ABSTRACT
Autoimmune diabetes shows extreme variation in age of onset and clinical presentation, although most studies have been done in children with the most severe subtype. Disease risk is strongly associated with HLA-DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2), but it has not been possible to separate the effects of the DR and DQ alleles. We have identified a large Bedouin kindred in which a high prevalence of islet autoimmunity is associated with two different DR3 haplotypes, one carrying the usual DQ2 and the other carrying DQA1*0102-DQB1*0502 (DQ5). Results of prospective follow-up studies indicate that DR3 is associated with the initial activation of islet autoimmunity whereas DQ2 is associated with early-onset and severe clinical disease. The association signals map to a 350-kb interval, thus implicating primary effects for DR3 and DQ2. Overall, our results emphasize the importance of prospective genetic studies that examine the full range of variation in the initiation, progression and expression of autoimmune disease.
Subject(s)
Autoimmunity/genetics , Diabetes Mellitus, Type 1/genetics , Genetic Predisposition to Disease , HLA-DQ Antigens/genetics , HLA-DR Antigens/genetics , Islets of Langerhans/immunology , Adolescent , Adult , Age of Onset , Aged , Arabs/genetics , Child , Child, Preschool , Female , Gene Frequency , HLA-DQ alpha-Chains , HLA-DQ beta-Chains , HLA-DRB1 Chains , Haplotypes , Humans , Infant , Infant, Newborn , Male , Middle AgedABSTRACT
AIMS/HYPOTHESIS: Our aim was to evaluate insulin autoantibody (IAA) levels over time in the Diabetes Prevention Trial Type 1 (DPT-1) oral insulin study to determine the effect of oral insulin compared with placebo on IAA levels. SUBJECTS AND METHODS: The DPT-1 trial randomised 372 relatives of subjects with type 1 diabetes, positive for IAA and with normal IVGTTs and OGTTs, to oral insulin 7.5 mg daily or placebo. Subjects were followed with IVGTTs, OGTTs and serial IAA measurements. The change in IAA level over time was modelled statistically using mixed model longitudinal data analysis with spatial exponential law for unevenly spaced data. In a separate analysis, subjects were divided into four groups by treatment and diabetes status at the end of the study. IAA levels were compared amongst the groups at randomisation, last sampling and at the maximum level. RESULTS: Longitudinal data analysis showed that treatment did not affect levels of IAA over time. After controlling for age, the IAA levels at randomisation and the last visit and the maximum values were different in the four groups. Significantly higher levels were noted in groups that developed diabetes compared with those that did not, with no significant difference by treatment group. CONCLUSIONS/INTERPRETATION: This suggests that IAA levels over time were not influenced by oral insulin in subjects already positive for IAA at the start of treatment.
Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Insulin Antibodies/blood , Insulin/therapeutic use , Administration, Oral , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/prevention & control , Female , Glucose Tolerance Test , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Insulin/administration & dosage , Insulin/immunology , Male , Time FactorsABSTRACT
Progression of renal disease and cardiovascular complications in type II diabetes mellitus have been shown to correlate with control of blood glucose, lipids, blood pressure, and smoking. These factors, however, do not appear to totally explain these diabetic complications. Renal disease and cardiovascular complications in type II diabetes are associated with vascular abnormalities and fibrosis, both of which may occur with impaired fibrinolysis. A cross-sectional study was therefore performed in 107 type II diabetic patients recruited from the Denver Metropolitan Area to examine the effect of impaired fibrinolysis, as assessed by the ratio of plasminogen activator inhibitor (PAI-1) to tissue-type plasminogen activator (t-PA). With urinary albumin excretion (UAE) as a risk factor for both renal disease progression and cardiovascular complications, the patients were analyzed with respect to UAE less than and greater than 1 gm/day. The age, blood glucose, hemoglobin A1C, duration of diabetes, lipids, body mass index, and smoking were no different between the groups. As expected, the group with greater UAE had worse renal function, the serum creatinine (1.98 +/- 0.24 vs 1.21 +/- 0.05 mg/dl, P < 0.001) and creatinine clearance (55.5 +/- 6.0 vs 76.8 +/- 2.7 ml/min, P < 0.001) were significantly different. The type II diabetic patients with greater UAE exhibited significantly higher PAI-1/t-PA (2.43 +/- 0.26 vs 1.85 +/- 0.07, P < 0.03). The past history of cardiac complications was also higher (87.5 vs 72.3%, P < 0.07) in the diabetic patients with more impaired fibrinolysis and greater UAE. Thus a prospective, randomized clinical trial in type II diabetes with PAI-1 inhibitors is needed.