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.

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.

Reduced risk of IDDM among breast-fed children. The Colorado IDDM Registry.

The hypothesis that breast-feeding can provide protection against the development of insulin-dependent diabetes mellitus (IDDM) and would, therefore, be less common among subjects with IDDM was tested with a retrospective design. Cases (n = 268) were selected from the Colorado IDDM Registry and the Barbara Davis Center for Childhood Diabetes (Denver, CO). Two control groups were recruited, one from physicians' practices throughout Colorado (n = 291) and the second through random-digit dialing from the Denver area (n = 188). Cases were less likely to have been breast-fed than controls after adjustment for birth year, maternal age, maternal education, family income, race, and sex [adjusted odds ratio (OR) = 0.70; 95% confidence interval (CI) = 0.50-0.97]. This finding was consistent for both control groups and by birth-year intervals. A greater decrease in risk of IDDM was seen among subjects who had been breast-fed to an older age (for breast-feeding duration of greater than or equal to 12 mo, adjusted OR = 0.54, 95% CI = 0.27-1.08). The amount of IDDM that might be explained by breast-feeding habits (population percentage attributable risk) ranged from 2 to 26%, varying according to the breast-feeding prevalence reported in other studies. Replication of this work in different populations, controlled for the strong secular trends in breast-feeding habits, is critical before the hypothesis of protection is accepted.

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.

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.

Clinical characteristics of IDDM in Hispanics and non-Hispanic whites. Little evidence of heterogeneity by ethnicity.

OBJECTIVE: To compare the clinical characteristics of IDDM in HD and NHWD subjects in order to evaluate potential heterogeneity of IDDM by ethnicity. RESEARCH DESIGN AND METHODS: HD subjects (n = 73) and NHWD subjects (n = 97) were recruited from the Colorado IDDM Registry. The registry included individuals who were Colorado residents, less than 18 yr old at diagnosis, placed on insulin within 2 wk of diagnosis, and had diabetes not secondary to other conditions. Residual beta-cell function was measured as the 1-h C-peptide response to a Sustacal challenge. RESULTS: HD subjects were similar to NHWD subjects in insulin dose, HbA1, HLA-DR antigens, ICAs, and family history of IDDM. HD subjects were more likely to have a family history of NIDDM than NHWD subjects (11 vs. 3%, P = 0.03). HD girls had higher C-peptide levels (0.27 vs. 0.11 nm/L [0.83 vs. 0.33 ng/ml], P = 0.01), BMI (22.7 vs. 20.9 kg/m2 P = 0.04), subscapular skinfold thickness (18.9 vs. 15.0 mm, P = 0.04), and WHR (0.81 vs. 0.77, P = 0.03) than NHWD females. After controlling for diabetes duration, BMI, sex, and family history of NIDDM, residual beta-cell function was associated significantly with Hispanic ethnicity, although the term accounted for just 3% of the overall variability in C-peptide levels. CONCLUSIONS: Little evidence of heterogeneity by ethnicity of IDDM patients in the Colorado IDDM Registry was found. Ethnic differences in C-peptide levels may be related to differences in body fat distribution in females rather than heterogeneity of the disease.

Increasing trend of outpatient management of children with newly diagnosed IDDM. Colorado IDDM Registry, 1978-1988.

OBJECTIVE: To examine the management of newly diagnosed insulin-dependent diabetes mellitus (IDDM) in Colorado over time and to determine the prevalence of outpatient care at IDDM diagnosis on a statewide basis. RESEARCH DESIGN AND METHODS: The Colorado IDDM Registry was used to assess medical care at the diagnosis of IDDM in 1182 patients less than 18 yr of age between 1978 and 1988. RESULTS: Twenty-three percent of children with IDDM in Colorado reported never being hospitalized during the diagnosis period. Treatment of IDDM at diagnosis (outpatient vs. inpatient) did not differ by age, sex, or ethnicity/race. Patients living in rural counties were less likely to have been treated as outpatients at diagnosis than those living in urban counties. Physicians at specialized diabetes clinics (e.g., The Barbara Davis Center for Childhood Diabetes and The Childrens Hospital) were more likely to treat newly diagnosed children in an outpatient setting than physicians not affiliated with these clinics. The proportion of patients receiving only outpatient care at IDDM diagnosis increased from 6% in 1978 to 35% in 1988. This increase can be attributed to three factors: 1) an increase in the number of Colorado children diagnosed at The Barbara Davis Center, where outpatient care is strongly advocated; 2) a change in treatment practices at The Childrens Hospital away from routine hospitalization at onset; and 3) a steady increase in outpatient care for newly diagnosed diabetic children by physicians who were not affiliated with the aforementioned specialized diabetes clinics. CONCLUSIONS: The relatively new practice of outpatient care at diagnosis of IDDM increased between 1978 and 1988 in Colorado, in both specialized diabetes clinics and physicians' practices not affiliated with specialized clinics.

