Urinary markers of renal inflammation in adolescents with Type 1 diabetes mellitus and normoalbuminuria.

AIMS: Patients with the highest albumin:creatinine ratio within the normal range are at an increased risk for developing microalbuminuria. The mechanistic basis for this is unknown, but may be related to renal inflammation. Our goal was to characterize the urinary excretion of cytokines/chemokines in normoalbuminuric adolescents with Type 1 diabetes to determine whether higher range normoalbuminuria is associated with evidence of renal inflammation. METHODS: Forty-two urinary cytokines/chemokines were measured in subjects who were screened for the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Urinary cytokines/chemokines were compared across low (n = 50), middle (n = 50) or high (n = 50) albumin:creatinine ratio tertile groups. RESULTS: At baseline, participants in the upper tertile were younger and had shorter diabetes duration compared with the other groups. Other clinical characteristics were similar. Urinary levels of interleukin 6, interleukin 8, platelet-derived growth factor-AA and RANTES differed across albumin:creatinine ratio tertiles, with higher values in patients in the middle and high tertiles compared with the lower tertile (ANCOVA P ≤ 0.01). CONCLUSIONS: Within the normal albumin:creatinine ratio range, higher urinary albumin excretion is associated with elevated urinary levels of inflammatory markers. Ultimately, this may provide mechanistic insights into disease pathophysiology and stratify the risk of nephropathy in Type 1 diabetes.

Investigating FGF-23 concentrations and its relationship with declining renal function in paediatric patients with pre-dialysis CKD Stages 3-5.

BACKGROUND: The aims of our study were to investigate (i) the prevalence of elevated fibroblast growth factor-23 (FGF-23), (ii) the relationship between FGF-23 concentrations and level of renal dysfunction and (iii) the main determinants of elevation of FGF-23 concentration in children with pre-dialysis chronic kidney disease (CKD) Stages 3-5. METHODS: In this single-centre prospective observational study, 71 children with pre-dialysis CKD Stages 3-5, aged 11.9 ± 3.1 years, had FGF-23 levels measured. Anthropometry and routine laboratory investigations were measured. RESULTS: Fourteen (19.7%) patients had normal FGF-23 concentrations defined as < 50 ng/L. FGF-23 [median (interquartile range)] concentrations were 78.7 (55.6-137.6) ng/L and following log transformation normalized data with log FGF-23 [mean (SD)] values of 1.96 ± 0.4 ng/L. Log FGF-23 concentrations had a negative reciprocal relationship with estimated glomerular filtration rate (eGFR) (P < 0.0001) and 1,25 vitamin D3 levels (P = 0.01) and a positive relationship with phosphate (P = 0.03) and percent fractional excretion of phosphate (P = 0.01) but not with log-intact parathyroid hormone (PTH) (P = 0.22). Multiple linear regression demonstrated a strong relationship between log FGF-23 and eGFR only. CONCLUSIONS: Elevated FGF-23 concentrations were observed in the majority of a carefully managed cohort of children with non-dialysis CKD with a dominant effect on FGF-23 concentrations with glomerular filtration rate (GFR). These data allow the potential confounding effects of PTH and phosphate elevation with declining GFR to be removed, leaving a clearer picture of the FGF-23-GFR relationship.

Asymmetric dimethylarginine in young people with Type 1 diabetes: a paradoxical association with HbA(1c).

AIMS: Asymmetric dimethylarginine (ADMA) is an independent risk factor for cardiovascular disease and its concentrations are increased in several diseases, including diabetes. However, there is limited information on this plasma marker in young people, particularly in those with Type 1 diabetes. The aim of the present study was therefore to perform a longitudinal evaluation of plasma ADMA and of its determinants in young people with childhood-onset Type 1 diabetes. METHODS: For measurement of ADMA using mass spectrometry, 1018 longitudinal stored blood samples were available from 330 young people with Type 1 diabetes followed in the Oxford Regional Prospective Study. Additional data concerning annual assessments of HbA(1c) , height, weight, insulin dose and three early morning urine samples for measurement of the albumin/creatinine ratio were available. RESULTS: ADMA levels were significantly higher in males than in females (mean ± SD: 0.477 ± 0.090 vs. 0.460 ± 0.089 µmol/l, P=0.002) and declined with chronological age (estimate ± SE: -0.0106 ± 0.0008, P<0.001). A significant inverse association was detected between ADMA and HbA(1c) (estimate ± SE:-0.0113 ± 0.001, P<0.001). ADMA levels were lower in subjects developing microalbuminuria (mean ± SD: 0.455 ± 0.093 vs. 0.476 ± 0.087 µmol/l, P=0.001) than in subjects with normoalbuminuria, but this difference disappeared after adjusting for HbA(1c) . CONCLUSIONS: In this longitudinal study, ADMA concentrations decreased with age and were significantly higher in males and lower in subjects developing microalbuminuria. These associations were largely explained by a paradoxical negative association between HbA(1c) and ADMA. We suggest that chronic hyperglycaemia might down-regulate mechanisms implicated in ADMA production or stimulate its metabolism confounding short-term associations with complications risk.

