Early kidney damage in diabetic adolescents with increased blood pressure and glomerular hyperfiltration.

BACKGROUND: The early impact of type-1 diabetes mellitus (DM1), increased blood pressure and glomerular hyperfiltration (GHF) on kidney damage in adolescents using two urinary markers of kidney injury - neutrophil gelatinase-associated lipocalin (uNGAL) and transferrin (uTransf) was assessed. METHODS: The study group consisted of 80 adolescents with DM1, of whom 42 were patients with increased blood pressure (IBP), and 38 were patients with normal blood pressure (NBP). Blood pressure was assessed by 24-hour ambulatory bloodpressure monitoring. All patients showed estimated glomerular-filtration rates (eGFRs) above 90 ml/min/1.73m2. The control group consisted of 19 healthy, age and gender-matched adolescents. RESULTS: All diabetic children showed a significant increase in uNGAL (p<0.001). This increase was not related to blood pressure. The uNGAL was elevated in all patients with normal albuminuria, normal eGFR and NBP. The concentration of uTransf was not increased in the entire studied group and was not related to blood pressure. Children with GHF had significantly higher levels of both uTransf (p=0.010) and uNGAL (p<0.001). In patients with GHF, blood pressure was normal. Patients with IBP showed a significantly higher value for triglycerides (r=0.247; p=0.032) and a longer duration of diabetes (r=0.264; p=0.019). CONCLUSIONS: Diabetes is the leading risk factor for early kidney injury. However, increased blood pressure does not lead to kidney damage, at least in the early stage of DM1. The uNGAL is the early indicator of kidney injury and increases in patients with normal albuminuria, normal glomerular filtration and normal blood pressure. Glomerular hyperfiltration seems to be a marker of diabetic-kidney involvement.

Nighttime Hypoglycemia in Children with Type 1 Diabetes after one Day of Football Tournament.

The aim of the study was to investigate factors related to the occurrence of nighttime hypoglycemia after a football tournament in children with type 1 diabetes mellitus. The multicenter study (GoalDiab study) included 189 children and adolescents with type 1 diabetes mellitus, from 11 diabetes care centers in Poland. Hypoglycemia was defined according to the International Hypoglycemia Study Group Statement. We analyzed the data of 95 participants with completed protocols with regards to nighttime hypoglycemia (82% male), aged 11.6 (9.8-14.2) years, diabetes duration 5.0 (2.0-8.0) years. There were 47 episodes of nighttime Level 1 hypoglycemia (≤3.9 mmol/L). Occurrence of clinically important Level 2 hypoglycemia (<3.0 mmol/L) during a game period was positively associated with nighttime hypoglycemia (≤3.9 mmol/L) incident (Odds Ratio=10.7; 95% Confidence Interval: 1.1-100.2; p=0.04). Using Continuous Glucose Monitoring was negatively associated with the occurrence of nighttime hypoglycemia (≤3.9 mmol/L) compared with using glucose meters or Flash Glucose Monitoring (Odds Ratio=0.31; 95% Confidence Interval: 0.12-0.83; p=0.02). The occurrence of clinically important hypoglycemia related to physical activity is associated with the occurrence of hypoglycemia during the night. Continuous Glucose Monitoring is negatively associated with nighttime hypoglycemia after a day of competition.

DETERMINING THE EFFECT OF DIABETES DURATION ON RETINAL AND CHOROIDAL THICKNESSES IN CHILDREN WITH TYPE 1 DIABETES MELLITUS.

