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Achieving normal or near-normal glycemic control as reflected by HbA1c levels in patients with type 1 diabetes (T1D) is important for preventing the development and progression of chronic complications. Despite delineation and dissemination of HbA1c management targets and advances in insulin pharmacology, insulin delivery systems, and glucose monitoring, the majority of children with T1D do not achieve HbA1c goals. In particular, African Americans are more likely not to reach HbA1c goals and have persistently higher HbA1c than Non-Hispanic Whites. Availability of pumps and other technology has not eliminated the disparity in HbA1c. Multiple factors play a role in the persisting racial disparity in HbA1c outcome. The carefully designed application and deployment of new technology to help the patient/family and facilitate the supportive role of the diabetes management team may be able to overcome racial disparity in glycemic outcome and improve patient quality of life.

Autosomal recessive SOPH syndrome was first described in the Yakuts population of Asia by Maksimova et al. in 2010. It arises from biallelic pathogenic variants in the NBAS gene and is characterized by severe postnatal growth retardation, senile facial appearance, small hands and feet, optic atrophy with loss of visual acuity and color vision, and normal intelligence (OMIM #614800). The presence of Pelger-Huet anomaly in this disorder led to its name as an acronym for Short stature, Optic nerve atrophy, and Pelger-Huet anomaly. Recent publications have further contributed to the characterization of this syndrome through additional phenotype-genotype correlations. We review the clinical features described in these publications and report on a 27-year-old woman with dwarfism with osteolysis and multiple skeletal problems, minor anomalies, immunodeficiency, diabetes mellitus, and multiple secondary medical problems. Her condition was considered an unknown autosomal recessive disorder for many years until exome sequencing provided the diagnosis by revealing a founder disease-causing variant that was compound heterozygous with a novel pathogenic variant in NBAS. Based on the major clinical features of this individual and others reported earlier, a revision of the acronym is warranted to facilitate clinical recognition.

Introduction Black patients have higher HbA1c than Whites even after adjustment for mean blood glucose (MBG). Decreased iron status has been associated with increased HbA1c independently of glucose. We hypothesized that decreased iron status might account for higher HbA1c in Black patients. Methods Pediatric patients with T1D in the Diabetes Center at Children's Hospital of New Orleans who self-identified as either Black or White were recruited for the study. At the time of their clinic visit labs were obtained for ferritin (Fer), soluble transferrin receptor (sTfR), HbA1c, and CBC. MBG was derived from patient's home glucose meter records over the last 30 days. Total body iron (TBI) and sTfr/log10 Fer (R/lFer) were calculated. Results A total of 80 (35 Blacks/45 Whites; 41 female/39 male) patients were recruited. Unadjusted levels of HbA1c, MBG, sTfR, Fer, RDW-CV, and RDW-SD were all higher in Blacks than Whites. TBI and R/lFer were not different between groups. Fer was correlated with Hb, MBG but not HbA1c. sTfR was correlated with HbA1c, MCV, MCH, and RDW-SD. In multiple variable analysis with HbA1c as the dependent variable, race and MBG were statistically significant in the model. However, measures of iron status: Fer, sTfR, R/lFer and TBI were not statistically influential. Conclusion After adjustment for race, MBG and RDW-CV, iron indices were not statistically significant independent predictors of HbA1c levels. These observations indicate that factors besides iron status and CBC indices contribute to MBG-independent racial disparity in HbA1c.

OBJECTIVE: Higher levels of HbA1c, independent of blood glucose levels, have been described in Blacks compared to Whites patients with established diabetes. The goal of this study was to determine if glucose-independent racial disparity in HbA1c is evident at diabetes onset. RESEARCH DESIGN AND METHODS: We conducted a retrospective single-center chart review of 189 youth with new onset Type 1 diabetes (T1D) 60 % Whites and 40 % Blacks. HbA1c, glucose and other biochemistry measures were obtained at presentation in the Emergency Department before initiation of any therapy. HbA1c levels were adjusted for presenting glucose, self-identified race, age, gender, hematocrit, and RDW-CV. RESULTS: Blacks with T1D had statistically significant higher unadjusted HbA1c (11.9 ± 1.9 vs 11.04 ± 2.0 %, p = 0.004), initial glucose (530.6 ± 230.4 vs 442 ±211.3 mg/dL, p = 0.0075) and lower pHs (7.28 ± 0.15 vs 7.33 ± 0.12, p = 0.02) compared to white patients. Least squares means of HbA1c remained higher in Black patients even after statistical adjustment for presenting glucose, age, gender, RDW-CV, and pH. In a multiple variable model (R(2) = 0.38, p < 0.0001) c-peptide was influenced by HCO(3) (p = 0.0035), gender (p = 0.0092), BMI (p < 0.0001), but not race or glucose. CONCLUSIONS: HbA1c at initial presentation of T1D is higher in young Black patients compared to Whites even after adjustment for glucose, age, gender, and RDW-CV. This racial disparity is consistent with other studies in individuals without diabetes and patients with long-standing diabetes under treatment.

We examined the relationship between two malleable risk factors, depressive symptoms and fear of hypoglycemia, in children and adolescents with Type 1 diabetes and their relationship to two important outcomes, adherence behaviors and metabolic control. To assess this relationship, we used a multidimensional measure of adherence, assessing frequency of both blood glucose monitoring and healthy behaviors including diet and exercise. We predicted that higher levels of depressive symptoms and higher levels of fear of hypoglycemia would be associated with worse metabolic control as mediated by poor adherence. Eighty-three children and adolescents ages 8 to 20 (M = 13.87, SD 3.21) were recruited from March 2014 to October 2014 at an outpatient diabetes clinic in a moderately sized Southeastern city within the USA. Nested models were evaluated using structural equation modeling. Adherence significantly mediated the relationship between depressive symptoms and metabolic control with more depressive symptoms leading to worse metabolic control. Adherence marginally mediated the relationship between fear of hypoglycemia and metabolic control; however, less fear of hypoglycemia was associated with worse metabolic control. In a combined model, adherence continued to significantly mediate the relationship between depressive symptoms and metabolic control, while also independently significantly mediating the relationship between fear of hypoglycemia and metabolic control. This finding was also contrary to the predicted relationship with less fear of hypoglycemia leading to worse metabolic control. The results indicate that youth with fewer depressive symptoms and more fear of hypoglycemia had better adherence to their treatment regimen, which was associated with better metabolic control. The results of this study highlight the importance of screening for depression and fear of hypoglycemia during routine clinic visits to optimize adherence and metabolic control.

