Research Project
6576319
DESCRIPTION (provided by applicant): The extent and severity of microangiopathy is a major determinant of long-term prognosis in diabetes. Large-scale therapeutical trials have demonstrated the global benefit of tight glycemic control in type 2 and in type 1 diabetic patients. To further improve the management of patients there is a need for 1/ very early markers of microangiopathy and 2/ markers exploring targets other than retina or kidney, such as leg microvasculature. Nuclear magnetic resonance (NMR) imaging and spectroscopy can explore various facets of skeletal muscle perfusion and oxygenation. A specific methodology that we have called "multi-parametric functional" (mpf) NMR, has been developed. It allows simultaneous determination of skeletal muscle perfusion, reoxygenation and mitochondrial adenosine triphosphate (ATP) production, at the recovery phase of an ischemic period or of an ischemic exercise bout. Exploiting the simultaneity of the NMR acquisitions and with the use of simple modelization of oxygen (02) fate, NMR data analysis provides a number of relevant additional evaluations: minimal muscle vascular resistance, perfusion heterogeneity, 02 transcapillary diffusion, mitochondrial 02 consumption and possibly also coupling of the oxidative phosphorylations. Explorations by mpf-NMR are proposed, to investigate the functional consequences of diabetic microangiopathy in the calf muscle of type 2 diabetic patients and of the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes. The aims in the two human studies are 1/ to test whether these functional evaluations can be used as very early markers of peripheral microangiopathy in patients with no or minimal signs of target-organ damages and 2/ in patients with overt signs of microangiopathy, to determine whether NMR functional evaluations simply correlate with the target-organ involvement or provide additional information on patients' potential risk of peripheral vascular complications. In the animal study, the progression of the abnormalities in skeletal muscle perfusion and oxygenation will be monitored in ZDF rats as compared to lean Zucker rats, over a 20 week period. The time-course of the changes will be confronted to serial biological, renal and neurologic evaluations. In addition, insulin therapy will be initiated in a subgroup of ZDF rats to determine the degree of reversibility achievable by glycemic control.