PURPOSE: Determining the effect of diabetes mellitus duration on retinal and choroidal thicknesses in children with Type 1 diabetes mellitus (T1DM). METHODS: Children (aged 6-18 years) with Type 1 diabetes and no diabetic retinopathy and age-matched controls were examined using Topcon spectral domain optical coherence tomography. Choroidal thickness and retinal thickness in macula area were measured. The study group was divided into 3 subgroups depending on diabetes mellitus duration-Group 1: <5 years (n = 52), Group 2: 5 to 10 years (n = 39), and Group 3: >10 years (n = 30). RESULTS: One hundred and twenty-one diabetic children and 32 controls were included. The central choroidal thickness increased from 305.5 µm (SD: 61.7 µm) in the control group to 309.2 µm (SD: 70.1 µm) in Group 1, 315.2 µm (SD: 64.3 µm) in Group 2, and 367.4 µm (SD: 66.0 µm) in Group 3. Group 3 differed significantly from Group 1 (P = 0.0002), Group 2 (P = 0.0014), and the control group (P = 0.0003). The choroid-to-retina thickness ratio was lowest in controls, 1.01 (SD: 0.17), and highest in Group 3, 1.21 (SD: 0.2). Group 3 differed significantly from Group 1, Group 2, and the control group with P = 0.0002, P = 0.0014, and P = 0.0001, respectively. No retina thickening was found. CONCLUSION: Changes in the choroid may occur before the development of diabetic retinopathy and seem to progress with increasing diabetes mellitus duration despite the absence of diabetic retinopathy and without associated retina thickening. Choroidal thickness could be valuable for screening in diabetic children.

Enlargement of the foveal avascular zone detected by optical coherence tomography angiography in diabetic children without diabetic retinopathy.

PURPOSE: Evaluation of foveal avascular zone (FAZ) in children with diabetes (DM) using OCTA. METHODS: We examined 112 diabetic children without DR aged 6-18 years and 30 age-matched controls using Topcon OCT Angiography and measured FAZ in superficial (SCP) and deep capillary plexus (DCP). The study group was divided into three subgroups depending on DM duration group 1: < 5 years (n = 40), group 2: 5-10 years (n = 42), group 3: > 10 years (n = 30). RESULTS: The mean DCP FAZ increased with DM duration from 502.2 µm2 (SD 137.8) in group 1 to 523.9 µm2 (SD 159.2) in group 2 and 539.7 µm2 (SD 189.1) in group 3. Control group differed significantly from group 1 (p = 0.0120), group 2 (p = 0.0019) and group 3 (p = 0.0011). The mean DCP to SCP FAZ surface ratio was 1.88 (SD 0.68) in the study vs 1.58 (SD 0.48) in the control group (p = 0.0232). The DCP and SCP FAZ surface difference was 217.6 µm2 (SD 100.8 µm2) in diabetics vs. 124.2 µm2 (SD 72.8 µm2) in controls (p < 0.0001). In the control group, it was significantly smaller than in group 1 (p < 0.006), group 2 (p < 0.0001) and group 3 (p < 0.0001). CONCLUSIONS: Changes can be detected in FAZ of diabetic children before DR development which can be vital for screening.

Sex-Related Variations of Retinal and Choroidal Thickness and Foveal Avascular Zone in Healthy and Diabetic Children Assessed by Optical Coherence Tomography Imaging.

PURPOSE OF THE STUDY: The aim of this study was to investigate the presence of gender differences in the chorioretinal microvasculature of children with and without vascular pathology. METHODS: Healthy and type 1 diabetic children without diabetic retinopathy underwent optical coherence tomography angiography (OCTA) and structural OCT. We measured the foveal avascular zone (FAZ) area in the superficial capillary plexus (SCP) and deep CP (DCP), central retina, and choroid thickness. RESULTS: OCTA examination was conducted in 112 diabetic and 30 healthy children, and structural OCT in 121 diabetic children and 32 controls. DCP FAZ area in boys was significantly smaller than in girls both in diabetics (p = 0.0010) and healthy children (p = 0.0302). In diabetics, SCP FAZ area was significantly smaller in boys (p = 0.0006), analogically to controls (p = 0.0870). Central retinal thickness was significantly greater in boys compared with girls in diabetics (p = 0.0001) and controls (p = 0.1008). CONCLUSION: Significant differences exist in the FAZ area and retinal thickness between sexes, likely representing physiological differences. Different norms must be used for boys and girls regardless of diabetic status.

Serum leptin and adiponectin levels in children with type 1 diabetes mellitus - Relation to body fat mass and disease course.