Introduction 24-h average (IC) plasma concentrations of cortisol and growth hormone are lower in obese youth and adults without Type 2 diabetes (T2D) compared to lean subjects. Here we examined IC-cortisol and IC-growth hormone levels in obese youth with and without T2D. Methods We pooled ½-hourly samples from 20 to 24-hour sampling to create an IC for cortisol, cortisone, C-peptide, insulin, growth hormone and cortisol-binding-globulin in obese African-American youth with (n = 8) and without T2D (N = 9). Analytes were assayed by standard methods. Results The groups were similar in age and sex, all participants had BMI% ≥94. T2D patients had slightly lower BMI z-score (2.25 ± 0.36 versus 2.58 ± 0.16, p = 0.0429). IC-cortisol (5.70 ± 1.8 μg/dl vs 4.18 ± 1.07 μg/dl, p = 0.0481) was higher and IC-C-peptide (2.33 ± 0.89 ng/ml vs 4.36 ± 1.12 ng/ml, p = 0.001) lower in T2D. There were no differences in cortisone/cortisol or for other analytes between groups. IC-cortisol was correlated with IC-cortisone (r = 0.46, p = 0.0471) but not with ICs of insulin, C-peptide, cortisol-binding-globulin, or growth hormone. Conclusions IC-cortisol levels are higher and IC-C-peptide lower in obese African-American youth with T2D. Higher levels of IC-cortisol in obese youth with T2D may indicate a change in hypothalamic-pituitary-adrenal regulation which may exacerbate hyperglycemia and other metabolic complications of obesity.

Background Patients with type 1 diabetes mellitus (T1DM) are at risk for premature atherosclerosis (AS), which has its origin in childhood. Carotid intima-media thickness (IMT) is an established surrogate marker for subclinical AS in adults. The first macroscopically detectable AS changes, however, begin in the abdominal aorta. Advanced glycation end products (AGE) predict microvascular complications in diabetes. Objectives To assess the sensitivity for early macrovascular changes of brachial, femoral, and aortic IMT compared to conventional carotid IMT in pediatric T1DM patients ; and the relationship of IMT with AGE. Methods Using high-resolution external ultrasound, carotid, brachial, femoral, and aortic IMT were prospectively analyzed in children and adolescents with established T1DM and in controls (Ctrls). AGE were estimated by skin intrinsic fluorescence (SIF). Other established cardiovascular risk factors were excluded. Results Seventy-six subjects (T1DM = 38; Ctrls = 38) with a mean age of 13.1 ± 4.0 years (6-19, median 13) qualified for analysis. Carotid, brachial, femoral, and aortic IMT analyses were feasible in 100%, 74%, 84%, and 92% of subjects, respectively. Aortic and femoral IMT were increased in T1DM patients (0.60 ± 0.11 vs 0.52 ± 0.10 mm, P

Diabetes is one of the most common incurable, chronic diseases of childhood. Metabolic changes associated with diabetes are associated with development of serious acute and chronic complications with increased morbidity and mortality. The incidence and prevalence of diabetes, success in achieving optimal management, outcomes, and risk for developing later complications have been found to vary between patients of different race, ethnicity, and socioeconomic backgrounds. Disparities between race/ethnic groups have been found to have persisted or worsened despite improvements in management technology. Potentially the interplay of genetic, biological factors along with environment and socioeconomic influences contributes to continued health disparities among children with diabetes. Better understanding of factors mediating health disparities can help bring about changes in management leading to optimal outcomes for all patients.

BACKGROUND Hemoglobin A1c (HbA1c) levels are higher in African-American (AA) individuals compared to Caucasians (EA) even after adjustment for blood glucose levels. To better understand the mechanism of this disparity we examined the relationship of an unstable (labile) form of HbA1c (L-HbA1c) with race and glucose. METHODS Samples for HbA1c were collected from pediatric patients self-identified as either AA (15F, 12M, age 13.4 ± 3.5 years) or EA (22F, 30M, age 14.6 ± 3.4 years) with type 1 diabetes at the time of a clinic visit. Clinic HbA1c (HbA1c) was performed by immunoassay. L-HbA1c equaled the difference in the HbA1c fraction by dynamic capillary isoelectric focusing before and after incubation in a low pH buffer. A capillary glucose (Clinic-BG) was measured at clinic visit. Mean blood glucose (MBG) was calculated from the last 30 days of the patient's glucose meter data. The influence of race on L-HbA1c was assessed in a multiple variable regression model adjusted for Clinic-BG. RESULTS The groups were similar for age and duration of diabetes. L-HbA1c was correlated with Clinic-BG, MBG, and HbA1c. The mean levels of L-HbA1c, HbA1c, MBG, but not Clinic-BG were higher in AA patients compared to EA. After adjustment for Clinic-BG, L-HbA1c was still higher in AA (2.8 ± 0.7% AA vs 2.1 ± 0.7% EA, P

Introduction: HbA1c is an important guide for management, diagnosis and prediction of complications in diabetes. We have shown that young black patients with established T1D have higher HbA1c than white patients even after adjustment for mean blood glucose, RBC indices, age, and gender. We hypothesized that glucose-independent racial disparity in HbA1c is also present at diagnosis of T1D. Methods: Data was collected by chart review for self-identified white and black patients who presented between Jan 2012 and Nov 2018 to the Hospital ER with untreated new onset T1D. Analyte data is from initial blood sample. Data was collected for date of birth, sex, self-identified race, weight, height, glucose, HbA1c, pH, bicarbonate, insulin, C-peptide, pancreatic autoantibodies, RBC indices. Simple correlation and comparison of means between groups was performed. This followed by multiple variable regression modeling to test the statistical effect of race, gender, age, glucose, RDW-CV and other variables on HbA1c. Results. We included 191 children with newly diagnosed T1D (69 blacks and 122 whites; 116 M, 75 F). HbA1c was correlated with glucose, insulin, c-peptide, age, RDW-CV, Hb, HCO3. blacks had higher HbA1c 11.9 ±1.9 vs. whites 11.04±2 (P=0.004), higher glucoses 530.6±230.4 vs. 441.9±211.3 mg/dL (P=0.0075), lower C-peptides 0.57± 0.42 vs. 0.76±0.61 ng/mL (P=0.019) and lower pH 7.28±0.15 vs. 7.33±0.12, (P=0.02). There was no statistical difference in age, BMI-z, HCO3 or insulin between the groups. After adjusting for age, sex, glucose, C-peptide and RDW-CV, HbA1c is still higher in blacks, P=0.037. Age, gender, glucose, C-peptide and RDW-CV were also significant covariates in the model. Conclusions. 1- HbA1c at presentation is influenced by Race, glucose, age, sex, RDW-CV, and c-peptide 2- Even after adjustment for glucose blacks have higher HbA1c than whites 3- Glucose-independent HbA1c racial difference should be taken into account for purposes of diagnosis and management of T1D. Disclosure A. Alaqeel: None. S. Chalew: None.

