Type 1 Diabetes
Principal Investigator
Åke Lernmark, Lund University
Ake.Lernmark@med.lu.se
Reserach area description
Type 1 diabetes is one of the most common chronic diseases in children. At the time of clinical diagnosis the pancreatic islet beta cells have been killed by the immune system of the child. The resulting replacement therapy with insulin is life-long and associated with late complications that shorten life expectancy. Celiac disease is also an autoimmune disease. The immune system is attacking the intestinal mucosa after the child has developed immunological intolerance to gluten. Life-long treatment with gluten is imperative and the disease is associated with severe complications if not properly diagnosed and treated.
The HLA DQ locus is the major genetic risk factor for both type 1 diabetes and celiac disease. Both diseases are also linked to several non−HLA candidate genes, which may modify risk. Several but different etiological factors in the environment have also been implicated in the disease risk for type 1 diabetes and celiac disease. The pathogenesis of type 1 diabetes is strongly associated with the appearance of autoantibodies against GAD65, IA−2, ZnT8 and insulin, alone or in combination. Our laboratory cloned human islet GAD65 and developed a novel assay now in worldwide use to detect these autoantibodies and other autoantibodies such as those against tissue transglutaminase that predict celiac disease.
We test the hypothesis that HLA and environmental factors including virus infections perhaps already during pregnancy trigger islet autoimmunity. In children who have developed islet autoantibodies we test whether non−HLA genetic risk factors combined with other factors such as virus infections or stress precipitate the clinical onset of type 1 diabetes. Similar hypotheses are tested for celiac disease.
Clinical investigations are used to dissect the etiopathogenesis of type 1 diabetes and celiac disease. All newborn children in Skåne are screened for HLA-DQ genotypes: 2000−2004 for the DiPiS (Diabetes Prediction Study in Skåne) and 2004−2009 for the TEDDY (The Environmental Determinants of Diabetes in the Young) study. GAD65, IA−2, ZnT8 and insulin autoantibodies are determined in cord blood as well as during 15 years of follow up of children with increased genetic risk. The aim is to identify genetic and environmental factors that trigger islet autoantibodies or progression to type 1 diabetes. Beta cell function in response to stress is determined. Metabolic changes prior to hyperglycemia are investigated in the BB rat.
Our ability to predict type 1 diabetes is high and novel treatment strategies to prevent the clinical onset are urgently needed. A phase II clinical trial with alum−GAD65 has been completed to demonstrate protection from beta cell loss. Our translational research therefore also includes prevention studies with immune tolerance induction using the GAD65 islet autoantigen. The incidence rate of type 1 diabetes in Sweden is next to Finland the highest in the world and has doubled during the past twenty years. The disease is devastating to the individual and his or her family and is very costly to the society. It is urgently needed to uncover the etiology and pathogenesis of type 1 diabetes and celiac disease as well as to develop effective treatments to predict and prevent these diseases.