PURPOSE: Leptin and adiponectin are adipokines presenting a wide range of impacts, including glycemic balance regulations. Insulin is one of the main regulators of adipose tissue function. In type 1 diabetes mellitus (T1DM) endogenous insulin secretion is replaced by the exogenous supply, which is not regulated naturally. The aim of the study was to establish serum leptin and adiponectin levels, and their relations to body fat mass and disease course in children with T1DM. MATERIAL/METHODS: The study included 75 children with T1DM and the control group of 20 healthy coevals. All children had estimated serum leptin and adiponectin concentrations, lipid profile, and bioelectrical impedance analysis. RESULTS: Serum leptin concentrations in children with T1DM were not significantly different from the control group (p=0.067, mean values±SD: 3.11±2.98 vs. 5.29±5.06µg/l, respectively), and related positively to body fat mass in both groups. Adiponectin serum concentrations were significantly higher in children with T1DM than in the control group (p<0.001; mean values: 18.82±9.31 vs. 12.10±5.53µg/ml, respectively), and were not related to the body fat content in the study group. Both, leptin and adiponectin, showed no relation to any of the analyzed parameters of the disease course. CONCLUSIONS: Differences observed between children with T1DM and their healthy coevals, when similar in terms of age, body weight, and body fat mass, seem not to depend directly on the disease duration, its metabolic control or insulin supply.

Urinary angiotensinogen and urinary sodium are associated with blood pressure in normoalbuminuric children with diabetes.

BACKGROUND: The aim of this study was to evaluate the association between blood pressure (BP) and urinary angiotensinogen excretion (uAGT) and renal sodium excretion (uNa) in children with type 1 diabetes mellitus (DM1). METHODS: The study group consisted of 52 children with DM1 (28 males and 24 females) with albumin/creatinine ratio (ACR) below 30 mg/g and glomerular filtration rate (eGFR) above 90 ml/min/1.73 m(2). BP was assessed by 24-h ambulatory blood pressure monitoring (ABPM). RESULTS: The patients showed significantly increased uAGT values with respect to controls (median 0.00 and range 1.76 vs. 0.00 and 0.00 ng/mg, respectively). The significant increase of uAGT was observed even in prehypertensive patients. uAGT concentrations showed positive correlation with systolic and diastolic 24-h BP and with mean arterial pressure (MAP) (r = 0.594). uNa values were negatively correlated with BP parameters, uAGT, ACR and eGFR. CONCLUSIONS: An increase in uAGT precedes hypertension (HTN) in normoalbuminuric children with DM1 and may be considered as a new marker of HTN. Decreased sodium excretion seems to be involved in the development of HTN and early renal injury. Both uAGT and uNa are associated with BP in normoalbuminuric diabetic children.

Neutrophil gelatinase-associated lipocalin and Cathepsin L as early predictors of kidney dysfunction in children with type 1 diabetes.

INTRODUCTION: The aim of this study was to evaluate serum levels and urinary excretion of neutrophil-gelatinase associated lipocalin (respectively sNGAL and uNGAL) and urinary excretion of Cathepsin L (uCathL) in children with type 1 diabetes mellitus (DM1) who presented normoalbuminuria and the estimated glomerular filtration rate (eGFR) above 90 mL/min/1.73 m2. MATERIAL AND METHODS: The study group consisted of 63 children with a diabetes duration of 5.16 ± 3.39 years. The degree of albuminuria was based on urine albumin-to-creatinine ratio (ACR), while eGFR was based on serum cystatin C. Glomerular hyperfiltration (GH) was defined as an eGFR value above 135 mL/min/1.73 m2. RESULTS: Children with DM1 showed significantly higher concentrations of uNGAL, and lower sNGAL and uCathL. Significant changes of uNGAL and uCathL levels were even found in children without GH and with optimal glycaemic control (HbA1c < 7.5%). Positive correlations between uNGAL, ACR and eGFR were shown, as well as between uCathL and eGFR. CONCLUSIONS: Significant changes in the concentration of markers of early kidney injury: sNGAL, uNGAL, and uCathL, can occur in children with DM1 and normoalbuminuria. The changes of uNGAL and uCathL can be even found in children without GH and with optimal glycaemic control. The earliest signs of diabetic kidney dysfunction seem to result from tubular damage.

Missense mutations and polymorphisms of the MC4R gene in Polish obese children and adolescents in relation to the relative body mass index.

