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.

Influence of sex on hyperfiltration in patients with uncomplicated type 1 diabetes.

The aim of this analysis was to examine sex-based differences in renal segmental resistances in healthy controls (HCs) and patients with type 1 diabetes (T1D). We hypothesized that hyperfiltration-an early hemodynamic abnormality associated with diabetic nephropathy-would disproportionately affect women with T1D, thereby attenuating protection against the development of renal complications. Glomerular hemodynamic parameters were evaluated in HC (n = 30) and in normotensive, normoalbuminuric patients with T1D and either baseline normofiltration [n = 36, T1D-N, glomerular filtration rate (GFR) 90-134 ml·min-1·1.73 m2] or hyperfiltration (n = 32, T1D-H, GFR ≥ 135 ml·min-1·1.73 m2) during euglycemic conditions (4-6 mmol/l). Gomez's equations were used to derive efferent (RE) and afferent (RA) arteriolar resistances, glomerular hydrostatic pressure (PGLO) from inulin (GFR) and paraaminohippurate [effective renal plasma flow (ERPF)] clearances, plasma protein and estimated ultrafiltration coefficients (KFG). Female patients with T1D with hyperfiltration (T1D-H) had higher RE (1,985 ± 487 vs. 1,381 ± 296 dyne·sec-1·cm-5, P < 0.001) and filtration fraction (FF, 0.20 ± 0.047 vs. 0.16 ± 0.03 P < 0.05) and lower ERPF (876 ± 245 vs. 1,111 ± 298 134 ml·min-1·1.73 m2P < 0.05) compared with male T1D-H patients. Overall, T1D-H patients had higher PGLO and lower RA vs. HC subjects, although there were no sex-based differences. In conclusion, female T1D-H patients had higher RE and FF and lower ERPF than their male counterparts with no associated sex differences in RA Prospective intervention studies should consider sex as a modifier of renal hemodynamic responses to renal protective therapies.

Technique, Safety, and Yield of Bone Biopsies for Histomorphometry in Children.

PURPOSE: To evaluate image-guided bone biopsy for bone histomorphometry to assess osteoporosis in children with respect to safety and yield. MATERIALS AND METHODS: A single-center retrospective review was performed of 79 bone biopsies in 73 patients performed between 2007 and 2015. Biopsies of the iliac bone were performed under general anesthesia, after tetracycline labeling, using a Rochester needle (Medical Innovations International, Inc, Rochester, Minnesota). Ultrasound and fluoroscopic guidance were used in all procedures. Biopsy technique, technical success, safety, and histomorphometry results (complete, incomplete, none) were analyzed. RESULTS: There were 41 male patients (51.8%). Technical success was achieved in 76/79 (96%) procedures. Of 79 biopsies, 75 (95%) were uneventful. Unplanned overnight observation was required in 3 (minor SIR grade B), and prolonged hospital stay owing to hematoma causing nerve compression pain was required in 1 (major SIR grade D). Complete histomorphometric reports were obtained in 69 (87%) procedures, incomplete reports were obtained in 7 (9%), and no reports were obtained in 3(4%). Incomplete reports were insufficient to provide a definitive diagnosis or guide treatment. Histomorphometry impacted subsequent therapy in 69 (87%) biopsies. CONCLUSIONS: Image-guided bone biopsy for osteoporosis using the Rochester needle is a valuable and safe technique for establishing the diagnosis of osteoporosis and directing treatment based on histomorphometry results.

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 effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes.

