Genetic interaction between Type 1 and Type 2 diabetes

Sammanfattning: There are two major types of diabetes, type 1 and type 2 diabetes. Similarly characterized by hyperglycaemia and long term micro- and macrovascular complications, type 1 and type 2 diabetes have different underlying pathophysiologic processes. In Scandinavia, type 1 diabetes is common; type 2 diabetes accounts for 85% of all cases with diabetes. There is emerging evidence that type 1 and type 2 diabetes cluster in the same families. 10% of patients diagnosed with type 2 diabetes have autoantibodies against GAD65 (GADabs). The presence of GADabs predicts the development of insulin deficiency in patients with type 2 diabetes (latent autoimmune diabetes in adults, i.e. LADA). The aim of the thesis was to study whether genetic interaction exists between type 1 and type 2 diabetes. In a population-based study in Finland, the prevalence of families with both type 1 and type 2 diabetes (mixed type 1/type 2 diabetes families, or mixed type 1/2) among type 2 diabetes families was 14%. 5% of type 2 diabetic probands had a first-degree relative with type 1 diabetes. Type 2 diabetic patients from the mixed families had more often GADabs (18% vs. 8%; p<0.0001) and HLA DQB1'0302/X genotype (25% vs. 12%; p=0.005) associated with an increased risk for type 1 diabetes than those from the common type 2 diabetes families. However, compared with adult onset type 1 diabetic patients (GADabs, 65%), mixed type 1/2 patients had lower frequencies of GADabs (p<0.0001) and DQB1'02/0302 genotype (4% vs. 27%, p<0.0001) conferring the highest risk for type 1 diabetes. Despite similar age and lipid profile, type 1/2 patients had a more severe beta cell dysfunction, but less features of metabolic syndrome than the common type 2 diabetic patients. Sharing a risk HLA haplotype at the IDDM1 locus with a type 1 diabetic family member could explain most of the genetic influence of type 1 on type 2 diabetes. Insulin gene VNTR at the IDDM2 locus modified the risk conferred by the HLA locus in patients with type 2 diabetes. The data point to a genetic interaction between type 1 and type 2 diabetes that is mediated by the type 1 diabetes susceptibility genes. Combined information from the clinical and genetic studies in the subgroup of type 1/2 patients could have important therapeutic implications for type 2 diabetes.