INTRODUCTION. Black youth with T1D have been reported to experience more episodes of hypoglycemia than white patients, despite blacks having higher levels of HbA1c. We hypothesized that black patients may be prescribed higher daily doses of insulin putting them at greater higher risk for hypoglycemia. METHODS. We performed a retrospective analysis of data from a study of social and environmental factors influencing HbA1c in a biracial pediatric population with T1DM. Changes in patient insulin dose were made at clinic visit based on their self-monitored glucose (SMG) data. Insulin dose (units/kg/d) was compared with HbA1c, reported hypoglycemic episodes and occurrence of low blood glucose from SMG data. RESULTS. Age, duration of diabetes and BMI-z were similar for black and white patients. Black patients had higher levels of HbA1c and mean blood glucose (MBG). HbA1c was higher in blacks even after adjustment for MBG. Reported insulin dose increased with increasing HbA1c (ρ=0.30, p=0.0052) or MBG (ρ=0.36, p

Black youth with T1D have been noted to have higher HbA1c’s, less frequent monitoring of capillary glucose and higher reported occurrence of hypoglycemia compared to white patients. We hypothesized that this combination of factors would be associated with higher prescribed doses of insulin in black patients compared to whites. A retrospective analysis was performed on data collected from patients at the Children’s Diabetes Center, New Orleans, LA who participated in a study of racial differences in hemoglobin glycation. Patients self-identified as either black or white and were under the clinical care of several different attending diabetologists. The influence of race on total daily prescribed dose of insulin per kg body weight (TDDI), was evaluated in a general linear model adjusted for HbA1c, insulin delivery method, gender, and chronologic age as well as the interactive effect of race and HbA1c. Hemoglobin Glycation Index (HGI) was also calculated and substituted in the model for HbA1c. The population studied consisted of 33 (19F, 14M) black patients and 52 (22F,30 M)whites. Average age was 14.0±3.6 years and duration of diabetes 5.7±3.9 years. As previously reported from this population blacks had higher HbA1c even after adjustment for age and mean blood glucose level (MBG). Mean TDDI was 0.89±0.33 units/kg/d. TDDI was highly correlated with both HbA1c (r=0.40,p Disclosure S. Chalew: None. R. Gomez: None. J.M. Hempe: None.

Sickle cell disease (SCD) is associated with increased oxidative stress which potentially enhances generation of advanced glycation endproducts (AGEs). We estimated skin accumulation of AGEs in SCD patients and assessed their relationship with hemolysis and nephropathy. Skin intrinsic fluorescence (SIF), an estimate of AGEs, was assessed in African American patients with and without SCD. After skin excitation with light at 375, 405, and 420 nm, raw autofluorescence was adjusted using specific intrinsic corrections. Group differences in SIF were evaluated by multiple variable regression using chronological age and sex as covariates. The relationship of SIF with reticulocyte count, serum lactate dehydrogenase, estimated glomerular filtration rate (GFR), plasma creatinine, bilirubin, and urine microalbumin was assessed. There were 48 SCD patients (29 male/19 female, age=13.4±3.6 y) and 51 controls (25 male/26 female, age=10.4±5.0 y). SIF375(1.0,0.0), SIF405(0.5,0.5), and SIF420(0.5,0.5) were significantly higher in SCD patients. There was no difference in SIF between SCD patients with and without microalbuminuria. SIF 420(0.5,0.5) was correlated with reticulocyte count (r=0.33; P=0.03). Skin AGEs as estimated by SIF were higher in children with SCD and weakly associated with 1 measure of hemolysis. Further study is needed to determine whether chronic increased deposition of AGEs is associated with development of complications of SCD.

Background Racial variation in the relationship between blood glucose and hemoglobin A1c (HbA1c) complicates diabetes diagnosis and management in racially mixed populations. Understanding why HbA1c is persistently higher in blacks than whites could help reduce racial disparity in diabetes outcomes. Objective Test the hypothesis that neighborhood disadvantage is associated with inflammation and poor metabolic control in a racially mixed population of pediatric type 1 diabetes patients. Methods Patients (n = 86, 53 white, 33 black) were recruited from diabetes clinics. Self-monitored mean blood glucose (MBG) was downloaded from patient glucose meters. Blood was collected for analysis of HbA1c and C-reactive protein (CRP). Patient addresses and census data were used to calculate a concentrated disadvantage index (CDI). High CDI reflects characteristics of disadvantaged neighborhoods. Results HbA1c and MBG were higher (p < 0.0001) in blacks [10.4% (90.3 mmol/mol), 255 mg/dL] than whites [8.9% (73.9 mmol/mol), 198 mg/dL). CDI was higher in blacks (p < 0.0001) and positively correlated with HbA1c (r = 0.40, p = 0.0002) and MBG (r = 0.35, p = 0.0011) unless controlled for race. CDI was positively associated with CRP by linear regression within racial groups. CRP was not different between racial groups, and was not correlated with MBG, but was positively correlated with HbA1c when controlled for race (p = 0.04). Conclusions Neighborhood disadvantage was associated with inflammation and poor metabolic control in pediatric type 1 diabetes patients. Marked racial differences in potential confounding factors precluded differentiation between genetic and environmental effects. Future studies should recruit patients matched for neighborhood characteristics and treatment regimen to more comprehensively assess racial variation in HbA1c.