AIMS/HYPOTHESIS: Acute clamped hyperglycaemia activates the renin-angiotensin-aldosterone system (RAAS) and increases the urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Our objective was to determine whether blockade of the RAAS would blunt the effect of acute hyperglycaemia on urinary cytokine/chemokine excretion, thereby giving insights into potentially protective effects of these agents prior to the onset of clinical nephropathy. METHODS: Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances) and urinary cytokines/chemokines were measured after 6 h of clamped euglycaemia (4-6 mmol/l) and hyperglycaemia (9-11 mmol/l) on two consecutive days in patients with type 1 diabetes mellitus (n = 27) without overt nephropathy. Measurements were repeated after treatment with aliskiren (300 mg daily) for 30 days. RESULTS: Before aliskiren, clamped hyperglycaemia increased filtration fraction (from 0.188 ± 0.007 to 0.206 ± 0.007, p = 0.003) and urinary fibroblast growth factor-2 (FGF2), IFN-α2 and macrophage-derived chemokine (MDC) (p < 0.005). After aliskiren, the filtration fraction response to hyperglycaemia was abolished, resulting in a lower filtration fraction after aliskiren under clamped hyperglycaemic conditions (p = 0.004), and none of the biomarkers increased in response to hyperglycaemia. Aliskiren therapy also reduced levels of urinary eotaxin, FGF2, IFN-α2, IL-2 and MDC during clamped hyperglycaemia (p < 0.005). CONCLUSIONS/INTERPRETATION: The increased urinary excretion of inflammatory cytokines/chemokines in response to acute hyperglycaemia is blunted by RAAS blockade in humans with uncomplicated type 1 diabetes mellitus.

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.

Hyperfiltration and effect of nitric oxide inhibition on renal and endothelial function in humans with uncomplicated type 1 diabetes mellitus.

Studies of experimental diabetes mellitus (DM) suggest that increased nitric oxide (NO) bioactivity contributes to renal hyperfiltration. However, the role of NO in mediating hyperfiltration has not been fully elucidated in humans. Our aim was to examine the effect of NO synthase inhibition on renal and peripheral vascular function in normotensive subjects with uncomplicated type 1 DM. Renal function and brachial artery flow-mediated vasodilatation (FMD) were measured before and after an intravenous infusion of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NMMA) in 21 healthy control and 37 type 1 DM patients. Measurements in DM participants were made under clamped euglycemic conditions. The effect of l-NMMA on circulating and urinary NO metabolites (NO(x)) and cGMP and on urinary prostanoids was also determined. Baseline characteristics were similar in the two groups. For analysis, the DM patients were divided into those with hyperfiltration (DM-H, n = 18) and normal glomerular filtration rate (GFR) levels (DM-N, n = 19). Baseline urine NO(x) and cGMP were highest in DM-H. l-NMMA led to a decline in GFR in DM-H (152 ± 16 to 140 ± 11 ml·min(-1)·1.73 m(-2)) but not DM-N or healthy control participants. The decline in effective renal plasma flow in response to l-NMMA (806 ± 112 to 539 ± 80 ml·min(-1)·1.73 m(-2)) in DM-H was also exaggerated compared with the other groups (repeated measures ANOVA, P < 0.05), along with declines in urinary NO(x) metabolites and cGMP. Baseline FMD was lowest in DM-H compared with the other groups and did not change in response to l-NMMA. l-NMMA reduced FMD and plasma markers of NO bioactivity in the healthy control and DM-N groups. In patients with uncomplicated type 1 DM, renal hyperfiltration is associated with increased NO bioactivity in the kidney and reduced NO bioactivity in the systemic circulation, suggesting a paradoxical state of high renal and low systemic vascular NO bioactivity.

Ability of Cystatin C to detect changes in glomerular filtration rate after ACE inhibition in patients with uncomplicated type 1 diabetes.

Although it is known that glomerular filtration rate (GFR) declines in response to angiotensin converting enzyme (ACE) inhibition, recent observations using GFR(CYSTATIN C) have shown a paradoxical increase calling into question its validity. In this descriptive study, we aimed to reconcile this observation by simultaneously measuring GFR(CYSTATIN C), GFR(CREATININE), and gold standard GFR(INULIN) responses to ACE inhibition. Adolescents with type 1 diabetes and hyperfiltration (n = 9, GFR(INULIN) ≥ 135 mL/min/1.73 m(2)) or normofiltration (n = 11) were studied during clamped euglycemia at baseline and after 3-week enalapril therapy. In hyperfilterers, the anticipated GFR(INULIN) decline before and after enalapril was observed (174 ± 29 mL/min/1.73 m(2) to 140 ± 26 mL/min/1.73 m(2), P = .01). Although GFR(CYSTATIN C) equations tended to underestimate while GFR(CREATININE) equations tended to overestimate baseline GFR(INULIN) in hyperfilterers, both approaches generally reflected declining GFR(INULIN) responses to enalapril. Normofilterers demonstrated a trend toward rising GFR(INULIN) in response to enalapril (112 ± 16 mL/min/1.73 m(2) to 119 ± 27 mL/min/1.73 m(2), P = .35). Although all estimating equations tended to overestimate baseline GFR(INULIN), they generally reflected the rising trend in GFR(INULIN) in response to enalapril in normofilterers. Although GFR(INULIN) declines in response to enalapril among hyperfilterers, we confirm the previous observation that it demonstrates a trend to rising among normofilterers. These group trends are both reflected by cystatin C- and creatinine-based estimates.

