Determination of Glucose-Independent Racial Disparity in HbA1c for Youth With Type 1 Diabetes in the Era of Continuous Glucose Monitoring.

BACKGROUND: The magnitude and importance of higher HbA1c levels not due to mean blood glucose (MBG) in non-Hispanic black (B) versus non-Hispanic white (W) individuals is controversial. We sought to clarify the relationship of HbA1c with glucose data from continuous glucose monitoring (CGM) in a young biracial population. METHODS: Glycemic data of 33 B and 85 W, healthy youth with type 1 diabetes (age 14.7 ± 4.8 years, M/F = 51/67, duration of diabetes 5.4 ± 4.7 years) from a factory-calibrated CGM was compared with HbA1c. Hemoglobin glycation index (HGI) = assayed HbA1c - glucose management index (GMI). RESULTS: B patients had higher unadjusted levels of HbA1c, MBG, MBGSD, GMI, and HGI than W patients. Percent glucose time in range (TIR) and percent sensor use (PSU) were lower for B patients. Average HbA1c in B patients 8.3% was higher than 7.7% for W (P < .0001) after statistical adjustment for MBG, age, gender, insulin delivery method, and accounting for a race by PSU interaction effect. Higher HbA1c persisted in B patients when TIR was substituted for MBG. Predicted MBG was higher in B patients at any level of PSU. The 95th percentile for HGI was 0.47 in W patients, and 52% of B patients had HGI ≥ 0.5. Time below range was similar for both. CONCLUSIONS: Young B patients have clinically relevant higher average HbA1c at any given level of MBG or TIR than W patients, which may pose an additional risk for diabetes complications development. HGI ≥ 0.5 may be an easy way to identify high-risk patients.

The 24-hour average concentration of cortisol is elevated in obese African-American youth with type 2 diabetes.

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 ±â€¯0.36 versus 2.58 ±â€¯0.16, p = 0.0429). IC-cortisol (5.70 ±â€¯1.8 µg/dl vs 4.18 ±â€¯1.07 µg/dl, p = 0.0481) was higher and IC-C-peptide (2.33 ±â€¯0.89 ng/ml vs 4.36 ±â€¯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.

Impaired insulin sensitivity and elevated ectopic fat in healthy obese vs. nonobese prepubertal children.

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 <2 (N = 94) and obese = z-score ≥2 (N = 29)). Insulin sensitivity was assessed by both a frequently sampled intravenous glucose tolerance test (S(i)) and the homeostatic model assessment of insulin resistance (HOMA(IR)). Intramyocellular lipids (IMCLs) from soleus and intrahepatic lipids (IHLs) were assessed by magnetic resonance spectroscopy, visceral adipose tissue (VAT) by magnetic resonance imaging, and total body fat by dual-energy X-ray absorptiometry. We also examined serum lipids (total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol) and blood pressure (diastolic and systolic). Obese children exhibited significantly lower S(i) (5.9 ± 5.98 vs. 13.43 ± 8.18 (mµ/l)(-1)·min(-1), P = 0.01) and HDL-C and higher HOMA(IR) (1.68 ± 1.49 vs. 0.63 ± 0.47, P < 0.0001), IMCL (0.74 ± 0.39 vs. 0.44 ± 0.21% water peak, P < 0.0001), IHL (1.49 ± 1.13 vs. 0.54 ± 0.42% water peak, P < 0.0001), VAT (20.16 ± 8.01 vs. 10.62 ± 5.44 cm(2), P < 0.0001), total cholesterol, triglycerides, low-density lipoprotein cholesterol, and systolic blood pressure relative to nonobese children. These results confirm significantly increased ectopic fat and insulin resistance in healthy obese vs. nonobese children prior to puberty. Excessive adiposity during early development appears concomitant with precursors of type 2 diabetes and the metabolic syndrome.

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.

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.

Feasibility of intravenous glucose tolerance testing prior to puberty.

OBJECTIVES: 1) Report the feasibility of completing the 180-minute Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) in healthy weight, overweight and obese pre-pubertal children and, 2) describe the finalized FSIVGTT protocol after addendums were implemented to decrease the frequency of mild adverse events and improve test completion rates. METHODS: Insulin sensitivity was determined by FSIVGTT. RESULTS: FSIVGTT was attempted in a total of 22 study participants. Insulin sensitivity was successfully assessed in 15 study participants (8 males, 7 females, 10 Caucasian, 4 African American, 1 Pacific Islander, age range 7-9 years). Mean insulin sensitivity was 15.1+/-9.8 (mmicro/l)(-1) min(-1) range 4.4-43.2 (mmicro/l)(-1) min(-1). However, seven study participants experienced mild adverse events of hypoglycemia. Several addendums were made to the FSIVGTT protocol to ensure study participants' comfort and safety, and to decrease the frequency of mild adverse events and increase test completion rates. CONCLUSIONS: Addendums made to FSIVGTT protocol allowed successful completion of FSIVGTT in 15 (68%) of the 22 children. These results demonstrate that FSIVGTT is challenging, yet feasible in healthy lean and obese pre-pubertal children.