Ambulatory blood pressure measurements are related to albumin excretion and are predictive for risk of microalbuminuria in young people with type 1 diabetes.

AIMS/HYPOTHESIS: The relationship between BP and microalbuminuria in young people with type 1 diabetes is not completely clear. As microalbuminuria is preceded by a gradual rise in albumin excretion within the normal range, we hypothesised that ambulatory BP (ABP) may be closely related to albumin excretion and progression to microalbuminuria. METHODS: ABP monitoring (ABPM) was performed in 509 young people with type 1 diabetes (age median [range]: 15.7 [10.7-22.6] years) followed with annual assessments of three early morning urinary albumin:creatinine ratios (ACRs) and HbA(1c). Systolic BP (SBP) and diastolic BP (DBP) and the nocturnal fall in BP were analysed in relation to ACR. RESULTS: All ABPM variables were significantly related to baseline log(10) ACR (p < 0.001). After the ABPM evaluation, 287 patients were followed for a median of 2.2 (1.0-5.5) years. ABP at baseline was independently related to mean ACR during follow-up. Nineteen initially normoalbuminuric patients developed microalbuminuria after 2.0 (0.2-4.0) years and their baseline daytime DBP was higher than in normoalbuminuric patients (p < 0.001). After adjusting for baseline ACR and HbA(1c), there was an 11% increased risk of microalbuminuria for each 1 mmHg increase in daytime DBP. Forty-eight per cent of patients were non-dippers for SBP and 60% for DBP; however, ACR was not different between dippers and non-dippers and there were no differences in the nocturnal fall in BP between normoalbuminuric and future microalbuminuric patients. CONCLUSIONS/INTERPRETATION: In this cohort of young people with type 1 diabetes, ABP was significantly related to ACR, and daytime DBP was independently associated with progression to microalbuminuria. Increasing albumin excretion, even in the normal range, may be associated with parallel rises in BP.

Reduced endogenous secretory receptor for advanced glycation end products (esRAGE) in young people with Type 1 diabetes developing microalbuminuria.

AIMS: The endogenous secretory receptor for advanced glycation end products (esRAGE) appears to work as a scavenger for AGEs and it has been implicated in the pathogenesis of diabetic complications. The aim of the present study was to perform a longitudinal evaluation of esRAGE in young people with Type 1 diabetes (T1D) in relation to the development of microalbuminuria (MA). METHODS: Serum esRAGE levels were measured in longitudinally collected blood samples from 49 T1D patients with MA (MA+) and 49 matched normoalbuminuric patients (MA-), followed in the Oxford Regional Prospective Study. esRAGE levels were compared between MA+ and MA- subjects in relation to the time of MA onset. RESULTS: Overall, esRAGE levels were significantly lower in MA+ than in MA- subjects (0.727 +/- 0.396 vs. 0.936 +/- 0.433 ng/ml; P = 0.015). These differences between the two groups were present both before (0.725 +/- 0.410 vs. 0.956 +/- 0.505 ng/ml, P = 0.038) and after the onset of MA (0.750 +/- 0.433 vs. 0.948 +/- 0.418 ng/ml, P = 0.04). In a longitudinal analysis there was no effect of age, duration, glycated haemoglobin (HbA(1c)) or body mass index standard deviation scores on esRAGE levels (all P > 0.05). In a Cox model, esRAGE levels significantly contributed to the probability of developing MA [Exp(B)(95% confidence interval): 0.34(0.12-0.98); P = 0.04), independently of HbA(1c). CONCLUSIONS: In this longitudinal study of young people with T1D, esRAGE levels were reduced in MA+ subjects, even before the onset of MA, and appeared to be related to its development, thus suggesting a potential role of esRAGE in the pathogenesis of this complication. Diabet. Med. 26, 815-819 (2009).

