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G Klingensmith

Publications and source records attributed to G Klingensmith.

14 recordsLinked to original sources
PubMed1996

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.

Animals↗
PubMed1996

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.

Alleles↗
PubMed1996

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.

Asian People↗
PubMed1996

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.

Adolescent↗
PubMed1994

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.

Adolescent↗
PubMed1993

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.

Adult↗
PubMed1992

Detection of cell-mediated immunity in type I diabetes mellitus.

Type I insulin dependent diabetes mellitus (IDDM) is thought to result from chronic, cell-mediated, 'autoimmune' islet damage. Antibody testing is extensively used to define and follow the pre-diabetic population. However, the assay for cell mediated immunity (CMI) should be more predictive of impending disease. This report shows that it is possible to detect human islet reactive CMI in the IDDM patient. Groups of athymic CD-1 nu/nu mice were injected intraperitoneally with either mononuclear blood cells (MBCs) or plasma from 10 newly diagnosed Type I diabetic patients and 10 normal control subjects. Both glycemic control and histopathology were used to assay islet specific CMI in diabetic individuals. None of the injected mice showed any impairment of glycemic control. However, MBCs from six of 10 diabetic patients, but from none of the 10 normal subjects, induced significant mononuclear cell infiltrate in the pancreas of the recipient mice (P = 0.005). The infiltrate was focused on the islet tissue and no damage was seen in control tissues. No histological abnormalities were observed when plasma was transferred. We conclude that cellular reactivity seen in this model is tissue specific and disease associated. Our findings provide evidence that CMI to human islet tissue can be detected in IDDM patients.

Adolescent↗
PubMed1992

Outpatient management vs in-hospital management of children with new-onset diabetes.

The long-term results of outpatient management of subjects with newly diagnosed insulin-dependent diabetes mellitus (IDDM) are unknown. The longest follow-up described to date is for only one year, a time when most children with IDDM still make endogenous insulin. In this study, 41 young subjects with IDDM, treated and educated in the outpatient setting (1980 to 1984), were compared to a group of 80 similar subjects who received their initial education as hospital inpatients. Long-term glycemic control, as measured by longitudinal glycohemoglobin (HbA1) values was not different in the two groups (p greater than .05). We conclude that outpatient education and management of newly diagnosed subjects with IDDM is as safe and effective as inpatient treatment.

Adolescent↗
PubMed1992

Accuracy of a filter paper method for measuring glycosylated hemoglobin.

OBJECTIVE: To compare glycosylated hemoglobin (GH) results obtained by filter paper fingerstick collection and mailed for assay by affinity chromatography with results from a venous sample assayed by ion-exchange chromatography (HbA1) in a local laboratory. RESEARCH DESIGN AND METHODS: Fifty-eight volunteer subjects with insulin-dependent diabetes mellitus (IDDM), aged 5-24 yr, included patients at a referral-based IDDM clinic and subjects in an ongoing research study. We obtained two blood samples from each subject. One was collected by fingerstick onto filter paper, the other by venipuncture into a vacutainer. We sent filter paper samples to the Diabetes Research Laboratory (Univ. of Missouri, Columbia, MO) for analysis. Vacutainer samples were sent to the Clinical Chemistry Department of the Clinical Laboratory, University of Colorado Health Sciences Center. RESULTS: Results were highly correlated (r = 0.89, P = 0.0001). Fifty-nine percent were classified identically when results were normalized to SD units and grouped to suggest levels of clinical concern. CONCLUSIONS: The filter paper method is a convenient, accurate measure of glycosylated hemoglobin in young people with IDDM. It should be considered a credible alternative research and clinical tool.

Adolescent↗
PubMed1991

Prediction of the course of pre-type I diabetes.

To increase knowledge on the predictability of the onset of insulin-dependent diabetes mellitus (IDDM; type I), we followed 38 subjects less than 18 years of age who had positive results on two or more islet-cell antibody tests and one identical twin who had positive results on one islet-cell antibody test. All 39 patients had longitudinal intravenous glucose tolerance tests to determine the first-phase insulin response (FPIR). Insulin dependence has developed in 10 untreated subjects less than 18 years of age. Of the 10 subjects, insulin dependence developed in eight a mean of 4.6 months after their FPIR fell to less than 30 microU/ml and a mean of 14 months after it fell to less than 46 microU/ml. Nine of the untreated subjects had an FPIR less than 67 microU/ml on at least two occasions and became insulin dependent a mean of 19 months after the value first fell below this level (95% confidence limit = 66.4% to 100%). All but one of the 10 subjects in whom IDDM developed initially had islet-cell antibody levels of greater than 80 JDF units. Insulin autoantibody values at onset were available for 9 of the 10 subjects and were positive (greater than 39 nU/ml) in six. We conclude that the combination of positive results on two islet-cell antibody tests and two diminished FPIRs (less than 67 microU/ml) in subjects less than 18 years of age reliably predicts the onset of IDDM. These data should permit intervention studies to be planned.

