Transfer from paediatric to adult care for young adults with Type 2 diabetes: the SEARCH for Diabetes in Youth Study.

AIM: To describe factors associated with transfer from paediatric to adult care and poor glycaemic control among young adults with Type 2 diabetes, using the SEARCH for Diabetes in Youth study. METHODS: Young adults with Type 2 diabetes were included if they had a baseline SEARCH visit while in paediatric care at < 18 years and ≥ 1 follow-up SEARCH visit thereafter at 18-25 years. At each visit, HbA1c , BMI, self-reported demographic and healthcare provider data were collected. Associations of demographic factors with transfer of care and poor glycaemic control (HbA1c ≥ 75 mmol/mol; 9.0%) were explored with multivariable logistic regression. RESULTS: 182 young adults with Type 2 diabetes (36% male, 75% minority, 87% with obesity) were included. Most (n = 102, 56%) reported transfer to adult care at follow-up; a substantial proportion (n = 28, 15%) reported no care and 29% did not transfer. Duration of diabetes [odds ratio (OR) 1.4, 95% confidence interval (95% CI) 1.1, 1.8] and age at diagnosis (OR 1.8, 95% CI 1.4, 2.4) predicted leaving paediatric care. Transfer to adult or no care was associated with a higher likelihood of poor glycaemic control at follow-up (adult: OR 4.5, 95% CI 1.8, 11.2; none: OR 4.6, 95% CI 1.4, 14.6), independent of sex, age, race/ethnicity or baseline HbA1c level. CONCLUSIONS: Young adults with Type 2 diabetes exhibit worsening glycaemic control and loss to follow-up during the transfer from paediatric to adult care. Our study highlights the need for development of tailored clinical programmes and healthcare system policies to support the growing population of young adults with youth-onset Type 2 diabetes.

Development, validation and use of an insulin sensitivity score in youths with diabetes: the SEARCH for Diabetes in Youth study.

AIMS/HYPOTHESIS: The ability to measure insulin sensitivity across the phenotypic spectrum of diabetes may contribute to a more accurate characterisation of diabetes type. Our goal was to develop and validate an insulin sensitivity (IS) score using the euglycaemic-hyperinsulinaemic clamp in a subset (n = 85) of 12- to 19-year-old youths with diabetes participating in the SEARCH study in Colorado, USA. METHODS: Youths with a diagnosis of type 1 (n = 60) or type 2 diabetes (n = 25) underwent a 3 h clamp to measure glucose disposal rate (GDR, mg kg⁻¹ min⁻¹). Demographic (age, sex, race), clinical (BMI, waist, Tanner stage) and metabolic characteristics (HbA1(c), lipids, blood pressure, urine albumin:creatinine) were used to estimate log(e)IS score via stepwise linear regression on a model-development set (n = 53). Estimated IS score was evaluated for reproducibility on two validation sets: youths with diabetes (n = 33) and healthy control youths (n = 22). RESULTS: The best model included waist, triacylglycerol (TG) and HbA1(c) levels (R² = 0.74). Diabetes type did not enter the model and there were no significant interactions between diabetes type and other predictors. Estimated IS score correlated well (r = 0.65, p < 0.0001; r = 0.62, p = 0.002) with GDR on the two validation sets. Based on this analysis, we propose the following formula to estimate insulin sensitivity in youths with diabetes: [Formula: see text]. CONCLUSIONS/INTERPRETATION: Insulin sensitivity can be estimated in adolescents with diabetes using routinely collected measures. This score can be applied to epidemiological studies of youths with diabetes to characterise relationships between dimensions of diabetes type.

Childhood growth and age at diagnosis with Type 1 diabetes in Colorado young people.

