: 51 subjects from our observational cohort of adolescents with T1D (JDRF-CCTN), and 59 healthy controls (HC) were studied. Serum cytokines-chemokines were quantified using Human 41-Plex Array, and vascular function was measured by Flow Mediated Dilatation (FMD), Pulse Wave Velocity (PWV) and Blood Pressure (BP). Factor Analysis was used to identify pro- and anti-inflammatory cytokine-chemokine factors, which were then correlated with vascular outcomes. RESULTS: Three pro-inflammatory factors were identified in HC and three in TID, and a single anti-inflammatory factor in both groups. In HC there was a positive correlation (r=0.33; p=0.01) between control proinflammatory Factor 1 and systolic BP and a negative correlation between control proinflammatory Factor 3(r=-0.29; p=0.02) and diastolic BP. Control proinflammatory Factor 2 correlated positively with PWV. In TID subjects, no correlations were found between any of the pro-inflammatory factors and the vascular measurements. No correlations were found between the anti-inflammatory factors and BP, FMD and PWV in either HC or T1D. Levels of pro-inflammatory analytes, EGF, GRO, PDGF-BB, PDGF-AA and sCD40L were significantly higher in T1D. CONCLUSIONS: The cytokine-chemokine signature in early T1D, prior to the development of arterial disease, is significantly different from that seen in healthy controls. This may be relevant to pathophysiology, determining risk and identifying target cytokines-chemokines for intervention in T1D.

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.

Assessing social determinants of health in a pediatric diabetes clinical research trial: Are recruited subjects representative of the larger clinical population?

Social determinants of health (SDH) impact clinical outcomes and are often poorly described in research trials. Using a validated tool, SDH dimensions were compared between adolescents enrolled and not enrolled into a large diabetes study. We observed that our study cohort reflected a SDH profile mirroring the eligible population.

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.

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.

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.