The long-term objective for this continuation application for four years is to elucidate the etiology and pathogenesis of insulin-dependent diabetes mellitus (IDDM). The unique resources of the nationwide Swedish Diabetes Registry, established in 1983, for incident cases of patients developing diabetes mellitus at 15-34 years is utilized in a case- control study with a proposed five year follow-up. In 1992 and 1993, a total of 786 (with a blood sample from 767) patients were recruited. At the time of clinical onset, these patients were classified as IDDM (74%), non-insulin dependent diabetes mellitus (NIDDM) (13%), secondary diabetes (3%) and unclassifiable diabetes (10%). A total of 831 controls donated blood to the study after being selected based on the Swedish civic registration numbers to identify individuals matched for age and sex. This case-control study with follow-up will define genetic, autoimmune and viral antibody markers for the development of IDDM. The primary goal remains to determine whether the same genetic markers known to be associated with IDDM in the 0-14 year olds are also operative in the 15-34 year old group. The 15-34 year olds need to be studied further since: 1) both IDDM and NIDDM as well as unclassifiable diabetes is present, and 2) this age group is particularly suited to test the hypothesis that genetic and antibody markers alone or in combination permit a differential diagnosis of diabetes mellitus already at the time of clinical onset. The five year follow-up is necessary to study the conversion rates from NIDDM/unclassifiable diabetes to IDDM as well as from IDDM to NIDDM. The preliminary results from year One and Two of follow up demonstrate the following: a) decreasing risk of DR3-DQ2 and DR4-DQ8 with increasing age at onset and decreasing protection with age of DQ6; b) increased diagnostic sensitivity with age for GAD65Ab; c) appearance of GAD65Ab and ICA after onset; d) stable C-peptide within the normal range during follow-up and e) that antibodies against certain strains of the Coxsackie B4 subtype are associated with IDDM.
The Specific Aims are therefore: 1) to analyze the large amount of data collected at baseline in the 1992-1993 case-control study; 2) to investigate the association between IDDM and HLA and non-HLA IDDM and NIDDM genetic markers; 3) to determine end-point titers and epitope-specificity of islet cell autoantigen antibodies at onset and during follow-up and 4) to determine antibodies against strains of coxsackie B4 for high infectability for human islets. The data will be analyzed using standard methods for case-control studies including descriptive tabulations, stratified analyses and multiple logistic regression analyses. The investigators state that these studies will help to define pathogenetic mechanisms of IDDM to produce insights to the possibility of prevention or cure of this disease.
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