Black youth with type 1 diabetes (T1D) have higher HbA1c than whites. To understand HbA1c differences, we examined the relationship of psycho-social factors and glucose testing with HbA1c.Glucose tests per day (BGs/d) and mean blood glucose (MBG) were calculated from meter data of youth self-identified as black (n = 33) or white (n = 53) with T1D. HbA1c, family income, insurance status, concentrated disadvantage (CDI), psychological depression (DSC), mother educational attainment (MEA), and insulin delivery method (IDM) data was were analyzed.Black patients had significantly higher HbA1c, MBG and disadvantage measures compared to whites. BGs/d correlated with HbA1c, MBG, age and CDI. Race (p 0.0158), age (p 0.0001) and IDM (p 0.0036) accounted for 50% of the variability (R2 = 0.5, p 0.0001) in BGs/d. Regardless of age, black patients had lower BGs/d than whites. MBG (p 0.0001) and BGs/d (p 0.0001) accounted for 61% of the variance in HbA1c (p 0.0001).BGs/d is easily assessed and closely associated with HbA1c racial disparity. BGs/d is intricately linked with greater social disadvantage. Innovative management approaches are needed to overcome obstacles to optimal outcomes.

Objective: The objective was to assess the relationship of skin advanced glycation endproducts (AGEs) between first-degree relatives estimated from skin fluorescence (SF) after adjustment for skin pigmentation. Study design: SF was excited by LEDs centered at 375, 405, and 420 nm from children with type 1 diabetes and their mothers. Data were adjusted to generate measures of skin intrinsic fluorescence (SIF) at the various excitation wavelengths, using 2 different pairs of correction coefficients for excitation (kx) and emission (km): kx = 0.5, km = 0.5 (not associated with skin pigmentation) and kx = 1.0, km = 0.0 (strongly associated with skin pigmentation). Pearson correlation analysis was performed, as well as a multiple variable analysis with maternal SIF adjusted for the effects of maternal age and race. Results: There were 50 matched pairs of children and their mothers. Children were 13.3 ± 3.7 years of age and there were 19 boys/31 girls and 15 black/35 white. Mothers were 41.8 ± 6.8 years of age. The age of mother and child was highly correlated, r = .64, P < .0001. In Pearson correlation analysis, child’s SIF (kx = 1.0, km = 0.0) the had strongest association with maternal SIF, while with SIF (kx = 0.5, km = 0.5) there was a trend for association. In the multiple variable model child SIF was associated with maternal SIF for all corrections and wavelengths but was stronger for kx = 1.0, km = 0.0. Conclusion: Even after adjustment for skin pigmentation and race, correlation of SIF between family members persists, suggesting that other genetic and/or environmental factors shared by parent and child may influence estimated skin AGEs.

The mean blood glucose (MBG) level obtained from self-monitored capillary glucose (SMCG) data is a readily available metric of glycemic control for patients and their physicians. However, whether there is agreement between SMCG MBG levels and MBG levels obtained from 24-hour intensive glucose sampling is unclear. Therefore, we analyzed the relationship between MBG levels derived from SMCG data and glucose data derived from continuous glucose monitoring (CGM).SMCG and CGM were concurrently performed in 104 patients with diabetes and prediabetes over 3 to 6 days. MBG data obtained from SMCG and CGM were compared by standard correlation and Bland-Altman analyses.SMCG and CGM MBG data from the longest duration of sampling were highly correlated (r = 0.965; P.001). Single-day MBG estimates from both sources were also highly correlated, with r values ranging from 0.833 to 0.927. A SMCG MBG level of 166.1 ± 55 mg/dL (derived from 14.1 ± 4.6 samples) tended to slightly underestimate the concurrent CGM MBG level of 171.1 ± 56.4 mg/dL (derived from 1,063 ± 283 samples). The SMCG MBG was within 30 mg/dL of the CGM MBG in 94.6% of patients and within 15 mg/dL in 67% of patients. The difference between the estimates tended to increase with increasing SD of the MBG obtained from CGM (r = 0.38; P.0001).MBG estimated from SMCG is a reasonable estimate of a patient's CGM MBG over the same period of time and with caveats could be used as a practical guide for long-term glycemic control that can be considered in tandem with the patient's hemoglobin A1c in endocrine practice.

OBJECTIVE To evaluate the relationship between skin advanced glycation end products (sAGEs) with mean blood glucose (MBG), hemoglobin A1c (HbA1c), and MBG-independent, between-patient differences in HbA1c among children with type 1 diabetes. RESEARCH DESIGN AND METHODS Children aged 5 to 20 years with type 1 diabetes of at least 1 year duration participated. At a clinic visit, sAGE was estimated noninvasively by measurement of skin intrinsic fluorescence (SIF). SIF data were adjusted to correct for variation in skin pigmentation. MBG-independent, between-patient differences in HbA1c were examined by statistically controlling HbA1c for MBG or alternatively by use of a hemoglobin glycation index (HGI). Results were similar whether HbA1c, MBG, and HGI were analyzed as single values from the time of the SIF examination visit or as the mean values from all available visits of the patient. RESULTS HbA1c was correlated with MBG (r = 0.5; P < 0.001; n = 110). HbA1c and HGI, but not MBG, were statistically associated with SIF after adjustment for age, duration of diabetes, race, sex, and BMI z-score. SIF increased with age and duration of diabetes and was higher in girls than boys. CONCLUSIONS sAGE levels estimated by SIF increase with age, duration of diabetes, and female sex. sAGE is correlated with MBG-independent biological variation in HbA1c, but not with MBG itself. These results suggest that factors besides MBG that influence HbA1c levels also contribute to accumulation of sAGE.