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.

Vitamin D supplementation and CD4 count in children infected with human immunodeficiency virus.

OBJECTIVE: To evaluate, in a randomized fashion, the impact of vitamin D supplementation on CD4 count and measures of vitamin D homeostasis in children infected with human immunodeficiency virus (HIV). STUDY DESIGN: Children infected with HIV (n = 54) were randomized to receive no supplementation (group 1), vitamin D 5600 IU/week (group 2), or vitamin D 11 200 IU/week (group 3) for 6 months. Viral load, CD4 percent, CD4 count, 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D, and other measures of vitamin D metabolism were measured at baseline and 6 months later. RESULTS: A total of 53 participants completed the study. The mean age, CD4 percent, CD4 count, and log(10) viral load at baseline were 10.3 ± 3.9 years, 33% ± 10%, 927 ± 468 cells/µL, and 1.63 (95% CI, 0.76-2.50), respectively. The mean baseline 25(OH)D level was 53.1 ± 24.8 nmol/L; 85% of participants were vitamin D insufficient or deficient (<75 nmol/L). Serum levels of 25(OH)D increased significantly in participants who received supplementation with vitamin D (P = .0002 and P < .001 for participants receiving 800 IU/day and 1600 IU/day, respectively), but not in participants who did not receive supplementation (P = .27). Participants treated with 1600 IU/day of vitamin D achieved a higher mean increase in 25(OH)D than participants treated with 800 IU/day (P = .02). However, only 67% of the group supplemented with higher dose achieved vitamin D sufficiency. Vitamin D supplementation did not lead to an increase in CD4 percent or CD4 count. CONCLUSION: In children infected with HIV with relatively preserved immune function, vitamin D supplementation in doses as high as 1600 IU/day does not impact CD4 count. Vitamin D insufficiency is common in this population, and achieving vitamin D serum levels of >75 nmol/L may require a daily intake ≥1600 IU.

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.

Age is a determinant of acute hemodynamic responses to hyperglycemia and angiotensin II in humans with uncomplicated type 1 diabetes mellitus.

Hyperglycemia is associated with hemodynamic changes in type 1 diabetes (DM), acting in part through renin-angiotensin system activation. Since aging is associated with vascular dysfunction in DM, we hypothesized that acute hemodynamic responses to clamped hyperglycemia and infused ANG II would be exaggerated in older adults compared with a group of adolescent/young adults with type 1 DM. Renal hemodynamic function, blood pressure, and arterial stiffness were assessed in adolescent/young adults (n = 34; mean age: 18 +/- 3 yr) and older adults (n = 32; mean age: 45 +/- 9 yr). Studies were performed during clamped euglycemia (4-6 mmol/l) and hyperglycemia (9-11 mmol/l). Renal and systemic hemodynamic responses to ANG II were measured during clamped euglycemia in diabetic subjects. ANG II responses were also assessed in a cohort of non-DM subjects (n = 97; mean age: 26; age range: 18-40 yr). Older DM adults exhibited higher baseline blood pressure, arterial stiffness, and renal vascular resistance, and lower glomerular filtration rate (GFR) and effective renal plasma flow, compared with adolescent/young DM adults (P < 0.05). Clamped hyperglycemia was associated with exaggerated peripheral and renal hemodynamic responses uniquely in older DM adults; only GFR increased in adolescent/young DM adults. ANG II infusion also produced exaggerated vasoconstrictive responses in older DM adults vs. adolescent/young DM adults (P < 0.05). The independent effect of age on hemodynamic responses to hyperglycemia and ANG II was confirmed using multivariate regression analysis in DM subjects (P < 0.05), and results were still significant when participants were matched for DM duration. Age-related alterations in hemodynamic function and ANG II response were not observed in healthy non-DM control subjects. Acute hemodynamic responses to clamped hyperglycemia and ANG II were exaggerated in older subjects with type 1 DM, highlighting an important interaction between age and factors that contribute to the pathogenesis of acute vascular dysfunction in DM.