Adaptive and maladaptive cortisol responses to pediatric obesity.

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.

Coronary artery calcification, serum lipids, lipoproteins, and peripheral inflammatory markers in adolescents and young adults with type 1 diabetes.

OBJECTIVE: To determine whether coronary artery calcification (CAC), elevated fasting lipids, and lipoproteins and peripheral inflammatory markers are present in insulin-dependent diabetic adolescents and young adults several years after diagnosis. STUDY DESIGN: Hispanic insulin-dependent diabetics (n = 32) diagnosed a mean of 7.8 +/- 4.5 years ago (range, 3 to 16 years), with a mean glycosylated hemoglobin concentration at the time of the study of 8.8% +/- 2.3% and a mean chronological age of 16.1 +/- 4.4 years, were evaluated. Healthy patients (n = 15) with a chronological age (CA) of 15.2 +/- 2.2 years served as control subjects. CAC was assessed by multiple slice computed tomography, and total CAC score in Agatston units was calculated. Fasting lipids, C-reactive protein, apolipoprotein (Apo) A, Apo B, and metalloproteinase-9 (MMP-9) concentrations were measured in all subjects. RESULTS: Neither adolescents with type 1 diabetes nor healthy control subjects presented with evidence of CAC. Fasting lipids, Apo A, Apo B, CRP, and MMP-9 concentrations were similar between diabetic subjects and control subjects. However, 34.4% and 25.0% of our type 1 diabetic subjects had elevated total and LDL cholesterol levels (>200 and >130 mg/dL, respectively), whereas 15.6% and 28.1% had elevated triglyceride and Apo B concentrations (>150 mg/dL and >100 mg/dL, respectively). In addition, 28.1% and 34.4% presented with elevated CRP and MMP-9 levels (>2 mg/L and >80 ng/mL, respectively). Total, LDL and HDL cholesterol, triglycerides, Apo B, CRP, and MMP-9 concentrations correlated positively with duration of the disease and with glycosylated hemoglobin levels. CONCLUSIONS: Although the study adolescents with type 1 diabetes did not present any radiologic evidence of CAC at this stage of the disease, they remain a high-risk group for the development of microvascular and macrovascular artery disease, as risk factors such as elevated lipoproteins and proinflammatory markers are already present in a significant percentage of patients studied.

Growth hormone deficiency, low levels of adiponectin, and unfavorable plasma lipid and lipoproteins.

OBJECTIVE: To examine the impact of adolescent growth hormone deficiency (GHD) on circulating adiponectin levels and the relation between adiponectin, fasting insulin, plasma lipid, and lipoprotein levels. STUDY DESIGN: Twelve children with GHD on GH treatment with a chronological age (CA) of 14.4 +/- 2.0 years and 12 untreated adolescents with GHD with a CA of 14.9 +/- 2.3 years were studied. Adiponectin concentrations were measured in all patients, and the association of adiponectin with fasting insulin, total, LDL, and HDL cholesterol, triglycerides, apolipoprotein A-1, and apolipoprotein B was evaluated. Twelve healthy adolescents served as control subjects. RESULTS: Adiponectin levels were significantly lower in untreated GHD adolescents than in treated GHD subjects or in control subjects (P < .008). Total and LDL cholesterol, triglycerides, and Apo B concentrations were increased in untreated GHD adolescents, whereas HDL cholesterol levels were similar in all three groups. Insulin levels were significantly increased in treated GHD adolescents when compared with control subjects (P < .05) but similar to those with untreated GHD. Adiponectin was found to be negatively associated with body mass index, waist-to-hip ratio, and with Apo B, total cholesterol, triglycerides, and LDL cholesterol concentrations in untreated GHD adolescents, whereas a positive correlation between adiponectin and HDL cholesterol was noted in both untreated and treated GHD subjects. Adiponectin correlated inversely with fasting insulin levels in untreated and treated GHD adolescents. CONCLUSIONS: GHD in adolescence is associated with low levels of adiponectin and with an unfavorable plasma lipid and lipoprotein profile. Our data suggest that treatment with GH may improve the abnormalities seen.

Endothelial function, carotid artery intima-media thickness, epicardial adipose tissue, and left ventricular mass and function in growth hormone-deficient adolescents: apparent effects of growth hormone treatment on these parameters.