We hypothesised that ectopic fat deposition is present in liver and skeletal muscle before puberty and that both are potentially important factors in the early pathogenesis of insulin resistance.Proton magnetic resonance spectroscopy was used to evaluate intramyocellular and intrahepatic lipids in 50 male and 42 female multi-ethnic, prepubertal (Tanner2) children (8.1 ± 0.8 years; 35.4 ± 10.7 kg; 27.9 ± 8.3% body fat; means ± SD). Intramyocellular lipid was measured in soleus muscle and intrahepatic lipid in the middle right lobe. Abdominal fat was measured by magnetic resonance imaging, body fat by dual energy X-ray absorptiometry, and insulin resistance using homeostatic model assessment.Intrahepatic lipid ranged from 0.11% to 4.6% relative to the liver water signal (mean 0.79 ± 0.79%) whereas intramyocellular lipid ranged from 0.13% to 1.86% relative to the muscle water signal (mean 0.51 ± 0.28%). Intramyocellular and intrahepatic lipids were significantly correlated with total adiposity (r = 0.49 and 0.59), abdominal adiposity (r = 0.44 and 0.54), and each other (r = 0.39, p0.05, Spearman). Both intramyocellular and intrahepatic lipid were positively correlated with fasting insulin (r = 0.37 and 0.38 respectively) and insulin resistance (r = 0.37 and 0.37; p0.01). After adjustment for race and sex, the relations between ectopic fat and insulin resistance remained, whereas both disappeared when further adjusted for body fat or BMI z scores.These results suggest that typical relations between body composition, ectopic fat and insulin resistance are present in children before puberty. Thus, interventions aimed at reducing adiposity have the potential to decrease ectopic fat accumulation, delay the onset of insulin resistance and decrease the risk for development of type 2 diabetes in children.

Soros AA, Chalew SA, McCarter RJ, Shepard R, Hempe JM. Hemoglobin glycation index: a robust measure of hemoglobin A1c bias in pediatric type 1 diabetes patients. Background: The hemoglobin glycation index (HGI) assesses biological variation in A1c after accounting for the effect of mean blood glucose (MBG). Previous studies minimized analytical variation that could mask biological variation and showed that HGI was consistent within individuals over time and positively associated with risk for microvascular complications. We tested the hypothesis that biological variation in A1c can be assessed by HGI calculated using routine MBG and A1c data obtained from a typical diabetes clinic. Methods: Self-monitored MBG and A1c were collected from charts of 202 pediatric type 1 diabetes patients attending 1612 clinic visits over 6 yr. Predicted A1c was calculated from the linear regression equation of A1c on MBG in the study population. HGI was calculated by subtracting predicted A1c from observed A1c. Patients were divided into low, moderate, and high HGI tertile groups. Results: Patients used 12 models of glucose meters. Download protocols varied with clinical practice over time. A1c was measured by multiple assays and laboratories. Despite this analytical heterogeneity, HGI was significantly different between individuals and correlated within individuals. MBG (mean ± SD, mg/dL) was similar in the low (186 ± 31), moderate (195 ± 28), and high (199 ± 42) HGI groups. A1c (%) was significantly different (p < 0.0001) in the low (7.6 ± 0.7), moderate (8.4 ± 0.7), and high (9.6 ± 1.1) HGI groups. Conclusion: Biological variation in A1c is a robust quantitative trait that can be assessed using HGI calculated from routine clinic data. This suggests that HGI could be used clinically for more personalized assessment of complications risk.

Background: Hemoglobin A1c (HbA1c) is highly correlated with mean blood glucose (MBG) levels and widely used in assessment of diabetes therapy. It has been proposed to report HbA1c in terms of an estimated average glucose (eAG) derived from the population regression of MBG on HbA1c. Pertinent to the clinical utility of eAG would be the degree of agreement between eAG and MBG estimated from multiple sampled glucose measurements over time. Methods: We examined agreement between eAG and MBG by Bland-Altman analysis from two different populations of type 1 diabetes patients: 150 children at our clinic in New Orleans and publicly available data from 1440 participants in the Diabetes Control and Complications Trial (DCCT). In New Orleans, MBG was derived from the mean of each patient's self-monitored glucose records over the 3 months before the HbA1c was obtained at the patient's clinic visit. Hemoglobin A1c was traceable to the DCCT. In DCCT participants, MBG was calculated from the patient's seven-sample glucose profile set submitted during each quarterly visit. Estimated average glucose was calculated from each individual's HbA1c using a previously reported regression equation of MBG versus HbA1c, eAG = (HbA1c * 28.7) − 47.7, derived from a continuous glucose monitoring protocol over a 12-week period. Results: The analysis showed that there is frequent and clinically significant disagreement between MBG and eAG. Estimated average glucose over or under estimated MBG by 28.7 mg/dl or greater (HbA1c difference of 1% or greater) in approximately 33% of patients from both populations. The eAG overestimation of MBG was highest at lower MBG. The difference between eAG and MBG was skewed upward with increasing mean of eAG and MBG in the DCCT. Conclusions: Frequent discordance between eAG and MBG in clinical practice will likely be confusing to patients and clinicians. In patients where eAG overestimates MBG, intensive management based on eAG alone will likely lead to greater frequency of hypoglycemic episodes. To overcome these limitations of eAG, a customized assessment of HbA1c with respect to a patient's MBG should be performed using directly monitored patient glucose levels over time.

The recent unprecedented increase of childhood obesity has led to an alarming rise in type 2 diabetes mellitus (T2D) among these children. The process underlying the progression from simple obesity to T2D is not well understood. Cortisol is a candidate factor in the pathogenesis of T2D, as it can exacerbate insulin resistance and provoke other disturbances of the metabolic syndrome. The 24-h integrated concentration (IC) of cortisol is suppressed in non-diabetic obese children compared to lean children. This difference in IC-cortisol is not due to changes in cortisol binding globulin or plasma cortisol to cortisone ratio between groups. In obese individuals, IC-cortisol suppression disappears with age after adolescence, which corresponds with increasing occurrence of T2D and other metabolic disorders of obesity. We consider the IC-cortisol levels of lean insulin sensitive children to be metabolically inappropriate for obese insulin resistant children. Thus, we hypothesize that suppression of IC-cortisol is an important adaptive response to obesity (cortisol adaptive suppression) in childhood that prevents pediatric T2D while failure to suppress IC-cortisol (cortisol suppression failure) exacerbates insulin resistance and contributes to the development of T2D. In further support of this hypothesis is early pilot data suggesting that cortisol suppression failure occurs in obese children with impaired fasting glucose levels. The mechanism(s) underlying cortisol adaptive suppression, how and why these mechanism(s) fail are unknown. Elucidation of these mechanisms may lead to interventions to prevent the development of T2D and its complications in obese individuals.

We assessed the association of erythrocyte indices on mean blood glucose-independent racial disparity in hemoglobin A1c (HbA1c) in youth with type 1 diabetes. Blacks still had higher HbA1c after adjustment for mean blood glucose, red blood cell indices, age, and sex. Such differences need to be taken into account when interpreting HbA1c in Black patients.

