Award Principal Investigator: Robert Nichols, PhD
Project Principal Investigators: Scott K. Ferguson, PhD, Assistant Professor (INBRE) & Noemi Polgar, PhD, Assistant Professor (COBRE)
Project Summary:
Type 2 Diabetes (T2D) is a complex disease that impacts over 34.2 million people in the U.S. alone, costing ~$327 billion in direct medical costs per year. Central to the reduced physical capacity of these patients is a decreased exercise capacity, resulting from a combination of metabolic and cardiovascular derangements that conspire to reduce maximal oxygen uptake (V̇O2 max), slow pulmonary oxygen uptake (V̇O2) kinetics at the onset of exercise, and impair skeletal muscle metabolic control. Crucially, T2D is associated with reduced skeletal muscle blood flow, impaired vascular control, and dysregulated skeletal muscle glucose uptake,
contributing to the reduction in both V̇O2 max and exercise tolerance. Sustained muscle contractions require an ample supply of glucose and oxygen to meet the metabolic demands of exercise. To facilitate glucose uptake within the contracting myocyte, GLUT4 is translocated to the cell membrane via exocyst activity. While it is clear that T2D impairs skeletal muscle glucose uptake, vascular and metabolic control, and exercise tolerance the impact of impaired exocyst function and the related translocation of GLUT4 on skeletal muscle function and exercise tolerance remain unknown.
This project brings together state-of-the-art in vitro and in vivo measurements to determine the role of the exocyst complex on skeletal muscle glucose uptake during exercise, and its impact on skeletal muscle vascular and metabolic control and exercise
tolerance.
Our findings will also shed light on the impact of the exocyst complex on the well-known switch from slow to fast-twitch skeletal muscle fiber types in patients with T2D, which also likely contributes to the exercise intolerance of this patient population.
