Siblings Of Type Research Articles

Age-corrected empirical genetic risk estimates for first-degree relatives of IDDM patients.

The families of 554 type I (insulin-dependent) diabetics were genetically analyzed according to probands' sex and age at onset applying a modification of Strömgren's method of age correction. Lifetime recurrence risk of type I diabetes (risk up to age 80 yr) for first-degree relatives in three consecutive generations was calculated. The overall risk (+/- 1 SE) for siblings was 6.6 +/- 1.1% and for children was 4.9 +/- 1.7%. The similar risks among siblings and children argue against a simple autosomal recessive trait. The results do not permit a conclusion about a distinct mode of inheritance. Regardless of age at onset, offspring of male probands always had a higher risk than offspring of female probands. Among all probands, fathers were significantly more often affected with type I diabetes (about twice) than mothers (4.1 +/- 0.9 vs. 1.7 +/- 0.6%, respectively). The risk for further siblings of the proband was significantly increased in the presence of a type I diabetic parent (25.2 +/- 10.3 vs. 5.8 +/- 1.0% for remaining probands), indicating a nonrandom clustering type I diabetes in families. Younger age at onset (less than 25 yr) was not associated with an increased risk to siblings. Type II diabetes was not more frequent among parents and siblings of type I diabetics than in the general population. The calculated risk estimates are of practical value in genetic counseling and are important for genetic models concerning type I diabetes.

DNA polymorphisms of the insulin receptor gene and non-insulin-dependent diabetes mellitus.

Non-insulin-dependent (Type II) diabetes mellitus has a strong familial basis with 100% concordance being observed in identical twins [1] and up to 40% of siblings of Type II diabetics may develop abnormal glucose tolerance, assuming survival to 80 years [2]. Nevertheless, these and other studies have failed to show a pattern of inheritence conforming to a simple Mendelian hypothesis. Additionally, environmental influences, particularly obesity, are crucial to the phenotypic expression of the condition in predisposed subjects.

AUTOANTIBODY MARKERS FOR INSULITIS IN THE FAMILIES OF INSULIN DEPENDENT DIABETICS

If specific markers for juvenile diabetes could be identified then future susceptible individuals could be recognised. Auto-antibodies to Islet Cells (ICA) and to insulin (IAA) were sought in 81 healthy, and insulin-naive siblings (38 boys, 43 girls) of childhood Type 1 diabetics by immunofluorescence on cryocut human group O pancreas and by enzyme linked immunosorbent assay respectively. ICA were found in 9 (11.1%) siblings (age range 5 - 22 years) and IAA in 6 (7.4%) (age range 3-13 years). None of the ICA positive siblings were IAA positive. IAA binding was clearly high (mean 21.8% - SD 6.8%: Normals 3.2 ± 2.0%). IAA positive siblings were significantly younger than those who were negative and showed a female preponderance (5F : 1M). These pilot data suggest that either IAA and ICA are markers for subtypes of autoimmune insulitis or (as we have previously proposed) IAA are markers for genetic susceptibility while ICA indicate active insulitis.

Anti-insulin antibodies in children with type I diabetes mellitus. Genetic regulation of production and presence at diagnosis before insulin replacement.

We evaluated the production of antibodies against insulin in a genetically well-defined population. In the first study, 124 young patients with type I diabetes for longer than 6 mo were included. Anti-insulin antibodies were detected by polyethyleneglycol (PEG) precipitation after incubation of acidified, charcoal-stripped sera with 125I-labeled pork insulin and were expressed as microunits insulin bound per milliliter whole serum. For comparison, the patients were divided into six groups based on HLA DR antigens: 3/3, 3/-, 4/4, 4/-, 3/4, and -/-(-is non-DR3 or -DR4). The mean age of the patients was 14.7 +/- 0.5 yr; the duration of diabetes was 5.8 +/- 0.4 yr; and the glucose control, as measured by hemoglobin A1c was average (7.6 +/- 0.2%). There were no significant differences in any of these parameters among the patients in any of the HLA DR groups. Patients expressing DR3/3 had significantly lower insulin binding than the rest of the groups (2.5 +/- 0.4 vs. 13.6 +/- 1.4 microU/ml, P less than 0.0001). Patients with DR3/ - did not differ in insulin-binding capacity from the other groups. The type of insulin used for replacement was not correlated with the serum insulin-binding capacity. In a second study, sera from 48 children, newly diagnosed with type I diabetes, were examined for the presence of insulin binding before treatment with exogenous insulin and compared with sera from 80 children without diabetes or a family history of diabetes and from 103 unaffected HLA-identical or haploidentical siblings of a child with type I diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose tolerance in siblings of type 1 diabetic patients: relationship to HLA status.

In this report, we present an analysis of glucose and insulin responses during oral glucose tolerance tests in 369 siblings of Type 1 diabetic patients. All have been HLA typed at the A, B and C loci. Though most had normal glucose tolerance by National Diabetes Data Group criteria (92% of the males and 95% of the females), siblings who shared both HLA haplotypes with the diabetic patient in the family had higher mean 3-hour glucose areas than those who shared one or neither HLA haplotype (p less than 0.01). This difference was more marked in males and older siblings. Insulin concentrations did not differ significantly between the two groups except that, for those aged less than 16 years, the group sharing both haplotypes had lower fasting insulin concentrations (p = 0.05); for 16-29 year olds, the corresponding group had marginally higher 3-hour insulin areas than the remainder of siblings (p = 0.17). Little association with specific haplotypes (A1B8 or A2B15) was seen. Multivariate analyses, adjusting for age and obesity, eliminated the 3-h glucose difference in females by HLA sharing status (p = 0.37) although in males it remained significant (p less than 0.001). Failure to account for age, sex and obesity may explain some of the conflicts in the reported literature. The glucose tolerance differences seen by HLA haplotype sharing status did not correlate with the presence of anti-islet cell antibodies. These results are consistent with the hypothesis that the HLA identical siblings, particularly males, have different (i.e. worse) glucose tolerance than their haploidentical and non-HLA identical siblings.

Epidemiological aspects of the natural history of childhood diabetes.

Studies in identical twins have shown only a 50% concordance for type 1 diabetes, indicating that environmental factors are of major importance. Prospective studies in twins and siblings of type 1 diabetics provide evidence of a long prediabetic phase. Environmental factors, inducing a pathological immune response in genetically susceptible individuals, may thus act long before the clinical onset. In Sweden a high and increasing incidence of childhood diabetes has been shown, with peak incidence rates at puberty in both boys and girls. The incidence rate is higher for boys than for girls. Significant geographical and seasonal variations are clearly indicated. The epidemiology of lost beta-cell function shortly after clinical onset differs significantly from the epidemiology of clinical onset as to sex and geographical and seasonal distribution. Environmental factors that affect the clinical onset of type 1 diabetes may thus differ from factors affecting the beta-cell function after onset. Factors affecting the peripheral insulin sensitivity should therefore be taken into consideration also when discussing the natural history of type 1 diabetes.

Beta cell function in siblings of diabetic children and HLA type.

Beta cell function was tested in HLA-DR typed siblings of insulin dependent diabetic children. HLA identical siblings showed an increased insulin response compared with controls and HLA nonidentical siblings. This beta cell hyperactivity may be an early carbohydrate intolerance or a genetically determined increase in beta cell metabolism.

The development of type 1 diabetes in HLA identical siblings of type 1 diabetic patients: associations with specific HLA antigens.

The development of type 1 diabetes in HLA identical siblings of type 1 diabetic patients: associations with specific HLA antigens.