Adolescent↗
PubMed1975

Evaluation of growth hormone release in children using arginine and L-dopa in combination.

L-Dopa in a dose ranging from 125-500 mg and arginine monochloride in a dose of 0.5 gm/kg were given simultaneously to 56 children with short stature (height less than third percentile). Sixteen of these children were subsequently diagnosed as having growth hormone deficiency. The diagnosis of hyposomatotropism was based on clinical findings and on responses to the combination test and to arginine and L-dopa administered as separate tests. All of the remaining 40 children had a normal GH response of greater than 6 ng/ml to the combination test. However, in this group, nine children were identified who responded to the combination test but who failed to respond to arginine and L-dopa in individual tests. The data suggest that a positive response to arginine and L-dopa in combination in children, who do not respond to the usual provocative tests when administered individually, may fail to identify children with partial GH deficiency who would benefit from treatment. The integrated stimulated GH response in the 31 children in whom a normal GH response to all three tests occurred suggests that the effects of L-dopa and arginine are additive.

Adolescent↗
PubMedDate not supplied

Colorado IDDM Registry: lower incidence of IDDM in Hispanics. Comparison of disease characteristics and care patterns in biethnic population.

The Colorado IDDM Registry identifies newly diagnosed cases of insulin-dependent diabetes mellitus (IDDM) throughout the state. Hispanics in Colorado are a racial mixture of American Indian and White populations. Because American Indians have a low risk of IDDM, and differing frequencies of HLA antigens and haplotypes are reported for Hispanics and non-Hispanics, we compared incidence rates and disease characteristics. Eligible participants were less than 18 yr of age and Colorado residents at time of diagnosis, diagnosed between 1 January 1978 and 31 December 1983, and on insulin within 2 wk of diagnosis. Subjects were reported by their physicians, and statewide validation of reporting was conducted through review of hospital discharge indexes. Incidence rates for Hispanics (n = 76) were significantly lower than those for non-Hispanics (n = 628), although 95% confidence intervals overlapped for children aged 10-17 yr. Age-adjusted rates were significantly lower in Hispanic than non-Hispanic males, whereas age-adjusted rates for females did not differ. The cumulative risk of IDDM was less for Hispanic males aged 0-17 yr than for non-Hispanic males (P less than .001); cumulative risk among females was males (P less than .001); cumulative risk among females was not different (P = .10). Clinical onset characteristics and medical care at diagnosis were similar. After diagnosis, hospitalizations per 100 person-yr appeared higher in Hispanics, but ketoacidosis and insulin reactions per 100 person-yr were similar. Difference in rate of hospitalizations may have been due to lower response rates among older non-Hispanics.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Medical care patterns at the onset of insulin-dependent diabetes mellitus: association with severity and subsequent complications.

The hospitalization of a child at the onset of insulin-dependent diabetes mellitus (IDDM) has become routine in many parts of the world, although controversy exists about its necessity. We examined the patterns of medical care use and the prognosis for acute complications after diagnosis for children with newly diagnosed IDDM in Colorado from 1978 to 1982. We reasoned that if children cared for entirely in outpatient settings at diagnosis had no more frequent acute complications after diagnosis than hospitalized children, we would be encouraged to further explore other potential benefits of outpatient care at onset. Twelve percent of 305 children studied statewide received only outpatient care during the first 2 wk after diagnosis, and, prognostically, their subsequent hospitalization and ketoacidosis rates were 2-3.7 times lower than those of children who received any inpatient care. No differences were noted for severe insulin reaction rates. Children classified as "severe" at onset, or with parents of lower education and income, or aged 10-14 yr at onset, regardless of care setting, had 2-4 times higher subsequent acute complication rates after onset than children without these characteristics. These findings, together with data on nights hospitalized and average length of stay in hospital at onset, suggest that a 42% reduction in total nights hospitalized could occur if children with "mild" or "normal" severity at onset were treated largely in the outpatient setting.

Acidosis↗