| One of the major complications observed in the pre-diabetic stage of what becomes the disease, Type 2 diabetes, is microvascular dysfunction, involving alterations in endothelial function, also referred to as endothelium dysfunction (ED). A characteristic of ED is the alteration of the microvascular barrier, affecting the microvascular permeability to a wide variety of materials whose partitioning into the vascular and tissue compartments is required to sustain organ function. We measured the venular leakage and clearance of albumin in response to suffusion with high-dose insulin (10-7M) in the autoperfused rat mesentery. We also compared the permeability responses of the mesenteric microvasculature of juvenile and adult male rats to determine whether maturation, per se, altered either basal properties or responses to insulin. Further, we assessed the influence of insulin on exchange function in sexually mature animals of to test whether the exchange responses differed between males and females.;Insulin suffusion lead to increased venular albumin leakage by 63% in adult male rats. Although we expected the venular permeability to reflect the overall clearance of proteins from the blood to the interstitial fluid, albumin and total protein clearance decreased with insulin treatment and hence, had an inverse relationship. In the juvenile male rats, venular albumin leakage was increased by 103% with insulin suffusion. The total protein clearance in the juvenile males was unchanged, while the albumin clearance increased with insulin suffusion, resulting in an uncoupling of the clearance responses between albumin and the other plasma proteins. Finally, as we expected, we did not observe any changes in the venular albumin leakage with insulin suffusion in the adult female rats. Insulin did decrease the total protein clearance, but not the albumin clearance, again reflecting an uncoupling of their clearance responses.;We demonstrated novel data that not only can insulin result in changes in macromolecule exchange in intact, autoperfused mesenteric microvasculature, but that these changes were dependant on the sex and the sexual maturity of the animal. We also determined that it is not appropriate to measure venular leakage response at the single vessel and expect it to reflect the overall protein clearance of the mesenteric network, or vice versa. The uncoupling of the relationship between albumin and total protein clearance response with insulin also provides clear evidence that albumin movement from the vessel and through the tissue is regulated via different mechanism/s compared to other plasma proteins.;Finally, in aggregate, this dissertation provides data demonstrating that it is not sufficient to study a physiological process in an animal model of a single sex and age and to then interpret the data as applicable to the circumstances of the species in general. The implication is that the treatment and progression of diseases need to be considered with the genomic and phenotypic backgrounds in mind. |