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.

Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children.

UNLABELLED: Three of 20 patients with juvenile osteoporosis were found to have a heterozygous mutation in the LRP5 gene. No mutations were found in the type I collagen genes. Mutations in the other family members with similar bone phenotype confirmed that LRP5 has a role in both juvenile and adult osteoporosis. INTRODUCTION: The gene encoding the low-density lipoprotein receptor-related protein 5 (LRP5) gene has recently been shown to affect bone mass accrual during growth and to be involved in osteoporosis-pseudoglioma syndrome and a high bone mass phenotype. Mutations in the type I collagen genes (COL1A1 and COL1A2) are known to cause osteogenesis imperfecta, characterized by increased bone fragility. MATERIALS AND METHODS: Here we analyzed COL1A1, COL1A2, and LRP5 for mutations in 20 pediatric patients with primary osteoporosis characterized by low BMD, recurrent fractures, and absent extraskeletal manifestations. RESULTS AND CONCLUSIONS: No mutations were detected in the type I collagen genes, but two missense mutations (A29T and R1036Q) and one frameshift mutation (C913fs) were found in the LRP5 gene in three of the patients. The frameshift mutation was also seen in the proband's father and brother, who both were found to have significant osteoporosis. R1036Q was observed in the proband's mother and two brothers, who all had osteoporosis. These results indicate that heterozygous mutations in the LRP5 gene can cause osteoporosis in both children and adults.

Relationship between diurnal blood pressure, renal hemodynamic function, and the renin-angiotensin system in type 1 diabetes.

In patients with diabetes, altered diurnal blood pressure (BP) regulation (high night-to-day [N/D] ratio, or "nondipping") is associated with increases in albumin excretion and a decline in the glomerular filtration rate (GFR) by an unknown mechanism. Because it is known that renin angiotensin system (RAS) activation and defective glucose control contribute to adverse renal outcomes, we examined renal responses to high glucose and to manipulation of the RAS in adolescents (mean age 14 +/- 2 years) with uncomplicated type 1 diabetes, segregated into two groups on the basis of the presence or absence of normal N/D BP ratio. In the first experiment, renal hemodynamic comparisons were made during euglycemia (4-6 mmol/l) and hyperglycemia (9-11 mmol/l), maintained by modified clamp techniques. The induction of hyperglycemia resulted in a significant increase in GFR and filtration fraction (FF) in the high N/D ratio group. In the second experiment, we examined the renal response to graded angiotensin II (Ang II) infusion while subjects were euglycemic and salt replete. High N/D ratio was associated with an enhanced FF response to Ang II. In the third experiment, the N/D ratio and GFR were assessed after 3 weeks of ACE inhibition. This maneuver corrected the high N/D ratio, but it had no effect on glomerular hyperfiltration. These results suggest that RAS activation does not explain the hyperfiltration state, nor can it explain the poor outcomes, at least in this population. However, the observed deleterious hemodynamic responses to high glucose and Ang II and the insensitivity to ACE inhibition may, taken together, provide an explanation for the adverse renal outcomes in patients with type 1 diabetes and high N/D ratio.

Cardiac and vascular function in adolescents and young adults with type 1 diabetes.