OBJECTIVE: Studies have suggested that the age at diagnosis of Type 1 diabetes (T1D) is decreasing over time. The overload hypothesis postulates that risk factors, such as accelerated growth, may be responsible for this decrease. We assessed changes in age, body mass index (BMI), weight and height at diagnosis with T1D in non-Hispanic white (NHW) and Hispanic (HISP) young people from Colorado, using data from the IDDM Registry and SEARCH Study. METHODS: In three time periods, 656 (1978-1983), 562 (1984-1988) and 712 (2002-2004) young people aged 2-17 years were newly diagnosed with T1D. Age, weight, height and presence of diabetic ketoacidosis (DKA) at diagnosis with T1D were obtained from medical records. Trends over the three time periods were assessed with regression analyses. RESULTS: Age at diagnosis decreased by 9.6 months over time (P = 0.0002). Mean BMI standard deviation score (SDS), weight SDS and height SDS increased over time (P < 0.0001), while prevalence of DKA decreased (P < 0.0001). Increasing height over time accounted for 15% (P = 0.04) of the decreasing age at diagnosis with T1D. CONCLUSIONS: Our study provides evidence that increased linear growth, but not increased BMI or weight over time, may account, at least in part, for the younger age at diagnosis of T1D in Colorado children. This finding supports the hypothesis that increasing environmental pressure resulting from changes in potentially preventable risk factors may accelerate the onset of T1D in children.

Height growth velocity, islet autoimmunity and type 1 diabetes development: the Diabetes Autoimmunity Study in the Young.

AIMS/HYPOTHESIS: Larger childhood body size and rapid growth have been associated with increased type 1 diabetes risk. We analysed height, weight, BMI and velocities of growth in height, weight and BMI, for association with development of islet autoimmunity (IA) and type 1 diabetes. METHODS: Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed children at increased type 1 diabetes risk, based on HLA-DR, -DQ genotype or family history, for the development of IA and type 1 diabetes. IA was defined as the presence of autoantibodies to insulin, GAD or protein tyrosine phosphatase islet antigen 2 twice in succession, or autoantibody-positive on one visit and diabetic at the next consecutive visit within 1 year. Type 1 diabetes was diagnosed by a physician. Height and weight were collected starting at age 2 years. Of 1,714 DAISY children <11.5 years of age, 143 developed IA and 21 progressed to type 1 diabetes. We conducted Cox proportional hazards analysis to explore growth velocities and size measures for association with IA and type 1 diabetes development. RESULTS: Greater height growth velocity was associated with IA development (HR 1.63, 95% CI 1.31-2.05) and type 1 diabetes development (HR 3.34, 95% CI 1.73-6.42) for a 1 SD difference in velocity. CONCLUSIONS/INTERPRETATION: Our study suggests that greater height growth velocity may be involved in the progression from genetic susceptibility to autoimmunity and then to type 1 diabetes in pre-pubertal children.

Continuous subcutaneous glucose monitoring in children with type 1 diabetes.

PURPOSE: To determine whether the use of continuous subcutaneous glucose monitoring will help in detecting unrecognized nocturnal hypoglycemia and in lowering hemoglobin A1c (HbA1c) levels (without increasing the risk for severe hypoglycemia) in children with type 1 diabetes. METHODS: Eleven children with type 1 diabetes and HbA1c values consistently >8.0% were randomized either to the Continuous Glucose Monitoring System (CGMS) group or to the control group. The CGMS group used 6 3-day sensors within a 30-day period. Both groups self-monitored their blood glucose levels a minimum of 4 times daily. HbA1c levels were measured at the start, at 1-month, and after 3 months of study. RESULTS: The 5 children using the CGMS had 17 asymptomatic episodes (85%) of glucose levels below 60 mg/dL (3.25 mmol/L) and 3 symptomatic episodes (15%) during the night in the study month. The 6 control children had 4 symptomatic nocturnal low episodes during the month. After the 30-day period of wearing the CGMS, the 5 children had a significantly lower mean HbA1c value compared with their initial value (mean +/- standard error of the mean [SEM] decrease =.36% +/-.07%). The mean decrease for the controls was.2% +/-.2%. After 3 months, 4 of the 5 children who used the CGMS continued to have lower HbA1c values in comparison to their initial values (mean +/- SEM decrease = 1.04% +/-.43%). Three of the 6 control participants also had lower HbA1c values at 3 months (mean +/- SEM decrease for the group =.62% +/-.44%). No severe hypoglycemic events occurred in either the CGMS or the control groups. CONCLUSION: In this pilot trial, continuous subcutaneous glucose monitoring was helpful in detecting asymptomatic nocturnal hypoglycemia as well as in lowering HbA1c values without increasing the risk for severe hypoglycemia in children with type 1 diabetes.

Continuous subcutaneous insulin infusion therapy for children and adolescents: an option for routine diabetes care.

