There are two major types of diabetes mellitus, Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D), however a number of subtypes have been defined and classified. Maternally Inherited Diabetes and Deafness (MIDD) and Maturity Onset Diabetes of the Young (MODY) are monogenic forms, whereas Latent Autoimmune Diabetes in Adults (LADA) is thought to be a polygenic subtype similar to T1D. Mutations in the Hepatocyte Nuclear Factor 1a (HNF1a) gene cause MODY3, however common genetic variation could predispose to the more common T2D.
It is important to learn more about genes causing or predisposing to diabetes to understand the mechanisms by which impaired beta cell function and insulin sensitivity lead to diabetes.
The aim of this thesis was to elucidate the role of and functionally characterize mutations and polymorphisms in candidate genes for different subtypes of diabetes. The L107I-mutation in the HNF1a gene resulted in decreased transcriptional activity and DNA-binding in vitro which by haploinsufficiency mechanisms led to a defect insulin secretion and MODY3. Another mutation in HNF1a, M626K, was found to co-segregate with the A3243G-mutation in mitochondrial DNA in a large pedigree with diabetes. The M626K mutation resulted in decreased transcriptional activity of HNF1a in vitro, while co-inheritance of M626K and A3243G was associated with an earlier age at onset of diabetes. Our studies on the role of common variation in HNF1a in T2D indicate that certain combinations of the I27L and A98V lead to decreased transcriptional activity of HNF1a in vitro and were in vivo associated with decreased insulin secretion and a moderately increased risk of future T2D. We also compared the role of genetic variation in TCF7L2, PAX4, PAX6 as well as HLA genotypes between LADA, T1D and T2D.
The results showed that LADA patients share genetic features with both T2D (TCF7L2) and T1D (HLA) but also retain characteristic features (PAX6), which justifies classifying LADA as a distinct diabetic subgroup in the twilight zone between T1D and T2D.