The objective was to prospectively define cardiac and vascular function in adolescents and young adults with type 1 diabetes over a 3-year period. Thirty-three subjects with type 1 diabetes were studied in 1998, and 28 returned for follow-up in 2001. There were 28 controls without diabetes. All subjects underwent ultrasonography of the carotid artery to determine distensibility, compliance, and intimal-medial thickness, as well as echocardiographic studies, lipid profile, and measurement of hemoglobin A1c (HbA1c) levels and urinary albumin excretion rate. The diabetes group showed no significant change over the 3-year follow-up in lipid profile, HbA1c level, or albumin excretion rate, but a significant increase in body mass index. The diabetes and control groups were similar in age, lipid profile, and albumin excretion rate. Carotid artery distensibility and compliance in the diabetes group increased significantly from baseline to follow-up but did not differ significantly from controls. The intimal-medial thickness of the diabetes group remained unchanged over time but tended to be higher than controls. Echocardiographic studies showed no difference between the diabetes and control groups, but there was a small change in left ventricular posterior diastolic wall diameter in the subjects with diabetes over the 3-year period. There was an overall improvement in carotid function and no change in cardiac measures in subjects with diabetes over the 3 years, such that cardiac and vascular function were similar to those of controls. The reason for the improvement is uncertain, but may relate to the improvement of insulin sensitivity at the end of the pubertal growth period, rather than to changes in metabolic control or lipid profiles.

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.

Sex differences in renal responses to hyperglycemia, L-arginine, and L-NMMA in humans with uncomplicated type 1 diabetes.

OBJECTIVE: Women exhibit exaggerated renal hemodynamic responses to hyperglycemia, which may promote kidney disease progression. Our aim was to determine if increased nitric oxide generation by l-arginine infusion would reverse this deleterious response to clamped hyperglycemia in women with type 1 diabetes mellitus. RESEARCH DESIGN AND METHODS: Renal function, blood pressure, and plasma cyclic guanosine monophosphate (cGMP) were measured in 20 men and 15 women with type 1 diabetes mellitus during clamped euglycemia and clamped hyperglycemia. Renal function, blood pressure, and plasma cGMP responses to graded infusions of intravenous l-arginine and N(G)-monomethyl-l-arginine (l-NMMA) were measured during clamped hyperglycemia. RESULTS: Subjects were young, normotensive, normoalbuminuric men and women who adhered to a high-sodium, moderate-protein diet. Plasma cGMP levels during euglycemia were generally lower in men compared with women, and systolic blood pressure (SBP) was higher in men. In response to hyperglycemia, cGMP levels did not change in men but did decline in women (Δ-1.10 ± 0.20 vs. Δ+0.05 ± 0.20 pmol/L, between-group effect of hyperglycemia on cGMP; P = 0.012). Hyperglycemia also was associated with an increase in SBP, glomerular filtration rate (GFR) (124 ± 6 to 143 ± 7 mL/min/1.73 m(2); P = 0.003) and filtration fraction (FF) in women, but these parameters did not change in men. In response to l-arginine during hyperglycemia, the increase in cGMP was exaggerated in women versus men and GFR and FF decreased in women only, back toward baseline values observed during clamped euglycemia. l-NMMA infusion did not exaggerate changes in hemodynamic function in response to hyperglycemia. CONCLUSIONS: l-Arginine reversed the renal hemodynamic effects of hyperglycemia in women, suggesting that nitric oxide is an important regulator of sex-dependent vascular responses to hyperglycemia in humans.

A child with autoimmune polyendocrinopathy candidiasis and ectodermal dysplasia treated with immunosuppression: a case report.

INTRODUCTION: Common features of autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia include candidiasis, hypoparathyroidism and hypoadrenalism. The initial manifestation of autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia may be autoimmune hepatitis, keratoconjunctivitis, frequent fever with or without a rash, chronic diarrhea, or different combinations of these with or without oral candidiasis. CASE PRESENTATION: We discuss a profoundly affected 2.9-year-old Caucasian girl of Western European descent with a dramatic response to immunosuppression (initially azathioprine and oral steroids, and then subsequently mycophenolate mofetil monotherapy). At four years of follow-up, her response to mycophenolate mofetil is excellent. CONCLUSION: The clinical features of autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia may continue for years before some of the more common components appear. In such cases, it may be life-saving to diagnose autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia and commence therapy with immunosuppressive agents. The response of our patient to immunosuppression with mycophenolate mofetil has been dramatic. It is possible that other patients with this condition might also benefit from immunosuppression.