OBJECTIVE: The purpose of this study was to determine the feasibility of continuous subcutaneous insulin infusion (CSII) (insulin pump) therapy in routine pediatric diabetes care by comparing the HbA(1c), body mass index (BMI), and hypoglycemic episodes before and after initiation of CSII therapy. RESEARCH DESIGN AND METHODS: Data from 56 patients (7-23 years old) were collected during regularly scheduled visits at a frequency similar to non-CSII patients. RESULTS: The data were analyzed for the entire cohort and 3 subgroups (decreased, stable, or increased HbA(1c)) stratified according to a >/=0.5% change in HbA(1c). The total cohort demonstrated a decrease in HbA(1c) from 8.5% to 8.3%. The decreased cohort (39.4% of the total cohort) demonstrated a significant decrease in HbA(1c) from 8.6% to 7.6%. The mean HbA(1c) of the stable cohort (41.0%) was 8.7%. The increased cohort (19.6%) had an increase in HbA(1c) from 7.8% to 8.8%. Thirty-six patients (64.3%) maintained or achieved a HbA(1c) <8.0% or achieved a HbA(1c) at least 1% lower than their pre-CSII level. Of concern, 6 patients (10.7%) demonstrated a clinically significant increase in HbA(1c) from 8.3% to 9.6%. For the entire cohort, the rate of severe hypoglycemia before and on CSII therapy was 12.3 and 9.5 events per 100 patient-years, respectively. A statistically significant proportion of patients reported a decrease in seizure frequency versus an increase (17.9% vs 1.8%) as well as a decrease in overall hypoglycemic frequency versus an increase (41.1% vs 17.9%). There was not a clinically significant increase in BMI, even in the decreased HbA(1c) cohort. CONCLUSIONS: CSII therapy is an appropriate option for some children in routine pediatric diabetes care. It can effectively decrease the HbA(1c) and reduce hypoglycemic episodes, without producing an abnormal increase in BMI.

Life with continuous subcutaneous insulin infusion (CSII) therapy: child and parental perspectives and predictors of metabolic control.

OBJECTIVE: The purpose of this study was twofold (i): to evaluate metabolic control in patients receiving CSII therapy in a routine pediatric diabetes clinic by describing reasons for initiating therapy and daily management issues, including needle fear; and (ii) to assess the change in parental involvement and anxiety once their child initiated CSII therapy. RESEARCH DESIGN AND METHODS: The study included 52 subjects (aged 7.6-23.6 yr) from a general pediatric diabetes clinic. Management issues were defined as diet, exercise, home blood glucose monitoring (HBGM) frequency, and self/staff assessment of needle fear. Characteristics were analyzed both according to a 0.5% change in HbA1c status (decreased vs. stable vs. increased) compared with pre-CSII therapy, and final HbA1c achieved (< or = 8.1 vs. > 8.1%). RESULTS: The primary recommendation source for CSII use was most often the physician/diabetes team (48.1%), followed by a combination of the former with a personal referral source (32.7%). The most common reason (71.2%) for CSII initiation was a combination of wanting to achieve better metabolic control, dislike of insulin injections, and/or increased flexibility in daily living. Over one-quarter (26.9%) of subjects were identified as being needle-fearful, and this characteristic was predictive of final metabolic control (3/25 subjects 8.1%, p = 0.03). On CSII therapy, dietary carbohydrate consistency was highly variable, and most subjects (65.3%) exclusively used an insulin to carbohydrate ratio for insulin bolus dosage calculation. The most common adjustment strategy (63.5%) for exercise was a combination of decreasing the insulin basal rate, disconnecting the pump, and/or eating extra carbohydrates. For the total cohort, the frequency of HBGM significantly increased on CSII therapy (4.31-4.85 tests/day, p = 0.02). Females did not have a significant change in HBGM frequency, while the youngest subjects had the highest HBGM frequency. Parental involvement and anxiety primarily stayed the same or decreased, regardless of the child's age (< or = 18 vs. > 18 yr) or metabolic control. CONCLUSIONS: Analyses of the various characteristics identified only needle fearfulness as being predictive of poor metabolic control. Interestingly, poor control with CSII therapy did not result in a significant increase in parental involvement and/or anxiety.

Effect of Bacillus Calmette-Guerin vaccination on new-onset type 1 diabetes. A randomized clinical study.

