Biomedical subjects

Jennifer M Barker

Publications and source records attributed to Jennifer M Barker.

12 recordsLinked to original sources

PubMed2007

Pre-type 1 diabetes dysmetabolism: maximal sensitivity achieved with both oral and intravenous glucose tolerance testing.

OBJECTIVE: To determine the relationship of intravenous (IVGTT) and oral (OGTT) glucose tolerance tests abnormalities to diabetes development in a high-risk pre-diabetic cohort and to identify an optimal testing strategy for detecting preclinical diabetes. STUDY DESIGN: Diabetes Prevention Trial-Type 1 Diabetes (DPT-1) randomized subjects to oral (n = 372) and parenteral (n = 339) insulin prevention trials. Subjects were followed with IVGTTs and OGTTs. Factors associated with progression to diabetes were evaluated. RESULTS: Survival analysis revealed that higher quartiles of 2-hour glucose and lower quartiles of first phase insulin response (FPIR) at baseline were associated with decreased diabetes-free survival. Cox proportional hazards modeling showed that baseline body mass index (BMI), FPIR, and 2-hour glucose levels were significantly associated with an increased hazard for diabetes. On testing performed within 6 months of diabetes diagnosis, 3% (1/32) had normal FPIR and normal 2-hour glucose on OGTT. The sensitivities for impaired glucose tolerance (IGT) and low FPIR performed within 6 months of diabetes diagnosis were equivalent (76% vs 73%). CONCLUSIONS: Most (97%) subjects had abnormal IVGTTs and/or OGTTs before the development of diabetes. The highest sensitivity is achieved using both tests.

Administration, Oral↗

PubMed2006

Extreme genetic risk for type 1A diabetes.

Type 1A diabetes (T1D) is an autoimmune disorder the risk of which is increased by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. The genotype associated with the highest risk for T1D is the DR3/4-DQ8 (DQ8 is DQA1*0301, DQB1*0302) heterozygous genotype. We determined HLA-DR and -DQ genotypes at birth and analyzed DR3/4-DQ8 siblings of patients with T1D for identical-by-descent HLA haplotype sharing (the number of haplotypes inherited in common between siblings). The children were clinically followed with prospective measurement of anti-islet autoimmunity and for progression to T1D. Risk for islet autoimmunity dramatically increased in DR3/4-DQ8 siblings who shared both HLA haplotypes with their diabetic proband sibling (63% by age 7, and 85% by age 15) compared with siblings who did not share both HLA haplotypes with their diabetic proband sibling (20% by age 15, P < 0.01). 55% sharing both HLA haplotypes developed diabetes by age 12 versus 5% sharing zero or one haplotype (P = 0.03). Despite sharing both HLA haplotypes with their proband, siblings without the HLA DR3/4-DQ8 genotype had only a 25% risk for T1D by age 12. The risk for T1D in the DR3/4-DQ8 siblings sharing both HLA haplotypes with their proband is remarkable for a complex genetic disorder and provides evidence that T1D is inherited with HLA-DR/DQ alleles and additional MHC-linked genes both determining major risk. A subset of siblings at extremely high risk for T1D can now be identified at birth for trials to prevent islet autoimmunity.

Adolescent↗

PubMed2006

Clinical review: Type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening.

CONTEXT: Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AIT), celiac disease (CD), Addison's disease (AD), and other autoimmune diseases. These diseases can occur together in defined syndromes with distinct pathophysiology and characteristics: autoimmune polyendocrine syndrome I, autoimmune polyendocrine syndrome II, and the immunodysregulation polyendocrinopathy enteropathy X-linked syndrome. EVIDENCE ACQUISITION: Review of the medical literature was performed with particular attention to the natural history, genetic factors, and syndromes associated with T1D, AIT, CD, and AD. EVIDENCE SYNTHESIS: Genetic risk for these diseases overlaps and includes genes within the major histocompatibility complex (MHC) such as the human leukocyte antigens (HLA) DR and DQ alleles and the MHC I-related gene A (MIC-A). Other genes outside of the MHC have been associated with these autoimmune diseases, including the gene encoding the lymphoid tyrosine phosphatase (PTPN22) and the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene. CONCLUSION: Genetic risk for T1D overlaps with AIT, CD, and AD. Disease risk is associated with organ-specific autoantibodies, which can be used to screen subjects with T1D.