Ethnicity of children with homozygous c.985A>G medium-chain acyl-CoA dehydrogenase deficiency: findings from screening approximately 1.1 million newborn infants.

OBJECTIVES: It has been suggested that homozygous c.985A>G medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a disease of White ethnic origin but little is known regarding its ethnic distribution. We estimated ethnic-specific homozygous c.985A>G MCADD birth prevalence from a large-scale UK newborn screening study. METHODS: Homozygous c.985A>G MCADD cases were ascertained in six English newborn screening centres between 1 March 2004 and 28 February 2007 by screening approximately 1.1 million newborns using tandem mass spectrometry analysis of underivatised blood spot samples to quantitate octanoylcarnitine (C8). Follow-up biochemistry and mutation analyses for cases (mean triplicate C8 value >/=0.5 micromol/L) were reviewed to confirm diagnosis. Ethnicity was ascertained from clinician report and denominators from 2001 UK Census estimates of ethnic group of children less than one year. RESULTS: Sixty-four infants were c.985A>G MCADD homozygotes (overall prevalence 5.8 per 100,000 live births; 95% CI 4.4-7.2). Sixty (93%) were White, two (3%) were mixed/other and two were of unknown ethnic origin. No Asian or Black homozygotes were identified. Proportions of White, mixed/other, Asian and Black births in screening regions were estimated, yielding homozygous c.985A>G MCADD birth prevalence of 6.9 per 100,000 (95% CI 5.2-8.8) in White, and 95% CI estimates of 0-2.7 per 100,000 in Asian and 0-5.8 in Black populations. The c.985A>G carrier frequency in the White group was estimated at one in 65 (95% CI 1/74, 1/61) under Hardy-Weinberg conditions. CONCLUSION: c.985A>G homozygous MCADD is not found in Black and Asian ethnic groups that have been screened at birth in England. This is consistent with the earlier published observations suggesting that MCADD due to the c.985A>G mutation is a disease of White ethnic origin.

Blood pressure does not rise before the onset of microalbuminuria in children followed from diagnosis of type 1 diabetes. Oxford Regional Prospective Study Group.

OBJECTIVE: To examine whether a rise in blood pressure could be detected before the onset of microalbuminuria (MA) in a cohort of children followed from diagnosis of type 1 diabetes. RESEARCH DESIGN AND METHODS: The Oxford Regional Prospective Study is an incident cohort study of children with type 1 diabetes aged (mean +/- SD) 9.8 +/- 3.7 years at diagnosis. Subjects were assessed annually from diagnosis, with measurement of HbA1c, arterial blood pressure (random zero), and three urine samples for estimation of the albumin/creatinine ratio. During follow-up, 63 of 494 children developed MA at one or more annual assessments and were designated as cases for a nested case-control study. Each case was matched for sex and age at diagnosis with two normoalbuminuric control subjects. Blood pressure (BP) data were compared at corresponding years of diabetes duration. RESULTS: Cases with MA were similar to normoalbuminuric control subjects with respect to age and BMI, but they had higher mean HbA1c levels (mean difference 1.1%, P < 0.001). In the years before the onset of MA, the diastolic BP standard deviation score (SDS) was significantly higher than zero in cases (mean 0.49, P < 0.001) and in control subjects (0.50, P < 0.001). No difference could be detected between cases and control subjects before the onset of MA in either systolic or diastolic BP (mean difference systolic -1.2 mmHg [95% CI -4.7 to 2.7], mean difference diastolic 0.1 mmHg [-2.4 to 2.6]). However, within the cases, the onset of MA was associated with elevations in systolic and diastolic BP SDSs (F = 16.1, P < 0.001; and F = 18.0, P < 0.001). BMI, but not HbA1c, was associated with systolic and diastolic BP SDSs in the subjects with MA (F = 0.6, P = 0.4; and F = 12.3, P = 0.001). However, the association of BP with MA remained signifcant for systolic BP (P = 0.001) and for diastolic BP (P < 0.001) after adjusting for BMI. CONCLUSIONS: A rise in systemic BP cannot be detected before the first appearance of MA in children with type 1 diabetes. BP rises concurrently with the onset of MA and is also closely related to BMI.