OBJECTIVE: The purpose of this study was to determine whether GH-deficient (GHD) adolescents have abnormalities of cardiac and vascular function detectable during the teenage years. DESIGN/METHODS: Ten GHD children on GH treatment with a chronological age (CA) of 14.6 +/- 1.7 yr and 12 untreated GHD adolescents with a CA of 15.0 +/- 3.0 yr were studied. Cardiac mass and function, carotid artery intima-media thickness, flow-mediated endothelium-dependent vasodilation (percent change from baseline diameter during hyperemia), and hyperemia-induced blood flow increase of the brachial artery (percent change from baseline) and epicardial adipose tissue were evaluated by echocardiography. Fourteen healthy adolescents served as controls. RESULTS: Untreated GHD adolescents present with a reduced left ventricular mass when compared with controls (P < 0.05) and a lower flow-mediated endothelium-dependent increase in the diameter of the brachial artery during hyperemia than both controls and treated GHD subjects (P < 0.02), whereas their epicardial adipose tissue is significantly higher than that of healthy controls (P < 0.02). Interventricular septum thickness, posterior wall thickness, left ventricular ejection fraction, and carotid artery intima-media thickness were similar in all three groups. Hyperemia-induced blood flow increase was greater in treated GHD adolescents than both untreated subjects and controls (P < 0.001). Body mass index correlated positively with epicardial adipose tissue in all three groups and with carotid intima-media thickness in treated and untreated GHD adolescents. CONCLUSIONS: GHD adolescents have a reduced left ventricular mass and vascular abnormalities manifested by lower flow-mediated endothelium-dependent vasodilation. These findings together with an increase in epicardial adipose tissue, a good indicator of abdominal/visceral fat, may contribute to an increased cardiovascular risk in the long term. An improvement in endothelial function and a reduction in arterial stiffness appear to occur after GH replacement.

Accelerated versus slowly progressive forms of puberty in girls with precocious and early puberty. Gonadotropin suppressive effect and final height obtained with two different analogs.

OBJECTIVES: To distinguish which children with precocious puberty (PP) and early puberty (EP) should be treated and which followed without therapy. To determine the effect of GnRH analog treatment on the final height of treated patients and compare the effect of two different analogs on gonadotropin suppression and final height. STUDY DESIGN: Sixteen females with PP or EP with a mean chronological age (CA) of 8.8 +/- 1.4 years and a mean bone age (BA) of 10.8 +/- 1.3 years were treated for a mean of 2.7 +/- 1.0 years with a GnRH analog (triptorelin or leuprolide acetate; group A), while 21 girls with a mean CA of 8.5 +/- 1.0 years, a mean BA of 9.7 +/- 1.4 years and a predicted adult height of >155 cm were followed without therapy (group B). Criteria for treatment were one of: a. predicted adult height (PAH) of <155 cm initially or at any time during follow up; b. PAH over 155 cm with a dramatic decrease in PAH over a 6-month follow-up period; c. advanced and rapidly progressing breast development for age (Tanner 3 before the age of 9 years). RESULTS: GnRHa therapy suppressed gonadotropins in group A, while gonadotropins increased gradually in group B. Height velocity (HV) decreased in group A, while it remained accelerated in group B; BA increased a mean of 1.7 +/- 0.5 years in group A and 3.2 +/- 0.3 years in group B. This resulted in a height increase in group A from a baseline PAH of 153.7 +/- 1.2 cm to a final height (FH) of 160.9 +/- 4.0 cm (p <0.001), clearly above their target height (TH) of 157.7 +/- 4.2 cm. The height of group B children did not change over time (164.1 +/- 4.1 cm before therapy and 166.0 +/- 6.0 cm at FH), both above their TH. The mean leuprolide acetate dose utilized in this study decreased during treatment, while both the initial and final triptorelin dose remained unchanged. Adequate gonadotropin suppression (peak level of LH and FSH of <2 IU/l after i.v. GnRH stimulation) was noted with both leuprolide acetate and triptorelin, although LH suppression was slightly more pronounced with triptorelin. BA advanced 1.8 +/- 0.4 years during leuprolide acetate treatment and 1.5 +/- 0.3 years with triptorelin, so that FH increased a mean of 5.5 +/- 1.3 cm with leuprolide acetate and 8.7 +/- 2.2 cm with triptorelin. CONCLUSIONS: PAH of <155 cm before or during therapy, PAH of >155 cm with a dramatic decrease in predicted height over a 6-month follow-up period and/or advanced and rapidly progressing breast development in girls with PP or EP were useful parameters in deciding which patients to treat. GnRHa therapy suppressed gonadotropins, HV and bone maturation in children with an accelerated form of PP or EP, resulting in a significant height increase. Final height remained stable over time in untreated patients. Adequate gonadotropin suppression was noted with both analogs, although with the doses of analog used in our study, LH and BA suppression were more pronounced with triptorelin, resulting in a larger height gain.

Decreased final height of children with growth deceleration secondary to poor weight gain during late childhood.

Eighteen healthy, short children with normal growth during most of their childhood were evaluated after a sustained fall in weight and reduced linear growth. Growth was followed after nutritional counseling until final height. This report demonstrates the need for an appropriate-for-age weight gain in growing children as a relatively minor but prolonged caloric restriction, leading to a sustained fall in weight centiles, will affect growth velocities long term and may lead to reduced final heights.