Colorado IDDM Registry. Incidence and validation of IDDM in children aged 0-17 yr.

The purpose of this study was to determine the incidence of insulin-dependent diabetes mellitus (IDDM) among children aged 0-17 yr for age, sex, season, and urban and rural residence of onset in Colorado. Retrospective registration of new-onset cases was conducted from 1978 to 1980, and then prospective registration continued through 1983 with the use of physician reporting with hospital validation. The annual incidence of IDDM was 15.2/100,000 per year (95% confidence interval [CI] 14.1, 16.3), with little difference between the sexes. The highest incidence was in the 10- to 14-yr age-group for both sexes. There was a seasonal peak of winter onset in those aged 10-17 yr, with similar patterns between sex and ethnic groups. No temporal trend over the 6 yr was seen, although an excess of cases was seen for 15- to 17-yr-old boys in 1980-1982. Rates were similar for urban and rural areas of the state. Case ascertainment was estimated to be 93.2% complete (95% CI 91.5, 95.5). Incidence was similar in Colorado to other populations in the United States at similar latitudes. These data serve as a baseline for evaluation of changes in incidence over time, by region, and for the identification of possible outbreaks.

Effect of growth hormone on metaphyseal uptake of 99mTc-methylene diphosphonate.

Eight children with short stature and GH deficiency were studied with 99mTc-methylene diphosphate before, during (occasionally), and after 4 months of GH therapy. Using digital images of the femoral shaft and distal metaphysis, the percent change in metaphysis-to-shaft, metaphysis-to-background (muscle), and metaphysis-to-injected dose ratios were calculated and compared to percent change in growth velocity over 4 months. The percent change in metaphysis-to-shaft and metaphysis-to-background ratios showed no significant correlation with percent change in growth velocity. The percent change in metaphysis-to-dose ratio demonstrated a significant correlation with change in growth velocity (r = 0.66; P less than 0.05). In addition, five of six patient studies before 4 months (after 1-68 days of GH therapy) demonstrated an increased metaphysis-to-dose ratio compared to baseline. In conclusion, GH therapy in GH-deficient children appears to increase the uptake of 9mmTc-methylene diphosphonate in the metaphysis, shaft, and muscle to a similar extent, and this increase appears to occur in most patients early after initiation of therapy.

Gonadotropin output and response to LRH administration in congenital virilizing adrenal hyperplasia.

Three premenarchial, 2 primary amenorrheic, and 5 post-menarchial patients with congenital virilizing adrenal hyperplasia (CAH) were examined, utilizing frequent blood sampling techniques and the administration of synthetic luteinizing hormone-releasing hormone (LHRH) to determine whether a normal pattern of gonadotropin output occurs in CAH. Pulsatile gonadotropin output was not observed in premenarchial patients, but was seen in all who had had spontaneous menses. Bone age did not correlate with baseline or episodic gonadotropin output, or with response to LRH, but did reflect the past or present therapeutic control. The normal developmental progression of gonadotropin output was only documented in those patients who had been maintained at doses of suppressive glucocorticoids appropriate for body surface.

Gonadotropin output in congenital adrenal hyperplasia before and after adrenal suppression.

Basal release of gonadotropin and the response to an infusion of 100 mug of synthetic luteinizing hormone releasing hormone (LRH) were studied in a teenage girl with congenital adrenal hyperplasia (CAH). The initial study was done during a period of poor adrenal suppression, and second study was done after adequate adrenal suppression was achieved. To assess adrenal function, circulating levels of adrenal steroid hormones were evaluated continuously over a 24 h period. During the period increased production of adrenal androgens, the pattern of gonadotropin release was that of a prepubertal child. After 3 months of adrenal suppression the pattern of gonadotropin secretion was similar to that of a normal girl in mid-puberty. This demonstrates the rapid change from prepubertal to pubertal gonadotropin dynamics in a teenage patient following adequate suppression of androgens from the adrenal.

Moderate hypocalcemia due to normal serum 1,25-dihydroxyvitamin D levels in an asymptomatic kindred with familial hypoparathyroidism.