Risk of nephropathy can be detected before the onset of microalbuminuria during the early years after diagnosis of type 1 diabetes.

OBJECTIVE: The early detection of a rise in albumin excretion within the normal range could permit early intervention to prevent the development of microalbuminuria (MA) in genetically susceptible subjects with type 1 diabetes. In the Oxford Regional Prospective Study we prospectively examined urine albumin excretion during the first years after diagnosis of childhood type 1 diabetes. RESEARCH DESIGN AND METHODS: Between 1986 and 1995, 511 subjects aged < 16 years were recruited at diagnosis and followed for a median of 6 years (range 1-14). In 78 subjects (designated cases), an annual assessment of the albumin-to-creatinine ratio (ACR) in three morning first-void urine samples detected MA (males: ACR > or =3.5 mg/mmol, females: ACR > or =4.0 mg/mmol in two of three urine samples). In 63 of these subjects and 396 normoalbuminuric diabetic control subjects, rates of change of the ACR were calculated as the slope of the ACR over diabetes duration. RESULTS: The baseline ACR (median [interquartile (IQ) range]), as measured at 1-2.5 years' duration of diabetes, was higher in microalbuminuric subjects than in the normoalbuminuric subjects (1.0 mg/mmol [0.6-2.1], n = 52, vs. 0.8 mg/mmol [0.6-1.2], n = 303; P = 0.02). The rate of increase of the ACR in the years before the onset of MA was higher in the microalbuminuric subjects than in the normoalbuminuric subjects (70% per year [37-149], n = 63, vs. 1% per year [-9 to 13], n = 396; P < 0.001). The mean HbA1c level after the onset of puberty was weakly correlated with the rate of change of the ACR (r = 0.11, P = 0.024, n = 418). CONCLUSIONS: Higher levels of ACR within the first 2 years after diagnosis and a significantly higher rate of increase of the ACR within the first 5 years from diagnosis can be detected in subjects who subsequently develop MA. HbA1c is a determinant of risk for MA, but pubertal factors have a greater effect on rates of progression of urine albumin excretion during adolescence in this cohort.

Microalbuminuria prevalence varies with age, sex, and puberty in children with type 1 diabetes followed from diagnosis in a longitudinal study. Oxford Regional Prospective Study Group.

OBJECTIVE: The predictive value of microalbuminuria (MA) in children with type 1 diabetes has not been defined. We describe the natural history of MA in a large cohort of children recruited at diagnosis of type 1 diabetes. RESEARCH DESIGN AND METHODS: Between 1985 and 1996, 514 children (279 male) who developed type 1 diabetes before the age of 16 years (91% of those eligible from a region where ascertainment of new cases is 95%) were recruited for a longitudinal study with central annual assessment of HbAlc and albumin excretion (three urine samples). Dropout rates have been < 1% per year, and 287 children have been followed for > 4.5 years. RESULTS: MA (defined as albumin-to-creatinine ratio > or = 3.5 and > or = 4.0 mg/mmol in boys and girls, respectively) developed in 63 (12.8%) and was persistent in 22 (4.8%) of the subjects. The cumulative probability (based on the Kaplan-Meier method) for developing MA was 40% after 11 years. HbAlc was worse in those who developed MA than in others (mean difference +/- SEM: 1.1% +/- 0.2, P < 0.001). In subjects who had been 5-11 years of age when their diabetes was diagnosed, the appearance of MA was delayed until puberty, whereas of those whose age was < 5 years at diagnosis of diabetes, 5 of 11 (45%) developed MA before puberty. The adjusted proportional probability (Cox model) of MA was greater for female subjects (200%), after pubertal onset (310%), and with greater HbAlc (36% increase for every 1% increase in HbAlc). Despite earlier differences based on age at diagnosis of diabetes (< 5, 5-11, and > 11 years), the overall cumulative risks in these groups were similar (38 vs. 29 vs. 39%, respectively) after 10 years' duration of diabetes. CONCLUSIONS: Prepubertal duration of diabetes and prepubertal hyperglycemia contribute to the risk of postpubertal MA. The differences in rates of development of MA relating to HbAlc, sex, and age at diagnosis relative to puberty may have long-term consequences for the risk of subsequent nephropathy and for cardiovascular risk.

Increasing splanchnic blood flow in the critically III.

