Glucose-independent racial disparity in HbA1c is evident at onset of type 1 diabetes.

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 (R2 = 0.38, p < 0.0001) c-peptide was influenced by HCO3 (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.

Mean blood glucose-independent HbA1c racial disparity and iron status in youth with Type 1 DM.

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.

Associations Between Depressive Symptoms, Fear of Hypoglycemia, Adherence to Management Behaviors and Metabolic Control in Children and Adolescents with Type 1 Diabetes.

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.

Sickle Cell Disease is Associated With Elevated Levels of Skin Advanced Glycation Endproducts.

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.

Intima-media thickness at different arterial segments in pediatric type 1 diabetes patients and its relationship with advanced glycation end products.

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 < .001; and 0.41 ± 0.07 vs 0.36 ± 0.07 mm, P < .01, respectively) while carotid and brachial IMT were not. AGE levels were elevated in T1DM patients and correlated with aortic IMT only. The influence of AGE on aIMT did not remain significant after adjusting for T1DM and age in our small population. CONCLUSION: We found aortic IMT-and to a lesser degree femoral IMT-to be more sensitive than carotid and brachial IMT for detecting early macrovascular changes in pediatric T1DM patients.

Racial differences in neighborhood disadvantage, inflammation and metabolic control in black and white pediatric type 1 diabetes patients.

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.

Skin advanced glycation endproducts are elevated at onset of type 1 diabetes in youth.

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.

How well do self-monitored capillary glucose measurements predict the mean blood glucose from 24-hour continuous monitoring in endocrine practice?

OBJECTIVE: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Advanced glycation endproducts in children with diabetes.

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.

Relationship of body mass index and GAD65 antibody status on ß-cell secretion at diabetes onset in African-American children.

Abstract 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<0.0001) levels. In general, higher BMI-z score, female gender and older age were associated with higher C-peptide levels. Although potentially helpful in eventually determining etiology, pancreatic auto-antibody levels do not have an association with HbA1c, insulin or C-peptide levels in African-American children with new onset diabetes. BMI-z score had the most robust association with insulin and C-peptide levels at presentation.

Two-dimensional analysis of glycated hemoglobin heterogeneity in pediatric type 1 diabetes patients.

Interindividual and ethnic variation in glycated hemoglobin levels, unrelated to blood glucose variation, complicates the clinical use of glycated hemoglobin assays for the diagnosis and management of diabetes. Assessing the types and amounts of glycated hemoglobins present in erythrocytes could provide insight into the mechanism. Blood samples and self-monitored mean blood glucose (MBG) levels were obtained from 85 pediatric type 1 diabetes patients. Glycated hemoglobin levels were measured using three primary assays (boronate-affinity chromatography, capillary isoelectric focusing (CIEF), and standardized DCA2000+ immunoassay) and a two-dimensional (2D) analytical system consisting of boronate-affinity chromatography followed by CIEF. The 2D system separated hemoglobin into five subfractions, four of which contained glycated hemoglobins. Glycated hemoglobin measurements were compared in patients with low, moderate, or high hemoglobin glycation index (HGI), a measure of glycated hemoglobin controlled for blood glucose variation. MBG was not significantly different between HGI groups. Glycated hemoglobin levels measured by all three primary assays and in all four glycated 2D subfractions were significantly different between HGI groups and highest in high HGI patients. These results show that interindividual variation in glycated hemoglobin levels was evident in diabetes patients with similar blood glucose levels regardless of which glycated hemoglobins were measured.

Characterization of unstable hemoglobin A1c complexes by dynamic capillary isoelectric focusing.

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.

Skin intrinsic fluorescence is associated with hemoglobin A(1c )and hemoglobin glycation index but not mean blood glucose in children with type 1 diabetes.

OBJECTIVE: To evaluate the relationship between skin advanced glycation end products (sAGEs) with mean blood glucose (MBG), hemoglobin A(1c) (HbA(1c)), and MBG-independent, between-patient differences in HbA(1c) 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 HbA(1c) were examined by statistically controlling HbA(1c) for MBG or alternatively by use of a hemoglobin glycation index (HGI). Results were similar whether HbA(1c), 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: HbA(1c) was correlated with MBG (r = 0.5; P < 0.001; n = 110). HbA(1c) 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 HbA(1c), but not with MBG itself. These results suggest that factors besides MBG that influence HbA(1c) levels also contribute to accumulation of sAGE.

Low birth weight is not associated with type 2 diabetes in African American children in New Orleans.

OBJECTIVES: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Estimated average glucose and self-monitored mean blood glucose are discordant estimates of glycemic control.

OBJECTIVE: The A1C-Derived Average Glucose study recommended reporting A1C in estimated average glucose (eAG) equivalents. We compared eAG with self-monitored mean blood glucose (MBG) to determine whether eAG is systematically biased due to biological variation in the relationship between MBG and A1C. RESEARCH DESIGN AND METHODS: MBG and A1C were recorded from charts of 202 pediatric type 1 diabetic patients at 1,612 clinic visits. Patients were divided into groups with low, moderate, or high A1C bias based on a hemoglobin glycation index (HGI). RESULTS: The mean +/- SD values for MBG versus eAG were as follows: total population, 194 +/- 34 vs. 196 +/- 36 mg/dl; low-HGI group, 186 +/- 31 vs. 163 +/- 20 mg/dl; moderate-HGI group, 195 +/- 28 vs. 193 +/- 19 mg/dl; and high-HGI group, 199 +/- 42 vs. 230 +/- 31 mg/dl. CONCLUSIONS: eAG underestimated MBG in low HGI patients and overestimated MBG in high HGI patients. Disagreement between eAG and MBG downloaded from patient glucose meters will cause confusion if eAG is implemented for clinical use.