Genetic and biochemical analysis of type 2 diabetes and diabetic complications.

摘要

Over 29 million Americans (9.3%) are affected by type 2 diabetes (T2D). T2D is characterized by the body not producing enough insulin and not responding to the insulin that it does produce resulting in high blood glucose. Common complications associated with T2D include cardiovascular disease (CVD), nephropathy or end-stage kidney disease (ESKD), and cognitive decline. CVD is the most common complication with up to 65% of individuals with T2D dying due to CVD. Individuals with T2D are 2 -- 4 times more likely to die due to CVD causes than those without T2D. Several explanations as to why individuals with T2D have an increased risk for CVD have been proposed. These include: high glucose independent of other risk factors, the atherogenic profile of diabetes (i.e. dyslipidemia, hypertension, obesity, etc.) often termed the "common soil" hypothesis, or that it is common genetic risk factors that contribute to both T2D and CVD. However, none of these adequately explain the increased risk. This thesis attempts to explain the genetic causes of T2D and complications including CVD in individuals with T2D. It also explores a possible biochemical link between T2D and CVD.;Within this thesis, the contribution of the Haptoglobin gene ( HP) to T2D and a range of diabetic complications were assessed. In the Diabetes Heart Study (DHS) HP was investigated for a possible association with T2D and CVD. This was expanded to a population of African Americans where HP was investigated for association with T2D and ESKD. A more global genetic assessment of diabetic CVD was performed in the DHS. This study extended results seen in a recent genome-wide association study (GWAS) meta-analysis to a family-based cohort enriched for individuals with T2D. Using genotype data from prior DHS GWAS and exome chip studies, CVD risk single nucleotide polymorphisms (SNPs) and genes were investigated for risk with diabetic CVD. Finally, advanced glycation end products (AGEs) were investigated as a potential biochemical link between T2D and diabetic complications. AGEs were measured through enzyme-linked immunosorbant assay (ELISA) in the DHS and were investigated with a range of CVD, kidney function, and cognitive function traits to see if they play a part in the observed increased risk for complications. In addition, genetic associations with AGEs were investigated through a GWAS and exome chip analyses.;The work presented here explores potential genetic and biochemical causes of complications that are common in T2D. The results from this thesis broaden our knowledge of risk factors for T2D and diabetic complications.