Adrenal Gland Diseases↗

PubMed2006

Gonadal hormone modulation of hippocampal neurogenesis in the adult.

Gonadal hormones modulate neurogenesis in the dentate gyrus (DG) of adult rodents in complex ways. Estradiol, the most potent estrogen, initially enhances and subsequently suppresses cell proliferation in the dentate gryus of adult female rodents. Much less is known about how estradiol modulates neurogenesis in the adult male rodent; however, recent evidence suggests that estradiol may have a moderate effect on cell proliferation but enhances cell survival in the DG of newly synthesized cells but only when estradiol is administered during a specific stage in the cell maturation cycle in the adult male rodent. Testosterone likely plays a role in adult neurogenesis, although there have been no direct studies to address this. However, pilot studies from our laboratory suggest that testosterone up-regulates cell survival but not cell proliferation in the DG of adult male rats. Progesterone appears to attenuate the estradiol-induced enhancement of cell proliferation. Neurosteroids such as allopregnalone decrease neurogenesis in adult rodents, while pregnancy and motherhood differentially regulate adult neurogenesis in the adult female rodent. Very few studies have investigated the effects of gonadal hormones on male rodents; however, studies have indicated that there is a gender difference in the response to hormone-regulated hippocampal neurogenesis in the adult. Clearly, more work needs to be done to elucidate the effects of gonadal hormones on neurogenesis in the DG of both male and female rodents.

Animals↗

PubMed2006

Prevention strategies for type 1 diabetes.

Type 1 diabetes (T1D) is a common chronic disease of childhood. Patients with T1D are at significant risk for developing serious health complications. Understanding of the genetics, environmental factors, and natural history of diabetes has lead to greater understanding of the etiology and epidemiology of T1D. Furthermore, technology has greatly improved glycemic control and reduction of complications. However, prevention of the development of diabetes remains elusive. This review article describes the past, current and upcoming strategies for diabetes prevention for patients at risk for developing autoimmunity, after antibody production, and patients with new onset diabetes.

Autoimmunity↗

PubMed2005

Genetic prediction of autoimmunity: initial oligogenic prediction of anti-islet autoimmunity amongst DR3/DR4-DQ8 relatives of patients with type 1A diabetes.

In this study, the combined risk for expressing anti-islet autoantibodies and type 1A diabetes (T1D) was prospectively examined in 85 sampled relatives who had the high-risk HLA genotype (DR3-DQ8 DR4-DQ2). An insulin gene polymorphism, -23 HphI, and a lymphocyte tyrosine phosphatase gene polymorphism at position 1858C>T (amino acid 620 Arg to Trp), PTPN22/LYP, were analyzed. Life tables were created evaluating time to anti-islet autoantibody development and T1D. Of relatives with the high-risk HLA type followed for 3years, 9 of 43 (28.1%) with the high-risk -23 HphI polymorphism developed anti-islet autoantibodies versus two of 36 (5.6%) relatives with the lower-risk -23 HphI genotypes (p=0.048). Of relatives with the high-risk HLA type followed for 5years, eight of 32 (25.0%) with the high-risk -23 HphI polymorphism (A/A) developed T1D versus zero of 26 (0%) relatives with the lower-risk -23 HphI genotypes (A/T and T/T) (p=0.006). The PTPN22/LYP polymorphism, with genotypes C/C, C/T, and T/T, did not show a significant difference in risk by genotype. These results highlight the multiplicative risk of combined high-risk genotypes at different loci in terms of time to autoantibody and autoimmune disease development.

Adolescent↗

PubMed2005

Polyendocrine autoimmunity.