STUDY OBJECTIVE: To assess the effect of low dose dopexamine and dopamine on splanchnic blood flow as measured by gastric intramucosal pH, hepatic metabolism of lidocaine (lignocaine) to monoethylglycinexy-lidide (MEGX), and plasma disappearance rate of indocyanine green (ICG). DESIGN: Single-blind randomization of patients with a gastric intramucosal acidosis to receive dopexamine (ten patients), dopamine (ten patients), or saline solution (five control patients) for 2 h. SETTING: All 25 patients were in the ICU of Guys' Hospital. PATIENTS: All patients met the criteria for the diagnosis of the systemic inflammatory response syndrome, were mechanically ventilated, and had pulmonary artery catheters placed. All had a low gastric intramucosal pH and had a median first 24-h acute physiology and chronic health evaluation (II) score of 22 (range, 7 to 40). MEASUREMENTS AND INTERVENTIONS: Baseline measurements of gastric intramucosal pH, MEGX formation from lidocaine, ICG plasma disappearance rate, heart rate, mean arterial pressure, pulmonary artery occlusion pressure, cardiac index, oxygen delivery index, oxygen uptake index, systemic vascular resistance, and arterial pH were taken. Dopexamine (1 mg.kg-1.min-1), dopamine (2.5 mg.kg-1.min-1), or 0.9% saline solution was then infused for 2 h, after which a repeated set of the measurements was taken. RESULTS: Dopexamine at a low dose had no effect on any of the systemic measurements. The median intramucosal pH rose from 7.23 to 7.35 (p < 0.005), the median ICG plasma disappearance rate from 7.6 to 11.3%.min-1 (p < 0.02), and the median MEGX concentration from 4 to 10.2 ng.mL-1 (p < 0.005). Dopamine had no effect on any of the measured variables. There were no changes in the control group. CONCLUSIONS: Low-dose dopexamine increases splanchnic blood flow as measured by gastric intramucosal pH, MEGX formation from lidocaine, and ICG clearance. The lack of any change in the systemic measurements suggests that these effects are the result of a selective vasodilatation of the splanchnic vessels. At the dose used in this study, dopamine had no effect on splanchnic blood flow. Dopexamine may be useful in the management of splanchnic ischemia in the critically ill.

Liver function and splanchnic ischemia in critically ill patients.

STUDY OBJECTIVE: To investigate the concept that splanchnic ischemia leads to hepatic dysfunction in the critically ill. DESIGN: Prospective study and analysis of patient data. SETTING: A general ICU in an inner-city London teaching hospital. PATIENTS: Twenty-seven consecutive critically ill patients with evidence of inadequate tissue perfusion requiring pulmonary artery catheterization and mechanical ventilation. MEASUREMENTS: In all patients, we measured the hepatic metabolism of lidocaine (lignocaine) to monoethylglycinexylidide (MEGX) and the clearance of indocyanine green (both dynamic, flow-dependent tests of hepatic function) over the first 3 days following admission to the ICU. These were compared with results of standard liver function tests and related to tonometric assessment of gastric intramucosal pH (pHim) and outcome. RESULTS: There were no significant differences in bilirubin, aspartate aminotransferase, alkaline phosphatase, and prothrombin levels, or in indocyanine green clearance between survivors and nonsurvivors. On day 3, the median MEGX level was higher in survivors than in nonsurvivors (16 vs 2.4 ng/mL, p < 0.001), and the median MEGX level in nonsurvivors fell over the 3 days (20.6 to 2.4 ng/mL, p < 0.002). MEGX levels were significantly correlated with pHim (Spearman rank correlation coefficient [Rs] = 0.69, p < 0.001) as were the changes in the two measurements over the 3 days (Rs = 0.46, p < 0.02). The MEGX formation test and gastric pHim were the most discriminatory with regard to death and survival. CONCLUSIONS: Our findings suggest that critically ill patients develop significant hepatic dysfunction that is associated with a poor outcome. This is likely to be due to a mismatch between hepatic metabolic demand and blood flow, and the MEGX formation test appears to be an extremely effective means of assessing liver function and flow in this group of patients.

Dimethylarginines in chronic renal failure.

