Type 2 Diabetes Genes Contributing to Insulin Secretion Defects

Abstract: Type 2 diabetes is caused by a combination of environmental and inherited factors influencing the progression of insulin resistance and impaired insulin secretion leading to chronically elevated blood glucose levels. The aim of this thesis was to functionally and genetically characterise the species-conserved diabetes locus Niddm1i of the GK rat encoding hyperglycaemia and defect insulin secretion. High-resolution QTL mapping revealed that Niddm1i is a composite of at least four subloci influencing diabetes-associated phenotypes (Niddm1i1-Niddm1i4). Sorcs3 and Sorcs1 were positionally mapped as diabetes candidate genes within Niddm1i2 and Niddm1i3. Investigation of pancreatic islets and beta-cells identified two separately inherited insulin secretion defects. A 3-Mb region in the proximal part of Niddm1i encoded impaired beta-cell glucose metabolism and ATP production, and a 4.5-Mb region in the distal half of Niddm1i encoded impaired insulin exocytosis. These findings were in line with the observed decreased transcript levels of genes involved in cellular respiration and vesicle transport in young NIDDM1I rat pancreas. Niddm1i also caused increased transcriptional levels of genes involved in pancreatic immune response and inflammation. By use of congenic strains dissecting the 4.5-Mb region in the distal half of Niddm1i, impaired insulin secretion in islets was mapped to the same chromosomal region as Niddm1i4 encoding hyperglycaemia. Increased gene expression level of Adra2a was observed for the GK genotype in islets. In conclusion, several loci and genes influencing glucose homeostasis and insulin secretion within Niddm1i were identified. Further studies of the identified candidate genes in human populations could establish their potential role in human type 2 diabetes.