Autoimmune polyendocrine disorders are characterized by the presence of more than one autoimmune endocrine disease. Study of such disorders has provided unique insight into the pathogenesis of autoimmunity and the development of tolerance in the normal individual. Autoimmune polyendocrine syndromes I and II have distinctive inheritance patterns, genetic causes, component diseases, and implications for follow-up. Care for individuals with these diseases requires monitoring for additional autoimmune disorders and aggressive treatment of identified diseases to prevent morbidity and mortality in affected individuals.

Autoimmune Diseases↗

PubMed2005

Preparing for winter: divergence in the summer-autumn hematological profiles from representative species of the squirrel family.

We examined hematological parameters in four related sciurid species in the late summer-autumn to assess the role of habitat, elevation, body size, and behavior in shaping these parameters. Red squirrels (Tamiasciurus hudsonicus) and Arctic ground squirrels (Spermophilus parryii) were sampled in southwestern Yukon, yellow-pine chipmunks (Tamias amoenus) in southern Alberta, and the eastern grey squirrel (Sciurus carolinensis) in southern Ontario. We obtained whole blood samples from each species and compared glucose levels, red blood cell characteristics (hematocrit, red blood cell count, hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration), and white blood cell counts (neutrophils, lymphocytes, monocytes, eosinophils, basophils) across species. We found species differences in glucose and red blood cell characteristics that may be a function of activity levels, phylogeny, or elevation, but not of body size, body condition, or adaptations to a semi-fossorial habitat. We also found species differences in white blood cell counts that remain unexplained by any single simple explanation and may be more useful for comparison of individuals within a given species than for interspecies comparisons.

Animals↗

PubMed2005

Autoantibody "subspecificity" in type 1 diabetes: risk for organ-specific autoimmunity clusters in distinct groups.

OBJECTIVE: Autoimmune thyroid disease (AIT), celiac disease, and Addison's disease are characterized by the presence of autoantibodies: thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb) in AIT, tissue transglutaminase antibody (TTGAb) in celiac disease, and 21-hydroxylase antibody (21-OHAb) in Addison's disease. The objective of this study was to define the prevalence of these autoantibodies and clinical disease in a population with type 1 diabetes. RESEARCH DESIGN AND METHODS: We screened 814 individuals with type 1 diabetes for TPOAb, TGAb, TTGAb, and 21-OHAb. Clinical disease was defined by chart review. Factors related to the presence of autoimmunity and clinical disease including age at onset of type 1 diabetes, duration of diabetes, age at screening, sex, and the presence of autoantibodies were reviewed. RESULTS: The most common autoantibodies expressed were TPOAb and/or TGAb (29%), followed by TTGAb (10.1%) and 21-OHAb (1.6%). Specific HLA DR/DQ genotypes were associated with the highest risk for expression of 21-OHAb (DRB1*0404-DQ8, DR3-DQ2) and TTGAb (DR3-DQ2- DR3-DQ2). The expression of thyroid autoantibodies was related to 21-OHAb but not to TTGAb. The presence of autoantibodies was associated with and predictive of disease. CONCLUSIONS: In this large cohort of individuals with type 1 diabetes, the expression of organ-specific autoantibodies was very high. The grouping of autoantibody expression suggests common factors contributing to the clustering.

Adolescent↗

PubMed2004

Endocrine and immunogenetic testing in individuals with type 1 diabetes and 21-hydroxylase autoantibodies: Addison's disease in a high-risk population.