OBJECTIVE: We undertook this study to test whether Bacillus Calmette-Guerin (BCG) vaccine preserves beta-cell function and increases the remission rate in children with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: This was a randomized double-blind placebo-controlled trial offered to children referred to the Barbara Davis Center for Childhood Diabetes or the Baystate Medical Center with a diagnosis of new-onset type 1 diabetes. There were 94 children aged 5-18 years who received either BCG or saline intradermally within 4 months of onset of symptoms and who were then evaluated at 3-month intervals for 2 years. The primary end point was remission, defined as insulin independence for 4 weeks. Secondary end points were C-peptide levels (fasting and in response to a mixed meal challenge), insulin dose, and HbA1c. RESULTS: Of the patients, 47 were randomized to each arm; 7 in the placebo group and 9 in the BCG group did not complete 1 year of the study and are not included in the analysis. One patient from each group achieved remission. Fasting and stimulated C-peptide levels did not differ by treatment arm but declined in both groups and were lower initially and during the entire 2-year period in younger children. Insulin requirements and HbA1c levels did not differ in the two groups. CONCLUSIONS: Vaccination with BCG at the time of onset of type 1 diabetes does not increase the remission rate or preserve beta-cell function.

Impact on maternal parenting stress of receipt of genetic information regarding risk of diabetes in newborn infants.

Our objective was to investigate whether notification of high-risk status for type 1 diabetes in newborn infants results in an increased maternal-parenting stress level when compared with notification of low-risk status for type 1 diabetes. Maternal parenting stress level was assessed at 5-7 weeks postpartum (baseline) and was reassessed 4-5 months after parents were informed of their newborn infants' genetic screening results (follow-up). Parenting stress level was measured using the total stress score (TSS) of the Parenting Stress Index/Short Form. The outcome variable, change in TSS, was calculated by subtracting the baseline TSS from the follow-up TSS. Demographic variables such as maternal race, maternal age, maternal education level, maternal marital status, child's birth order, and total family income were assessed through a structured phone interview at the time of baseline assessment. The risk factor of interest was the child's human leukocyte antigen (HLA) status for type 1 diabetes, i.e., whether child was at a high or moderate (combined into "high") genetic risk or at a low genetic risk for type 1 diabetes. A sample of 88 mothers (23 with a high-risk child and 65 with a low-risk child) was evaluated. Baseline median TSSs were 65 and 74 for mothers of low-risk infants and mothers of high-risk infants, respectively. Both groups' median TSS decreased between baseline and follow-up. No significant differences were found between change in TSS and maternal age, race, education level, marital status, total family income, or child's birth order. Although the median decrease in TSS was smaller in mothers with a high-risk child when compared with mothers of a low-risk child, this difference was not statistically significant. We did not find an association between newborn's HLA status and change in maternal TSS. The results of this study suggest that notification of high-risk status for type 1 diabetes in newborn infants may not result in an increased level of parenting stress among mothers.

Identification and treatment of cystic fibrosis-related diabetes. A survey of current medical practice in the U.S.

OBJECTIVE: To describe physicians' attitudes and practices in screening for and treating abnormalities in glucose homeostasis in cystic fibrosis (CF) patients and to test the hypotheses that guidelines for screening for CF-related diabetes (CFRD) are not followed at most centers and that screening and treatment vary by the care provider's background. RESEARCH DESIGN AND METHODS: This cross-sectional survey included three groups of physicians: 1) 593 members of the Lawson Wilkins Pediatric Endocrine Society (LWPES), 2) 462 members of the pediatric assembly of the American Thoracic Society (ATS), and 3) 194 directors of cystic fibrosis centers (CFD). A mailed questionnaire was used for the survey. RESULTS: The overall response rate was 67%. Of these, 224 LWPES, 143 ATS, and 135 CFD physicians reported actively seeing CF patients. About two-thirds of CF physicians (ATS and CFD) reported routine screening for impaired glucose tolerance (IGT) in asymptomatic CF patients; a random glucose is most often used (60%), followed by HbA1c (50%), urine glucose (44%), fasting glucose (21%), and oral glucose tolerance test (2%). Only 40% of LWPES physicians reported intervening for stress-induced hyperglycemia, but 61% reported use of insulin for persistent IGT. Management of CFRD was similar for all groups; most physicians used insulin (91%). LWPES recommended more intensive glucose testing and nutritional guidelines than did ATS/CFD (P < 0.0001). LWPES reported less concern about risks of diabetes complications (P < 0.0001) and the importance of minimizing burdensome interventions (P < 0.01). All groups considered weight management a top priority. CONCLUSIONS: Screening for IGT is not routinely done in CF patients and screening tests vary. Greater agreement exists on methods of treating patients with persistent IGT or CFRD, although goals and aggressiveness of treatment vary with the provider's background. A consensus conference is recommended.