BACKGROUND: Nitric oxide (NO) is a potent chemical mediator involved in many functions. In vivo production of NO is thought to be regulated by endogenous analogues of L-arginine: asymmetric dimethylarginine (ADMA). AIM: To examine the effect of renal function and dialysis on the serum concentrations of ADMA and symmetric dimethylarginine (SDMA). METHODS: Blood samples were obtained from nine healthy subjects, patients with renal failure before (n = 17) and after haemodialysis (n = 9), nine patients on chronic ambulatory peritoneal dialysis (CAPD), and 13 patients with chronic renal failure on conservative treatment. Serum samples were extracted using a solid phase cation exchange column and the extracts were analysed by high performance liquid chromatography (HPLC). RESULTS: Serum concentrations of ADMA in patients with renal failure (mean, 1.04 micromol/litre; SD, 0.17) were significantly higher than those of controls (mean, 0.61 micromol/litre; SD, 0.13). Haemodialysis significantly decreased the serum concentration by 36% (before dialysis: mean 0.99 (SD, 0.25) micromol/litre; after dialysis: mean, 0.63 (SD, 0.15) micromol/litre). Serum SDMA concentrations were higher in patients with renal failure, and haemodialysis decreased the concentration by 60%. There was no difference in serum arginine concentrations between the groups. CONCLUSION: Serum concentrations of ADMA are increased in renal failure and haemodialysis reduces the concentration.

The relationship between branched-chain amino acids and alpha-keto acids in blood in uremia.

Branched-chain alpha-keto acid (BCKA) supplements are used as a nitrogen-free source of branched-chain amino acids (BCAA) in patients with chronic renal failure. Their use is dependent on the freely reversible interconversion of BCKA and BCAA in muscle tissue. In a group of eight young adults on dialysis compared to 11 normal healthy adults, the ratios of the fasting plasma concentrations of leucine and isoleucine to their corresponding alpha-keto acids, alpha-keto isocaproic acid and alpha-keto-beta-methyl-eta-valeric acid, respectively, were significantly elevated. These ratios appear to be sensitive to changes in intracellular glutamate and pyruvate. The ratios increased in seven insulin-dependent diabetics following insulin withdrawal, a situation where intracellular glutamate is increased. The ratios decreased in six normal healthy adults in response to submaximal treadmill exercise, a situation where intracellular pyruvate is increased. The elevated BCAA/BCKA ratios in uremia could be a reflection of reduced peripheral glucose utilization. A consequence of this will be enhanced conversion of supplemented BCKA to their corresponding BCAA. The close association between muscle BCAA and glucose metabolism suggests that the timing of BCKA administration in relation to energy intake might prove important.

Metabolism of orally administered branched-chain alpha-keto acids.

The changes in serum branched-chain alpha-keto acid (BCKA) and plasma amino acid concentrations, in response to a therapeutic oral dose of an essential amino acid/keto acid mixture, were studied in fasting healthy adults. Of the branched-chain amino acids (BCAA), only the plasma leucine concentration rose significantly despite increases in al three serum BCKA concentrations. The plasma valine concentration tended to rise, but plasma isoleucine concentrations fell. When KMVA (keto-isoleucine) alone was given, there followed an increase in plasma isoleucine concentration and a fall in valine and leucine. Similarly, when KIVA (keto-valine) was given, plasma valine rose and leucine and isoleucine fell. These results suggest some transamination of the keto acid with amino groups of the other BCAA. KICA (keto-leucine), however, produced larger falls in plasma valine and isoleucine than was expected from the rise in leucine. In addition, KICA caused significant, insulin-independent reductions in plasma threonine, serine, cystine, methionine, tyrosine, phenylalanine, and alanine. We conclude that although orally administered BCKA's will increase the BCAA supply, their value may not simply relate to the supply of essential amino acids for protein synthesis but to a direct effect of KICA on protein metabolism.

Measurement of beta 2-microglobulin, retinol-binding protein, alpha 1-microglobulin and urine protein 1 in healthy children using enzyme-linked immunosorbent assay.

Enzyme-linked immunosorbent assays (ELISA) have been developed for the measurement of beta 2-microglobulin (B2M), retinol-binding protein (RBP), alpha 1-microglobulin (A1M) and urine protein 1 (UP1) in children. Results from random urine samples in 43 children (31 for B2M) are, when corrected for urine creatinine (geometric mean (range)): B2M 9.8 (6.0-40.7) micrograms/mmol, RBP 8.1 (less than 1-24.5) micrograms/mmol, A1M 0.4 (0.1-2.2) mg/mmol and UP1 17.8 (less than 2-309.4) micrograms/mmol. Fractional excretions (FE) in 23 children (14 for B2M) are (geometric mean (range)): FEB2M 0.04% (0.02-0.10%) and FEUP1 0.10% (0.01-1.21%). Results in overnight urine collections are also presented. Our results extend existing data for normal ranges in adults to include children and provide data on UP1 concentrations.