OBJECTIVE—We hypothesized that biological variation in HbA1c, distinct from variation attributable to mean blood glucose (MBG), would predict risk for microvascular complications in the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS—A longitudinal multiple regression model was developed from MBG and HbA1c measured in the 1,441 DCCT participants at quarterly visits. A hemoglobin glycation index (HGI = observed HbA1c - predicted HbA1c) was calculated for each visit to assess biological variation based on the directional deviation of observed HbA1c from that predicted by MBG in the model. The population was subdivided by thirds into high-, moderate-, and low-HGI groups based on mean participant HGI during the study. Cox proportional hazard analysis compared risk for development or progression of retinopathy and nephropathy between HGI groups controlled for MBG, age, treatment group, strata, and duration of diabetes. RESULTS—Likelihood ratio and t tests on HGI rejected the assumption that HbA1c levels were determined by MBG alone. At 7 years’ follow-up, patients in the high-HGI group (higher-than-predicted HbA1c) had three times greater risk of retinopathy (30 vs. 9%, P < 0.001) and six times greater risk of nephropathy (6 vs. 1%, P < 0.001) compared with the low-HGI group. CONCLUSIONS—Between-individual biological variation in HbA1c, which is distinct from that attributable to MBG, was evident among type 1 diabetic patients in the DCCT and was a strong predictor of risk for diabetes complications. Identification of the processes responsible for biological variation in HbA1c could lead to novel therapies to augment treatments directed at lowering blood glucose levels and preventing diabetes complications.

Idiopathic adipsic hypernatremia (AH) is a rare disorder associated with hypokalemia and alkalosis. Hypokalemic alkalosis has been presumed to be secondary to hyperaldosteronism. We evaluated plasma renin activity, serum aldosterone, serum and urine electrolytes in a 17-year-old patient with AH on several occasions. Despite evidence of mild dehydration, serum Na >160 and K

CD1d presents lipid antigen to a conserved population of natural killer (NK) T cells, which participate in host immune defense, tumor cell rejection and suppression of autoimmunity. The levels of human CD1d expression vary significantly between individuals. To understand such variation, we sequenced the region up to 1.7 kb 5 0 upstream of the translation start site and partially through exon 2 in 44 white Americans. We also studied two tagged single nucleotide polymorphisms (SNP) in 112 white Americans, 60 African-Americans, 88 Europeans, and 84 Chinese people from the region. Six SNP present in the region (� 836C!T, � 773C!T, � 764C!G, � 713A!T, � 365A!G and þ363A!G) were found to be in a complete linkage disequilibrium and comprised three haplotypes. Haplotype 1 had � 836C, � 773C, � 764C, � 713A, � 365A and þ363A. Haplotype 2 had � 836C, � 773T, � 764C, � 713A, � 365A and þ363A. Haplotype 3 had � 836T, � 773C, � 764G, � 713T, � 365G and þ363G. � 773C!T and � 764C!G can serve as the tagged SNP to differentiate the three haplotypes. The frequency of haplotype 1 was significantly higher in African Americans than in the other three ethnic groups, whereas the frequency of haplotype 3 was significantly higher in the Chinese people than those in the other three groups. The finding of the three haplotypes provides a genetic marker for CD1d and facilitates the study of the functional role of the genetic variations in human CD1d expression and regulation.

OBJECTIVES: To compare skin advanced glycation endproducts (AGEs) in children at onset of type 1 diabetes with children without diabetes. STUDY DESIGN: Skin AGEs (sAGEs) were estimated by measurement of skin intrinsic fluorescence (SIF) at diagnosis of type 1 diabetes (NewD; n=47, F=45%, M=55%, Age=10±3.7) and in youth without diabetes (NoD; n=112, F=53%, M=47%, Age=10.4±4.8). HCO₃, pH, pCO₂, glucose level, and HbA₁c effect on SIF was evaluated in NewD patients. RESULTS: SIF at 405 nm and 420 nm excitation were higher (p=0.03) in NewD children compared to NoD. HCO₃, pH, pCO₂, glucose, and HbA₁c were not associated with SIF levels. CONCLUSIONS: Despite the short duration of untreated diabetes, sAGEs were higher in children with NewD compared to children with NoD. Further study will be needed to determine whether early accumulation of sAGEs is associated with higher risk for development and progression of complications.

This study tested the hypothesis that there are consistent individual differences in the relationship between glycated hemoglobin (HbA1c) and mean blood glucose (MBG) levels in individuals with similar preceding blood glucose levels. Blood glucose data were collected for up to 2.3 years by 128 children and adolescents with type 1 diabetes. HbA1c values were date-matched with MBG levels calculated from an average of 85 self-monitored blood glucose measurements collected in the previous 30 days. There was significant linear correlation between MBG and HbA1c (HbA1c=0.027xMBG+5.8, n=682, r=.71, P

Previous studies indicate that the intrarenal renin-angiotensin system (RAS) is activated in type-1 diabetes mellitus (T1DM) experimental animal models and human subjects, and is reflected by augmentation of urinary angiotensinogen (uAGT) excretion rate. Studies were performed to evaluate uAGT in young patients with short duration diabetes mellitus (DM) and its relationships with HbA1c and urinary 8-isoprostane excretion rate. Blood and urine samples were collected from 77 young (15±1 years) patients (44 male, 33 female) with short duration T1DM treated only with insulin and 36 (17 male, 19 female) control subjects. Serum glucose levels were 85±4 mg/dl in control subjects and 192±11 mg/dl in DM patients. Urinary Alb/Cr and uPro/Cr ratios were not significantly different in DM patients compared to control (8.6±.9 vs 9.7±.6 and 51±8 vs 62±14 mg/g). However, the uAGT/Cr ratios were significantly elevated in the DM patients (6.8±.8 vs 16.5±1.5 ug/g). Correlation analysis demonstrated highly significant relationships (P

OBJECTIVE Mean blood glucose (MBG) and MBG-independent factors both influence A1C levels. Race was related to A1C independent of MBG in adults. The goal of this study was to determine if racial disparity exists in A1C independent of MBG in children with diabetes. RESEARCH DESIGN AND METHODS Participants included 276 children with type 1 diabetes. A1C and MBG were obtained from multiple clinic visits, and a hemoglobin glycation index (HGI) (an assessment of A1C levels independent of MBG) was calculated. A1C and HGI were analyzed controlling for age, diabetes duration, and MBG. RESULTS African Americans had statistically significantly higher A1C (9.1 ± 0.1) and HGI (0.64 ± 0.11) than Caucasians (A1C 8.3 ± 0.1, HGI −0.15 ± 0.07) independent of covariates. CONCLUSIONS Because of racial disparity in A1C, which is independent of MBG, we recommend that A1C and MBG be used together to make therapeutic decisions for children with diabetes.

