The objectives of the proposed studies are to test the following hypothesis relating to microvascular changes associated with diabetes mellitus: That specific microangiopathies - venular dilation, arteriolar constriction, altered reactivity of arterioles and venules to vasoactive substances, and increased permeability of postcapillary venules to macromolecules - will develop in an animal in which hormonal and metabolic abnormalities, closely resembling those observed in humans with insulin-dependent (Type 1) diabetes mellitus, have been chemically-induced. That the development of the morphometric alterations (venular dilation, arteriolar constriction) precedes the development of functional alterations (reactivity and permeability changes). That insulin therapy which is effective in preventing the development of metabolic abnormalities will prevent the development of morphologic alterations and, thereby, prevent the development of the functional alterations. Accordingly, the specific aims are: 1) To treat hamsters with streptozotocin to produce hormonal (insulinopenia and elevated glucagon: insulin ratios) and metabolic (hyperglycemia, glucosuria, and ketonuria) abnormalities which closely resemble those existing in humans with clinical Type 1 diabetes mellitus. 2) To use noninvasive metabolic monitoring of such hamsters to provide a history of metabolic states, as an adjunct to longitudinal studies on the microcirculation of the hamster cheek pouch, the microvascular preparation most amenable for such studies. 3) Initially, to determine when alterations occur in the morphometry (vascular dimensions, lumen diameters, and wall thickness) of arterioles and venules in the cheek pouch of diabetic hamsters. The data will be analyzed to obtain temporal reference points to be used in the subsequent experiments. 4) Then, to determine if venular dilation or arteriolar constriction precedes altered responsiveness of venules or arterioles to vasoactive substances. 5) Next, to test whether venular dilation precedes increased permeability of postcapillary venules to macromolecules. 6) Finally, to determine if insulin therapy, designed to prevent the development of ketonuria, glucosuria, and hyperglycemia, concomitantly, will prevent any or all of the microangiopathies.
NIH ExPorter
NIH ExPorter