Extensive studies of the MC4R gene polymorphism showed that, among numerous variants, there are mutations responsible for monogenic obesity, as well as polymorphisms negatively correlated with the risk of obesity. In this report, we present the first studies of the whole coding sequence of the MC4R gene in 243 Polish obese children and adolescents (the mean relative body mass index [RBMI] was 163.6). In addition, 101 non-obese adults were also analyzed. Direct sequencing facilitated the identification of six missense (K73R, V103I, T112M, S127L, M215L, and I251L) and one silent (c.756 C > T) single-nucleotide polymorphisms (SNPs). Two non-synonymous polymorphisms (K73R and M215L) appeared to be novel and one was found in obese patients (M215L, one patient) and one in non-obese adults (K73R, one person). The overall frequency of non-synonymous variant carriers reached 4.1% and 6.9% in obese patients and non-obese adults, respectively. Only one obesity-associated variant (127L) was found in two obese patients (0.82%) and in two non-obese adults (1.98%). The obesity-protecting variants (103I and 251L) appeared to be the most common in both groups: 3.3% and 4.0%, respectively. It was also observed that the RBMI in obese children and adolescents carrying the minor variants did not differ significantly from the non-carriers; however, the expected trends for the associated and protecting variants were observed. We conclude that the contribution of the MC4R gene variants to the pathogenesis of obesity in Polish children and adolescents is low.

Polymorphisms in 5'-flanking regions of genes encoding adiponectin, leptin, and resistin are not associated with obesity of Polish children and adolescents.

Genes encoding adipokines are important functional candidates for development of obesity. In this study we screened for polymorphism 5'-flanking regions of the adiponectin (ADIPOQ), leptin (LEP) and resistin (RETN) genes in a cohort of Polish obese children and adolescents (n = 243) and a control group of non-obese adults (n = 100). Altogether 13 SNPs (single nucleotide polymorphisms) and 1 InDel (insertion/deletion polymorphism) were found. Among them five polymorphisms, localized in the LEP gene, turned out to be novel, but their distribution was insufficient for association studies. We found no consistent evidence for association between obesity and the SNPs demonstrating minor allele frequency (MAF) above 0.2 (ADIPOQ: -11377C>G, LEP: -2548C>T, 19A>G, RETN: -1300G>A, -1258C>T, -420C>G). Comparison of polymorphisms distribution in patients and control group suggested association with ADIPOQ -11377C>G (Pearson test P = 2.76 × 10(-11)), however, we did not observe any effect of this polymorphism on BMI or relative BMI (RBMI) within obese patients (P = 0.41). We conclude that the tested SNPs are not useful markers of childhood and adolescence obesity in Polish population.

Normal-range albuminuria does not exclude nephropathy in diabetic children.

Clinically detectable diabetic nephropathy (DN) begins with the development of microalbuminuria (MA). However, early renal dysfunction may be overlooked despite using that method. On the other hand, the gold standard in DN detection-that is, renal biopsy-is highly invasive. The aim of this study was to evaluate the level of neutrophil-gelatinase-associated lipocalin (NGAL) and interleukin (IL)-18 and their relations to albumin excretion rate (AER) in children with normal-range albuminuria, e.g. in those considered as not presenting diabetic nephropathy. The study group consisted of 22 children (age 12.7 +/- 3.5 years) with type 1 diabetes mellitus (T1DM). Long-term glycemic control was assessed on hemoglobin A1c (HbA1c) levels (8.52 +/- 1.78%). All patients presented normal estimated glomerular filtration rate (eGFR) (141 +/- 23 ml/min/1.73 m(2)) and normal urinary albumin excretion (13.09 +/- 7.63 mg/24 h). Fourteen healthy children served as a control group. Children with T1DM showed increased NGAL values with respect to controls-interestingly, both in serum (sNGAL) (867.43 +/- 341.98 vs. 655.29 +/- 196.17 ng/ml; p = 0.04) and in urine (uNGAL) (420.04 +/- 374.16 vs. 156.53 +/- 185.18 ng/ml, p = 0.04). IL-18 levels were not different in both groups both in serum (58.52 +/- 20.11 vs. 69.79 +/- 58.76 ng/ml; NS) and in urine (14.53 +/- 12.74 vs. 14.60 +/- 10.92 ng/ml; NS). Despite the relatively small study group, the positive correlation between sNGAL and AER was found [AER (mg/24 h) = 3.1893 + 0.01141 x sNGAL (ng/ml); r = 0.51; p = 0.014] as well as between uNGAL and AER [AER (mg/24 h) = 8.7538 + 0.01032 x uNGAL (ng/ml); r = 0.51; p = 0.016]. No relationship between sNGAL and uNGAL, and GFR and HbA1c were found. Normal-range albuminuria does not exclude diabetic nephropathy defined as increased sNGAL and uNGAL concentration. NGAL measurement can be more sensitive than MA and may become a useful tool for evaluating renal involvement in diabetic children.