DAX1 mutations map to putative structural domains in a deduced three-dimensional model.

The DAX1 protein is an orphan nuclear hormone receptor based on sequence similarity in the putative ligand-binding domain (LBD). DAX1 mutations result in X-linked adrenal hypoplasia congenita (AHC). Our objective was to identify DAX1 mutations in a series of families, to determine the types of mutations resulting in AHC and to locate single-amino-acid changes in a DAX1 structural model. The 14 new mutations identified among our 17 families with AHC brought the total number of families with AHC to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. These mutations included 23 frameshift, 12 nonsense, and six missense mutations and one single-codon deletion. We mapped the seven single-amino-acid changes to a homology model constructed by use of the three-dimensional crystal structures of the thyroid-hormone receptor and retinoid X receptor alpha. All single-amino-acid changes mapped to the C-terminal half of the DAX1 protein, in the conserved hydrophobic core of the putative LBD, and none affected residues expected to interact directly with a ligand. We conclude that most genetic alterations in DAX1 are frameshift or nonsense mutations and speculate that the codon deletion and missense mutations give insight into the structure and function of DAX1.

Effectiveness of postprandial Humalog in toddlers with diabetes.

OBJECTIVE: The purpose of this study was to determine whether postprandial administration of the new rapid-acting insulin analog Humalog could effectively reduce glucose excursions in children <5 years old. DESIGN: Human Regular insulin given before a meal was compared with the same dose of Humalog after a meal of equal carbohydrate content in five toddlers with insulin-dependent (type 1) diabetes mellitus. In addition, the use of Humalog before a meal was compared with Humalog given after a meal of equal carbohydrate content in five other toddlers. The dose of long-acting insulin was not changed during the study period. Blood glucose levels were determined at fasting and at 1, 2, and 4 hours postprandially. RESULTS: The 2-hour glucose excursions were significantly lower when postprandial Humalog administration was compared with preprandial Human Regular insulin administration. In contrast, glucose excursions were similar when Humalog was taken before or after the meal. CONCLUSION: These data show that it is efficacious to give Humalog insulin postprandially in toddlers with type 1 diabetes, allowing increased safety for the young child. The insulin dose can be both matched to the actual food intake and timed to give families increased flexibility and control at mealtime.

Antiislet autoantibodies usually develop sequentially rather than simultaneously.

The goal of this study was to address whether antiislet autoantibodies appear sequentially or simultaneously before the onset of type I diabetes. We analyzed sequential serum samples from 155 siblings and offspring (aged < 7 yr) of patients with type I diabetes from the Denver Diabetes Autoimmunity Study in the Young study and from a separate group of first degree relatives (aged 2-40 yr) for autoantibodies reacting with three defined autoantigens: glutamic acid decarboxylase (GAD65), insulin, and ICA512/IA-2. The youngest age at which 1 of the 3 autoantibodies appeared was 1.1 yr, and the oldest was 60.9 yr. Of the total 26 autoantibody conversion events observed, in only 3 instances did more than 1 autoantibody appear simultaneously. Among individuals (n = 12) with sequential conversion to expression of multiple autoantibodies, anti-GAD65 autoantibodies or antiinsulin autoantibodies appeared first (4 expressed antiinsulin autoantibodies first, and 8 anti-GAD65 autoantibodies first). We conclude that antiislet autoantibodies usually appear sequentially and not simultaneously. This corroborates early suggestions that humoral autoimmunity to islets develops chronically in a process usually measured in months to years. As expression of multiple autoantibodies is associated with a high risk of progression to diabetes, and sequential appearance of autoantibodies can occur late in life, long term follow-up is necessary to fully delineate the relationship of diabetes risk to autoantibody expression.

Epidermal nevus syndrome: association with central precocious puberty and woolly hair nevus.

