This project is designed to evaluate the molecular mechanisms involved in the early
development of endothelial dysfunction in type 2 diabetic patients. The investigators intend
to correlate increases in insulin signaling pathway activity following pioglitazone therapy
with improvements in nitric oxide synthase expression in skeletal muscle. In addition, the
investigators will evaluate vascular responses and in vivo nitric oxide release during
administration of acetylcholine and nitroprusside in patients with type 2 diabetes. Enhanced
knowledge of the molecular mechanisms responsible for endothelial dysfunction, an early
abnormality in the pathogenesis of atherosclerosis, is critical before novel therapies to
arrest or delay the appearance of cardiovascular complications in diabetes can be developed.
The investigators intend to recruit fifty type 2 diabetic patients treated with diet alone or
diet plus sulfonylureas or meglitinides and add Pioglitazone (45 mg), an insulin sensitizer,
for 6 months. In addition to assessment of clinical and metabolic parameters, insulin
sensitivity and brachial artery and skin microcirculatory responses to acetylcholine and
nitroprusside in combination with simultaneous determination of nitric oxide release will be
documented before, 3 and 6 months after Pioglitazone therapy is initiated. Circulating levels
of markers of endothelial damage (VCAM, ICAM, selectins), inflammation (C-reactive protein
and interleukins), increased coagulability (PAI-1) as well as lipids and apolipoproteins will
measured during the study. Skeletal muscle biopsies will be performed during the euglycemic
insulin clamp before and 6 months after therapy for measurements of NO synthase activity and
key elements of the insulin signal transduction pathway involved in the regulation of glucose
metabolism (IRS-1, PI-3 kinase, PI-3 kinase associated with IRS-1 and the mitogenesis
MAP-kinase.
Type 2 diabetes confers a substantial increase in the risk of cardiovascular disease. This is
believed to be due, in part, to endothelial dysfunction, which correlates closely with
impaired vascular responsiveness. Our study will clarify further the extent to which
resistance to insulin action and impaired nitric oxide release from endothelial cells are
interrelated. We also expect to demonstrate that insulin sensitizers (pioglitazone) can help
to restore normal endothelial function, and ultimately prevent/delay the appearance of
vascular disease in patients with type 2 diabetes.
Phase:
Phase 4
Details
Lead Sponsor:
The University of Texas Health Science Center at San Antonio