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Retinopathy After Diabetes Onset

Diabetes retinopathy (DR) refers to any of the vascular changes in the retina. These are observed clinically as microaneurysms, dot and blot hemorrhages, edema, hard and soft exudates, neovascularization and newly formed fibrovascular tissue. The major sight-threatening manifestations of DR, macular edema and proliferative diabetes retinopathy, PDR, are the end result of increased vascular permeability and vascular occlusion.

Specific aims

This study presented a unique opportunity to identify biomarkers that can be determined at the onset of clinical diabetes that may indicate which patients are at greatest risk for developing DR.  The study is a follow-up of a previously identified cohort of young adults who were newly diagnosed with DM in 1992 and 1993.  The primary aims of the study included:

1)  Determine whether subjects with T1DM that have no autoantibodies against the 65 kilodalton (kD) isoform of glutamate decarboxylase (GAD) at the time of diagnosis are more likely to develop DR 15 years after the clinical onset of diabetes compared with those that have GAD autoantibodies (GADA). 

2)  Determine if the human leukocyte antigen (HLA) haplotypes commonly associated with T1DM, DQ2 (DQα1*0501-DQβ1*0201-DRβ1*0301), DQ8 (DQα1*0301-DQβ1*0302-DRβ1*04) and DQ6 (DQα1*0102-DQβ1*0602-DRβ1*1501), are associated with the presence of DR. 

3)  Determine if the presence or the amount of measurable C-peptide at the time of diagnosis or change during the first 6 years after the onset of diabetes is associated with the presence of DR. 

Patients

The cohort for the present study was first identified in the Diabetes Incidence Study in Sweden (DISS).  The DISS is an on-going prospective study that attempts to enroll all incident cases of diabetes for patients between the ages of 15 and 34 years old.  During 1992 and 1993, 879 cases were identified in this registry and invited to participate in a 6-year follow up-study to identify risk factors for the loss of measurable C-peptide and to describe the course of diabetes autoantibodies after diagnosis.   Starting in 1992, subjects provided blood samples at diagnosis and each year thereafter for 6 years to determine their levels of serum C-peptide and the diabetes associated autoantibodies including GADA, insulinoma antigen-2 autoantibodies (IA-2A), insulin autoantibodies (IAA) and islet cell autoantibodies (ICA).

At the time of this study, 231 subjects had declined to participate in any further studies. Current addresses were obtained from the Swedish Population and Address Register.  In 2007, over 92% of the entire DISS cohort was alive and residing in Sweden.  The initial mailing included the consent form, a short health history questionnaire and a kit to collect a dried capillary blood spot.  We received informed consents from 60% (387/648) of the subjects.  This study has been approved by the Regional Ethical Committee, Lund, Sweden.

Fundus photographs were collected from patient records across Sweden.  The questionnaire was designed to elicit yes or no responses to the presence or treatment of the following conditions, hypertension, diabetic nephropathy and high cholesterol or triglycerides.  Blood glucose control was ascertained by the analysis of the dried blood spot to determine each subjects current HbA1c.

HLA genotyping for DQβ1, DQα1 and DRβ1 was performed. C-peptide levels were determined at the Department of Clinical Chemistry, University Hospital of Lund, Sweden. Four diabetes associated autoantibodies (GADA, IA-2A, IAA and ICA) were assayed. 

This study allows us to evaluate the main and joint effects of immunologic, metabolic and genetic factors determined at the time of clinical onset of diabetes and their association with DR 15 years later.  We are currently working with the statistical evaluation and interpretation of these data.

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00