Hypoparathyroidism was diagnosed in nine members of a kindred of three generations. This study investigated why these persons were asymptomatic and without developmental abnormalities, in contrast to the common presentation of idiopathic hypoparathyroidism. In the hypocalcemic subjects, serum calcium level was 7.4 +/- 0.8 mg/dl (mean +/- SD) and ionized serum calcium level was 3.48 +/- 0.21 mg/dl. Immunoreactive parathyroid hormone values were inappropriately low. Injection of EDTA in one patient lowered ionized calcium levels, but immunoreactive parathyroid hormone values did not rise. Serum levels of 1,25-dihydroxyvitamin D and other vitamin D metabolites were normal or elevated and substantially higher than in other hypoparathyroid states. The normally observed positive correlation between the fasting urinary calcium/creatinine ratio and serum 1,25-dihydroxyvitamin D that reflects the dependence of net bone resorption on 1,25-dihydroxyvitamin D was upheld in hypoparathyroid patients. It is proposed that the subjects with familial hypoparathyroidism in this kindred had moderate asymptomatic hypocalcemia without developmental abnormalities because normal or elevated serum 1,25-dihydroxyvitamin D levels enhanced intestinal calcium absorption. This may represent one point in the spectrum of idiopathic hypoparathyroidism. Alternately, both the moderate degree of hypocalcemia and the normal serum calcitriol values could have been related to mild, partial hypoparathyroidism, which could have been inherited in this kindred.

Cyclosporine A for the treatment of new-onset insulin-dependent diabetes mellitus.

It is not known whether early immunosuppressive treatment can preserve long-term endogenous insulin secretion in subjects with insulin-dependent diabetes mellitus. In the present study, clinical remissions during the first year and C-peptide production for 3 years were followed after 43 subjects with newly diagnosed insulin-dependent diabetes mellitus were randomly assigned to a cyclosporine A treatment group for 4 months or to a control group. Of the six cyclosporine A-treated subjects who had remissions, five were 19 years of age or younger, compared with two of the four in the control group. C-peptide production was present in 98% of all subjects after 4 months, in 88% after 1 year, and in 43% after 3 years. There were no significant differences in numbers of subjects with C-peptide production or in mean hemoglobin A1 levels, between cyclosporine A-treated and control subjects after 3 years. Cyclosporine A treatment of subjects with newly diagnosed insulin-dependent diabetes mellitus for a period of 4 months does not have the ability to preserve residual beta-cell function.

Effect of hypophysectomy and hormonal replacement on the uptake of Tc-99m methylene diphosphonate in the metaphysis and shaft of the rat femur: concise communication.

We have investigated the uptake of Tc-99m methylene diphosphonate (Tc-MDP) in the metaphysis and shaft of the rat femur as affected by hypophysectomy and hormonal replacement with growth hormone and thyroxine. Two hours following injection of Tc-MDP, the metaphysis and a specimen of shaft were obtained and the metaphysis-to-shaft radioactivity ratio was measured. By five days after hypophysectomy the metaphysis-to-shaft ratio fell from a control value of 3.8 +/- 0.2 (mean +/- s.e.) to 2.4 +/- 0.2 (p less than 0.05) and remained significantly decreased throughout the 30-day study. When daily hormonal replacement with 0.5 mg of bovine growth hormone and 10 micrograms of thyroxine (both administered intraperitoneally) was given, beginning on the eighth day after hypophysectomy, the metaphysis-to-shaft ratio of Tc-MDP returned to control levels in twelve days. This model demonstrates the effect of growth hormone and thyroxine on the distribution of Tc-MDP, and may be useful as a radiobioassay of net circulating skeletal growth-promoting activity.

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.

Secondary surgical treatment of the masculinized external genitalia of patients with virilizing adrenal hyperplasia.

Among 84 patients with virilizing adrenal hyperplasia operated on for deformed genitalia and followed for 7 to 22 years (mean 12 9/12 yr), 25 (30%) required secondary operations. For the most part, the secondary procedures were to provide a vaginal orifice adequate for coitus. The difficulties were due either to failure to adequately exteriorize the orifice at the first operation or to contraction of the outlet due to scar formation. Simple operative procedures to correct these difficulties are described.

Performance of seven blood glucose testing systems at high altitude.

Consumers and health care professionals expect blood glucose monitoring systems to consistently generate results that are close to actual blood glucose levels. Numerous environmental, physiologic, and operational factors can affect system performance, yielding results that are inaccurate or unpredictable. This study examined the effect of one factor--high altitude--on the performance of seven blood glucose monitoring systems. One of the systems overestimated blood glucose results; the other six systems underestimated blood glucose values (more than the expected variance). The findings of this study support previous reports of altered blood glucose monitoring system performance at high altitude. Diabetes educators can use this information when counseling consumers who reside or who plan to visit locations at high altitude.

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.