Early impairment of glucose tolerance and ß-cell function in obese children.

INTRODUCTION: A clinical criterion of the Wolfram syndrome is the coexistence of diabetes and optic atrophy recognized before the age of 15. Diabetes present in Wolfram syndrome is a result of the selective ß cell loss and failed insulin secretion which is probably associated with non-autoimmune pathogenesis. AIM OF THE STUDY: The aim of the study was an evaluation of HLA subtypes and presence of ß-cell autoantibodies in patients with molecularly confirmed Wolfram syndrome. MATERIAL AND METHODS: 9 patients with Wolfram syndrome aged 10-24 years were examined. We also studied 218 patients with type 1 diabetes as a reference group. A control group of 176 healthy individuals was included in the study. Besides the clinical assessment the HLA typing by PCR-SSO was performed. Islet cell antibodies (ICA), antibodies to glutamic acid decarboxylase (GADA), thyrosine phosphatase antibodies (IA2A) and insulin antibodies (IAA) were also detected. RESULTS: In all nine patients the coexistence of diabetes with optic atrophy was observed and in 8/9 individuals additional symptoms were recognized. In patients with Wolfram syndrome a significantly lower age of diagnosis of diabetes (Me=5.0 years) than in type 1 diabetic children (Me=10.4; p=0.002) was observed. Studies of HLA subtypes demonstrated an increased prevalence of HLA-DQw1, DRB1⋅03 and/or 04 and DR2. A comparison of the frequency of the HLA alleles in patients with Wolfram syndrome with type 1 diabetic children showed a more frequent presence of the DRB1⋅1501 (p=0.03; OR=13.28 (2.44-72.12)) and DQB1⋅06 (p=0.016; OR=10.15 (2.49-41.35)) alleles in patients with Wolfram syndrome. CONCLUSIONS: Polish patients with Wolfram syndrome have a different profile of the HLA antigens with the presence of DR2, DQw1 and DRB3/4 allele and are negative for diabetes-related autoantibodies, which may confirm non-autoimmune ß-cell destruction in this syndrome.

[Influence of Eqb 761 on the function of the retina in children and adolescent with long lasting diabetes mellitus--preliminary report]. / (146)Wplyw preparatu Egb 761 na czynnosc siatkówki u dzieci i mlodziezy z dlugo trwajaca cukrzyca insulinozalezna--doniesienie wstepne.

PURPOSE: Early detection of patological function of the retina, before anatomical changes, plays very important role in monitoring of visual complications in patients with diabetes mellitus. The aim of the study was the evaluation of anatomical and functional changes in visual organ in children and adolescents with long lasting diabetes mellitus type 1 and taking Egb 761 (Tanakan Beaufour Ipsen) as an adjuvant. MATERIALS AND METHODS: Group consists of 15 patients, age between 11 and 19 years, with diabetes mellitus lasting 6-12 years. All patients had full ophthalmologic examination and color vision tests (Panel D 15 saturated and desaturated). The examination was done 3 times, every 3 months. Egb 761 was given: 1 tablet - 3 times a day, during 3 months. RESULTS: No diabetic retinopathy was found. The results of color vision test were better after therapy (25% of pathological results) and 3 months later (only 4 % of patients). CONCLUSIONS: 1. Egb 761 seems to be good adjuvant in patient with long lasting diabetes mellitus. 2. Color vision tests are sensitive tests of the retinal function and are easy to perform.