The overall hypothesis to be tested in this investigation is that in diabetes mellitus (DM), it is hyperinsulinemia and hyperglycemia in combination with differences in the specific alleles of the genes of the renin-angiotensin and PAI-1 systems that predispose the individual to vascular complications. The hypothesis is based on studies that have shown that the renin-angiotensin system (RAS) profoundly influences vascular responsiveness, cardiovascular remodeling, and plasminogen activator-inhibitor-1 (PAI-1) production. Further, aldosterone can modify the actions of the RAS on these target tissues, e.g., it modulates AngII receptor expression, enhances collage formation and fibrosis and modifies PAI-1 production. Hyperglycemia and insulin also can modify these systems. Therefore, the investigators feel that RAS, hyperinsulinemia and hyperglycemia all may play substantial roles in mediating the adverse vascular (pressor, cardiac and atherosclerotic) complications in diabetes mellitus (DM). In addition, variations in the occurrence of these complications may be secondary not only to the control of glucose and the level of exogenous and/or endogenous insulin, but also to variations in the function of critical genes in the diabetic population. To evalulate the hypothesis, the investigator will address four Specific Aims: 1) to determine the relationship between angiotensinogen (AGT) genotype and hypertension in DM; 2) to test the hypothesis that variation in the pressor and hemodynamic responses to AngII in DM is mediated by variations in the genetic environment, specifically, the AGT and angiotensin converting enzyme (ACE) genes; 3) to determine the relationships between PAI-1 levels and insulin resistance and its response to insulin and AngII and to correlate these with PAI-1 and AGT genotypes; and 4) to access the influence of hyperglycemia on vascular function and PAI-1 levels To accomplish these goals, the investigator proposes to study normal subjects and patients with DM in the controlled environment of a General Clinical Research Center. Pressor and renal hemodynamic responses will be determined. The responsiveness of PAI-1 to AngII and insulin infusions, low salt diet and ACE inhibition will be assessed. Each subject's alleles at the AGT, ACE and PAI-1 loci will be determined. It is anticipated that the results of these studies will clarify the potential role of the RAS and hyperglycemia in mediating the vascular and atherosclerotic (via its effect on PAI-1 production and release) complications of DM. An additional benefit derived from these studies will be to provide clues as to the role of variations in the genetic environment of the systems noted on the variable expression of these complications as indicated by changes in surrogate markers. With this information, specific preventive and therapeutic measures could then be tested as to their efficacy in retarding the development of these complications.
| Underwood, Patricia C; Chamarthi, Bindu; Williams, Jonathan S et al. (2012) Replication and meta-analysis of the gene-environment interaction between body mass index and the interleukin-6 promoter polymorphism with higher insulin resistance. Metabolism 61:667-71 |
| Underwood, Patricia C; Sun, Bei; Williams, Jonathan S et al. (2011) The association of the angiotensinogen gene with insulin sensitivity in humans: a tagging single nucleotide polymorphism and haplotype approach. Metabolism 60:1150-7 |