The epidermal nevus syndrome is characterized by the association of epidermal nevi with abnormalities of the skin, skeletal system, central nervous system, eyes, and cardiovascular system, as well as with malignant conditions. We describe a 2-year-old girl with an extensive epidermal nevus involving the left side of the body (nevus unius lateris) and associated with a woolly hair nevus on the left parietal area of the scalp and multiple acquired melanocytic nevi. Idiopathic central precocious puberty characterized by premature breast and public hair development and advanced bone age developed at the age of 20 months. A sharp increase in serum gonadotropins after a luteinizing hormone releasing hormone (LHRH) stimulation test confirmed the presence of central precocious puberty. This is the third reported case of precocious puberty associated with the epidermal nevus syndrome.

Lack of association between early exposure to cow's milk protein and beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young (DAISY)

OBJECTIVE: To examine whether infant dietary exposure to cow's milk is associated with beta-cell autoimmunity (BCA), an early predictor of insulin-dependent diabetes mellitus (IDDM). SETTING: Denver, Colo. DESIGN: Cross-sectional with retrospective analysis. PARTICIPANTS: Between January 1994 and December 1995, 253 children from 171 families of persons with IDDM were screened for BCA. All children were between the ages of 9 months and 7 years. MAIN OUTCOME MEASURES: BCA was defined as elevated levels of insulin autoantibody, glutamic acid decarboxylase autoantibody, or insulinoma-associated islet tyrosine phosphatases autoantibody (IA-2) above the 99th percentile of 198 normal subjects. RESULTS: Eighteen cases of BCA were detected; 153 unrelated autoantibody-negative children were selected from the cohort as controls. There were no differences in the proportion of cases and controls who were exposed to cow's milk or foods containing cow's milk or to cereal, fruit and vegetable, or meat protein by 3 months or by 6 months of age. Children with BCA were breast-fed for a slightly longer duration than controls (median duration 10 vs 8 months, P=.07). CONCLUSIONS: These data suggest that early exposure to cow's milk or other dietary protein is not associated with BCA. This calls into question the importance of cow's milk avoidance as a preventive measure for IDDM.

Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY).

Autoimmunity causing insulin-dependent diabetes mellitus (IDDM) begins in early childhood due to interactions between genes and unknown environmental factors that may be identified through follow-up of a large cohort of genetically susceptible children. Such a cohort has been established using a simple and rapid cord blood screening for HLA alleles. The DRB1 and DQB1 second exon sequences were co-amplified using the polymerase chain reaction and hybridized with single and pooled sequence-specific oligonucleotide probes. Four individual probes were used to detect the susceptibility alleles DRB1*03, DRB1*04, and DQB1*0302 as well as the usually protective DRB1*15/16 (DR2) alleles. In addition, pooled probes allow the distinction of DR3/3 from the DR3/x genotype (where x is neither DR2, 3, nor 4) and DR4/4 from DR4/x. Among 5000 newborns from the general Denver population, we have found the high-risk genotype (DRB1*03/ DRB1*04, DQB1*0302) to be present in 2.4% of non-Hispanic whites, 2.8% of Hispanics, and 1.6% of African Americans. The moderate-risk genotypes (DRB1*04, DQB1*0302/DRB1*04, DQB1*0302, DRB1*04, DQB1*0302/x, or DRB1*03/DRB1*03) are present in 17% of American non-Hispanic whites, 24% of Hispanics and in 10% of African Americans. These results demonstrate the feasibility of a large-scale newborn screening for genes associated with IDDM. The ultimate role for such a screening in future routine prediction and prevention of IDDM will depend on the availability of an effective and acceptable form of clinical intervention.

Beta-cell autoantibodies in infants and toddlers without IDDM relatives: diabetes autoimmunity study in the young (DAISY).