Individuals with type 1 diabetes mellitus (T1D) at risk for Addison's disease (AD) can be identified with RIAs for autoantibodies to the adrenal antigen 21-hydroxylase (21-OHAA). Screening individuals with T1D for 21OH-AA shows a relatively high prevalence of positive autoantibodies (1.4%, 38 of 2696 subjects). After detection of 21-OHAA, individuals were evaluated with endocrine testing, including baseline cortisol, ACTH, and plasma renin activity and low (1 mug) and high (250 mug) dose cortrosyn stimulation. Typing for DR and DQ alleles and for the major histocompatibility complex class I-related chain A (MICA) gene polymorphisms was performed. Six individuals were diagnosed with AD; five were identified on initial endocrine evaluation. Follow-up over 2.9 yr yielded one additional diagnosis of AD. Endocrine testing showed a correlation between baseline ACTH and peak cortisol (r = -0.61; P < 0.0001), baseline and peak cortisol (r = 0.70; P < 0.0001), and stimulated cortisol after low- and high-dose testing (r = 0.92; P < 0.0001). DR3-DQ2/DR4-DQ8 with DRB1* 0404 was associated with expression of 21-OHAA. At 2 yr, individuals homozygous for MICA5.1 had AD-free survival of 60% compared with 100% AD-free survival in those who were not homozygous for MICA5.1. Homozygosity for MICA5.1 may increase progression to overt AD among 21-OHAA-positive individuals.

Addison Disease↗

PubMed2004

Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY).

Diabetes Autoimmunity Study in the Young (DAISY) has followed 1972 children for islet autoimmunity and diabetes: 837 first-degree relatives of persons with type 1 diabetes and 1135 general population newborns identified through human leukocyte antigen (HLA) screening. During follow-up of 4.06 yr (range, 0.17-9 yr), serial determination of autoantibodies to glutamic acid decarboxylase, protein tyrosine phosphatase IA2, and insulin has generated approximately 20,000 results. Among 162 children with at least one positive autoantibody, in 31% the test was false positive (autoantibodies were negative twice on blinded duplicate aliquots), in 31% it was transiently positive (confirmed on blinded duplicate aliquots but negative on follow-up), and in 36% it was persistently positive. Using proportional hazards modeling, the HLA-DR3/4 DQ8 genotype, another positive autoantibody at the first positive visit, and level of autoantibody were predictive of persistent positivity. Only HLA-DR3/4 DQ8 genotype was predictive of progression to diabetes in proportional hazards modeling. This prospective study reveals that cross-sectional determination of islet autoantibodies in a population with relatively low previous probability of autoimmunity identifies as "positive" a large number of individuals who are either false or transiently positive. Predictive value of autoantibodies increases with blinded duplicate and independent sample retesting and incorporation of the level of autoantibody in the predictive algorithm.

Autoantibodies↗

PubMed2004

Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up.

OBJECTIVE: The objective of this study was to determine whether earlier diagnosis of diabetes in prospectively followed autoantibody-positive children lowered onset morbidity and improved the clinical course after diagnosis. RESEARCH DESIGN AND METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) follows genetically at-risk children for the development of diabetes. Increased genetic risk is identified by family history of type 1 diabetes or expression of diabetes-associated HLA genotypes. Of the 2,140 prospectively followed children, 112 have developed islet autoantibodies and 30 have progressed to diabetes. Diabetes onset characteristics and early clinical course of these 30 children followed to diabetes were compared with those of 101 age- and sex-matched children concurrently diagnosed with diabetes in the community. RESULTS: Pre-diabetic children followed to diabetes were less often hospitalized than the community cases (3.3 vs. 44%; P < 0.0001). They had a lower mean HbA(1c) at onset (7.2 vs. 10.9%; P < 0.0001) and 1 month after diagnosis (6.9 vs. 8.6%; P < 0.0001) but not after 6 months of diabetes. The mean insulin dose was lower in the DAISY group at 1 (0.30 vs. 0.51 U. kg(-1). day(-1); P = 0.003), 6 (0.37 vs. 0.58; P = 0.001), and 12 months (0.57 vs. 0.72; P = 0.03). There was no difference in growth parameters between the two groups. Comparisons limited to children with a family history of type 1 diabetes in both groups showed a similar pattern. CONCLUSIONS: Childhood type 1 diabetes diagnosed through a screening and follow-up program has a less severe onset and a milder clinical course in the first year after diagnosis.

Autoantibodies↗