Information on genetic susceptibility to Graves' disease in African Americans is limited. We studied DRB1, DQB1, DRB3 subtypes, DQA1*0501, DQA1*0201, and CTLA-4 polymorphisms in 49 African American patients with adult onset Graves' disease and 47 racially-matched controls using PCR-based sequence-specific priming methods. There were no significant differences in DRB1 or DQB1 allelic frequencies or CTLA-4 polymorphisms between patients and controls. However, we found that the frequency of DRB3 was significantly increased in the patients (75.5% vs. 57.4%, P = 0.006, X2 = 3.52), especially for the DRB3*0202 subtype (53.1% vs. 23.4, P = 0.003, X2 = 8.91). In this one respect, the finding was in concordance with our previous observations in Caucasian patients with adult-onset Graves' disease. In addition, whereas the frequency of DQA1*0501 was increased (P = 0.018, X2 = 5.63) in our patients, the haplotype of DRB3/DQA1*0501, or DRB3*0202/DQA1*0501 was found to be more strongly associated (P = 0.008, X2 = 7.0; P = 0.0008, X2 = 11.34, respectively). These data suggest that DRB3*0202, particularly when found with DQA1*0501 in a haplotype is a susceptible gene(s) for Graves' disease in adult African Americans. Considering these data with those in Caucasian patients, our results would suggest that the primary Graves susceptible locus is likely DRB3 and not DRB1.

Diabetes is a common cause of kidney failure and blindness among young adults, particularly of African-American descent. Since glycemic control is a predictor of diabetes complications, we evaluated the impact of multiple factors including a special multidisciplinary management program on glycosylated hemoglobin in children with Type 1 diabetes. Data was collected from pediatric diabetes clinics in New Orleans, LA and Baltimore, MD. In New Orleans, hemoglobin A(1c) was higher in African-American patients 12. 5+/-3.3% (n=71) vs. 10.7+/-2.1% (n=80) in Caucasian children, p

Type 1 diabetes (T1D) is associated with the development of debilitating, life-shortening complications related to chronic hyperglycemia. In 1993, the landmark Diabetes Control and Complications Trial (DCCT) demonstrated that carefully supervised, intensive basal-bolus insulin therapy that led to the chronic reduction of HbA1c to normal or near-normal levels could prevent the occurrence and progression of microvascular complications.1 The DCCT findings led to the use of HbA1c as the main clinical indicator of treatment effectiveness, recommendations for patient HbA1c treatment goals in the normal/near normal range, and advocacy of intensive insulin management to achieve those goals.2,3 In the 2 decades since the DCCT, there have been many technical advances in insulin formulations, insulin delivery systems, and blood glucose monitoring to facilitate the achievement of HbA1c outcome goals. Despite these changes, the T1D Exchange Clinic Network found that the majority of pediatric patients in their survey still did not reach recommended HbA1c goals4 and thus remain at potentially higher risk … Address correspondence to Stuart A. Chalew, MD, 200 Henry Clay Ave, Children’s Hospital of New Orleans, New Orleans, LA 70118. E-mail: schale{at}lsuhsc.edu

Body mass and anti-pancreatic antibody status potentially influences the presentation of diabetes in children. We hypothesized that anti-pancreatic auto-antibody positive patients with new onset diabetes would have lower levels of insulin and C-peptide at presentation, and hence higher HbA1c. Records of children with new onset diabetes self-identified as African American were retrospectively analyzed. Patients were under 19 years of age. Anti-GAD65 antibody titer, HbA1c, blood glucose, insulin and C-peptide levels were drawn at the time of diagnosis. Patients were classified as antibody positive if anti-GAD65 was ≥ 0.5. HbA1c, insulin and C-peptide levels were considered as dependent variables in statistical models that included auto-antibody status, gender, age, body mass index z score (BMI-z score), and blood glucose as independent covariates. Records of 61 African-American children were available for analysis. There was no statistical association of auto-antibody status or initial clinical diagnosis with HbA1c, insulin or C-peptide level. BMI-z score was strongly associated with insulin (p=0.0006) and C-peptide (p

The recent finding of an activating mutation in the Gs alpha protein, the protein that couples receptors to stimulation of adenylate cyclase, from endocrine and nonendocrine tissues of patients with McCune-Albright syndrome (MAS) suggests that alterations in adenylate cyclase activity may account for the clinical abnormalities in these patients. Many patients with MAS have hypophosphatemia. This may result from the presence of the activating Gs alpha mutation in proximal renal tubules or the elaboration of a phosphaturic factor from fibrous dysplasia. We, therefore, sought to characterize renal cAMP generation and phosphate handling in MAS patients. Intravenous infusion of PTH is a classic clinical test used to evaluate hormonal responsiveness of renal proximal tubule adenylate cyclase and examine PTH-dependent phosphate clearance. We performed PTH infusion in 6 MAS patients, 10 normal subjects, and 6 patients with pseudohypoparathyroidism (PHP). The basal urinary cAMP (UcAMP) level in the MAS group [5.5 +/- 2.6 nmol/dL glomerular filtration (GF)] was elevated (P < 0.05) compared to those in both normal subjects (3.2 +/- 1.2 nmol/dL GF) and patients with PHP (1.9 +/- 0.6 nmol/dL GF). However, PTH-stimulated peak UcAMP (15.0 +/- 7.0 nmol/dL GF) and the peak/basal UcAMP ratio (3.1 +/- 1.7) in MAS were significantly lower than the respective values in normal subjects (30.8 +/- 16.9 nmol/dL GF and 9.3 +/- 2.9; P < 0.05 for both) and were statistically similar to the blunted levels in PHP (respectively, 3.1 +/- 1.5 nmol/dL GF and 2.0 +/- 1.7). By contrast, the PTH-induced phosphaturic response in MAS patients was similar to that in the normal subjects. Our study provides clinical evidence that MAS patients have altered renal adenylate cyclase activity, manifested by an elevated basal UcAMP, but a blunted UcAMP response to PTH stimulation. These observations are presumably due to a mutation in the Gs alpha protein in the renal tubules. Despite the blunted UcAMP excretion, the phosphaturic response to PTH in MAS patients is intact.