Little is known concerning the natural history of beta-cell autoimmunity in infants and toddlers, especially in those without a first degree IDDM relative. A population-based cohort of Colorado infants at increased IDDM risk due to their HLA genotype has been identified through a PCR-based HLA screening of cord blood and is being prospectively studied. We report the distribution of insulin (IAA), GAD65 (GAA), and ICA512 autoantibody levels in 312 children aged 9 months and in 131 children aged 15 months from this cohort, without family history of IDDM. The levels of IAA, GAA and ICA512 did not differ by the HLA genotype (DR3/4,DQB1*0302 vs. DR3/3, vs. DR2/DR4,DQB1*0302 vs. DRx/4,DQB1*0302, where x is not DR3 or DR2), by ethnicity (non-Hispanic whites vs. other ethnic groups), or by age (9 vs. 15 months). The 95th and 99th percentiles of the IAA distribution were respectively 40 and 61 nU/ml at the age of 9 months and 38 and 59 nU/ml at the age of 15 months. The 95th and 99th percentiles of the GAA distribution were respectively 0.020 and 0.046 at the age of 9 months and 0.022 and 0.098 at the age of 15 months. We propose to use IAA levels greater than 60 nU/ml and GAA index greater than 0.05 to define the presence of beta-cell autoimmunity in children younger than 2 years.

Ethnic differences in human leukocyte antigen markers of susceptibility to IDDM.

OBJECTIVE: To determine whether genetic differences explain the lower risk of developing insulin-dependent diabetes mellitus (IDDM) for Hispanic versus non-Hispanic white children in Colorado. RESEARCH DESIGN AND METHODS: Hispanic (n = 62) and non-Hispanic white (n = 82) subjects with IDDM identified from the Colorado IDDM Registry and healthy, nondiabetic control subjects were recruited. Human leukocyte antigen (HLA) serologic typing and sequence-specific oligonucleotide typing of DQA1 and DQB1 alleles were performed. RESULTS: HLA and allele associations with IDDM were similar in both ethnic groups. HLA-DR3 and HLA-DR4 were more common in IDDM subjects in both ethnic groups. Subjects with DQBl alleles encoding aspartic acid (Asp) in position 57 were less likely to have IDDM, irrespective of ethnic background. HLA-DR3 was less common among Hispanic subjects than non-Hispanic white control subjects (4.4 vs. 17.5%, Hispanics vs. non-Hispanic whites, P = 0.04). CONCLUSIONS: These data suggest that the lower prevalence of HLA-DR3 in the Hispanic population, a pattern consistent with the presence of Amerindian admixture, may explain the lower rate of IDDM in the Hispanic population.

First-phase insulin release in normal children.

Normal values for the first-phase insulin release during an intravenous glucose tolerance test are not yet well defined for children and adolescents. In this study, 69 normal subjects (aged 7 to 22 years) who had no family history of type I diabetes, a normal glycohemoglobin value, and a negative islet cell antibody test result underwent a standard intravenous glucose tolerance test. The mean (+/- SEM) first-phase insulin release increased with age and pubertal status: 7 to 10 years, 93 +/- 10.1 mIU/L; 11 to 15 years, 172.7 +/- 22.3 mIU/L; and 16 to 22 years, 163 +/- 28.5 mIU/L. The mean intraindividual variability in 11 subjects who underwent a second test was 23.6%. Acute stress, as estimated by observer assessment or by blood catecholamine levels, did not significantly correlate with first-phase insulin release. We conclude that first-phase insulin release is markedly lower in prepubertal children than in adolescents and young adults.

Early exposure to cow's milk and solid foods in infancy, genetic predisposition, and risk of IDDM.

Using a case-control study design, we examined the hypothesis that early exposure to cow's milk and solid foods increased the risk of IDDM. An infant diet history was collected from 164 IDDM subjects from the Colorado IDDM Registry with a mean birth year of 1973, and 145 nondiabetic population control subjects who were frequency matched to diabetic subjects on age, sex, and ethnicity. Early exposure was defined as exposure occurring before 3 mo of age. After controlling for ethnicity, birth order, and family income, more diabetic subjects were exposed early to cow's milk (OR 4.5, 95% CI 0.9-21.4) and solid foods (OR 2.5, CI 1.4-4.3) than control subjects. To examine this association while accounting for the genetic susceptibility to IDDM, we defined individuals as high and low risk by an HLA-DQB1 molecular marker. Early exposure to cow's milk was not associated with elevated risk for IDDM in low-risk individuals. Relative to unexposed low-risk individuals, early exposure to cow's milk was strongly associated in individuals with a high risK marker (OR 11.3, CI 1.2-102.0). Similar findings were observed for early exposure to solid foods. These data indicate that early exposure to cow's milk and solid foods may be associated with increased risk of IDDM. The inclusion of HLA-encoded risk in the analyses demonstrates the combined effect of genetic and environmental factors.