Plasma catecholamines: experience with a single-isotope radioenzymatic assay.

The performance of a rapid and sensitive single-isotope radioenzymatic assay for plasma catecholamines, in a routine clinical chemistry laboratory, is reported and discussed. The value of plasma adrenaline and noradrenaline as tumour markers in the diagnosis, tumour localisation, and post-operative follow-up of four patients with phaeochromocytoma is emphasised.

Changes in Dickkopf-1 (DKK1) and Sclerostin following a Loading Dose of Vitamin D 2 (300,000 IU).

Background. Vitamin D is important for bone health, although high loading doses have been associated with an increase in fracture risk. The mechanisms remain uncertain. Aim. We hypothesize that supraphysiological concentrations of 1,25 (OH)2 vitamin D may inhibit formation by increasing the production of Wnt inhibitors: sclerostin and DKK1. Subjects and Methods. We measured serum sclerostin and DKK1 in 34 patients (21 F, 13 M) aged mean (SD) 61.3 (15.6) years with vitamin D deficiency/insufficiency treated with a loading dose of vitamin D2 (300,000 IU) intramuscularly. Blood samples were taken at baseline and serially up to 3 months. Results. Serum 1,25 (OH)2 vitamin D increased markedly at 3 months (mean (SD) baseline 116 (63), 3 months : 229 (142) pmol/L, P < 0.001). There was a significant correlation between sclerostin and DKK1 at baseline (r = 0.504, P = 0.002) and at 3 months (r = 0.42, P = 0.013). A significant inverse correlation was observed between sclerostin and eGFR at 3 months (r = -0.494, P = 0.007). Sclerostin increased significantly at 3 months (P = 0.033). In a multilinear regression analysis with % change in sclerostin and DKK1 as dependent variable, a positive significant association was observed with % change in 1,25 (OH)2 vitamin D (P = 0.038), independent of changes in PTH and following correction for confounders such as age, gender, BMI, BMD and eGFR. Conclusions. Supraphysiological concentration in 1,25 (OH)2 vitamin D achieved following a loading dose of vitamin D increases sclerostin and may inhibit Wnt signalling. This may have detrimental effects on bone.

Short-term administration of pegvisomant improves hepatic insulin sensitivity and reduces soleus muscle intramyocellular lipid content in young adults with type 1 diabetes.

CONTEXT: Data on the metabolic effects of GH derived from studies using GH suppression by pharmacological agents may not reflect selective actions. OBJECTIVE: The purpose of this study was to evaluate the effects of GH antagonism on glucose and lipid metabolism using pegvisomant, a selective GH receptor antagonist in patients with type 1 diabetes (T1D). DESIGN AND PARTICIPANTS: In a randomized, placebo-controlled, crossover study, 10 young adults with T1D were evaluated at baseline and after 4 weeks of treatment with either 10 mg of pegvisomant or placebo. The assessments included an overnight euglycemic steady state followed by a hyperinsulinemic euglycemic clamp and used glucose and glycerol cold stable isotopes. OUTCOME MEASURES: Hepatic and peripheral insulin sensitivity (IS), lipid turnover, and intramyocellular lipid (IMCL) were measured. RESULTS: Compared with placebo, pegvisomant treatment resulted in lower IGF-I levels (P < .001). During the overnight steady state, insulin requirements for euglycemia (P = .019), insulin levels (P = .008), and glucose production rates (Ra) (P = .033) were reduced. During the clamp study, glucose infusion rates (P = .031) increased and glucose Ra (P = .015) decreased whereas glucose disposal rates were unchanged. Free fatty acid levels were similar during the steady state but were lower during the clamp (P = .040) after pegvisomant. Soleus muscle IMCL decreased after treatment (P = .024); however, no change in tibialis anterior muscle was observed. CONCLUSIONS: The study demonstrates that GH antagonism in T1D results in improved hepatic insulin sensitivity. Lack of consistent changes in free fatty acid levels may suggest a direct effect of GH on IS. Unchanged peripheral IS despite reductions in IMCL indicate that GH-induced alterations in IMCL may not be causally linked to glucose metabolism.