The hypothalamic-pituitary-adrenal (HPA) axis normally maintains the concentration of Cortisol within a narrow range with a diurnal variation characterized by higher Cortisol concentrations in the morning and reduced levels in the evening. Excessive or deficient secretion of Cortisol is associated with pathologic changes. Obesity has been linked with age, sex and racial alterations in the functioning of the HP A axis which are reviewed. The possible relationship of altered HPA axis activity with the long-term complications of obesity are considered.

Objectives To estimate skin content of advanced glycation endproducts (AGEs) by measurements of skin intrinsic fluorescence (SIF) from youth with diabetes in comparison with a population of youth and adults without diabetes. Study design Using a specialized instrument, skin AGEs were estimated from skin auto-fluorescence induced at 420 nm and corrected for skin pigmentation (SIF420 [kx0.5, km0.5] ) in children with types 1 and 2 diabetes, as well as children and adults without diabetes. The effect of age, sex, ethnicity, and diabetes status on SIF420 [kx0.5, km0.5] was analyzed. Results SIF420 [kx0.5, km0.5] increased with chronologic age and was higher in children with diabetes compared with children without diabetes ( P = .0001). SIF420 [kx0.5, km0.5] from 43% of children with type 1 diabetes and 55% with type 2 diabetes overlapped the range of adults without diabetes. SIF420 [kx0.5, km0.5] was higher in girls than boys in patients with diabetes patients. However, there was no effect of sex or race on SIF420 [kx0.5, km0.5] in subjects without diabetes. Conclusions After 4-6 years' exposure to diabetes, many children will have precociously high estimates of skin AGEs, comparable with levels that would naturally accumulate only after ∼25 years of chronologic aging. Potentially, this technology identifies children who are at increased risk for complications.

We evaluated the effect of growth hormone (GH) therapy on bone age, pubertal maturation and predicted adult height in two groups of boys treated for 4 years: 40 growth hormone-deficient boys who had growth hormone response to provocative stimulation or = 10 micrograms/L (group with neurosecretory dysfunction (NSD)). All patients had a subnormal integrated concentration of growth hormone < or = 3.2 micrograms/L, height < -2 SD, growth velocity < 4.5 cm/yr, and bone age < or = -2 SD for chronologic age. Patients were treated with recombinant growth hormone, 0.1 mg/kg per dose given three times a week. The pretreatment height SD of the GHD group (-3.6 +/- 1.0) was less than that of the NSD group (-2.7 +/- 0.7; p < 0.001). After 4 years of therapy, both groups had catch-up growth (GHD group to -2.0 +/- 1.3 height SD (n = 35), and NSD group to -1.4 +/- 0.7 height SD (n = 32)); the rate of height SD gain was better in patients with GHD (p < 0.01). The response to growth hormone was inversely related to pretreatment chronologic age (p < 0.001). The Tanner-Whitehouse II predicted adult height improved for both groups: +9.3 +/- 7.7 cm in the GHD group, giving an adult height SD of -0.9 +/- 1.0, and +5.4 +/- 5.5 cm in patients with NSD, for an adult height SD if -0.8 +/- 0.7. Testosterone levels became higher in the NSD group after 2 years and remained higher at year 4. We conclude that patients respond favorably to growth hormone therapy and in a manner similar to patients with GHD. Initiation of therapy at a younger age gives a greater improvement in gained height and predicted adult height.

Glucose spontaneously reacts with hemoglobin amino groups to produce unstable Schiff base complexes that can dissociate or rearrange to form stable Amadori products. We used dynamic capillary isoelectric focusing and boronate affinity chromatography to assess the formation and dissociation of unstable hemoglobin complexes in vitro. Formation was studied by incubating erythrocytes at 37°C for up to 24h in phosphate-buffered saline (PBS) supplemented with 0 to 55.6 mmol/L glucose. Dissociation was studied by incubating glucose-loaded erythrocytes in PBS without glucose. Dynamic capillary isoelectric focusing separated hemoglobin A1c into two subfractions identified as A1c1 and A1c2. The A1c1 subfraction contained both stable and unstable hemoglobin complexes. The A1c2 subfraction contained only unstable hemoglobin complexes. Both subfractions quantitatively increased in the presence of glucose and decreased in its absence. Rates of increase and decrease were faster and time to equilibrium was shorter for A1c2 (~4 h) compared with A1c1 (~20 h). Unstable hemoglobin complexes did not bind to boronate affinity columns but instead eluted intact in A1c1 and A1c2 subfractions from nonglycated affinity fractions. Cyanoborohydride reduction confirmed the presence of Schiff base complexes. Evidence of multiple unstable hemoglobin complexes with different rates of glycation suggests that new models are needed to describe nonenzymatic hemoglobin glycation.

Insulin sensitivity is impaired and ectopic fat (accretion of lipids outside of typical adipose tissue depots) increased in obese adults and adolescents. It is unknown how early in life this occurs; thus, it is important to evaluate young children to identify potential factors leading to the development of metabolic syndrome. We examined an ethnically diverse cohort of healthy, exclusively prepubertal children (N = 123; F = 57, M = 66; age 8.04 ± 0.77 years) to examine differences in insulin sensitivity and ectopic and visceral fat deposition between obese and nonobese youth. Obesity was categorized by age- and sex-adjusted BMI z-scores (nonobese = z-score

We sought to determine if low birth weight (LBW) occurs more frequently in African American children with type 2 diabetes (T2D), and if patients with LBW differ metabolically.We collected birth weight, anthropometric and metabolic data from African American children with T2D born in New Orleans from clinic charts. Comparable birth weight data from all African American infants born in New Orleans were obtained from Louisiana state vital statistics.In African American patients with T2D, 14.3% had LBW compared to 13.9% in the reference population (z = 0.997, p = 0.33). There was no difference between LBW and non-LBW patients with regard to body mass index (BMI) at diagnosis, presenting insulin, c-peptide, glucose levels, or HbA1c one year post diagnosis.African American children with T2D were not enriched with LBW individuals. LBW patients were not anthropometrically or metabolically different from non-LBW T2D patients. Thus prenatal factors may not be the driving force in the development of T2D in African American children.