Grant: Project Grant

Background Cardiovascular (CV) diseases (heart attack and stroke) are the leading cause of death for people with type 2 diabetes (T2D). Recent clinical trials using 2 new classes of diabetes medications have shown that these drugs lower blood sugar levels AND reduce CV complications caused by T2D. The details of how these drugs prevent CV disease remains unknown. Chronic exposure to high blood sugar levels during T2D generates a 'perfect storm' for blood vessel damage combined with the loss of stem cells that coordinate vessel repair. Over the past 5 years, Drs Verma and Hess have established a unique collaboration investigating this novel concept termed 'regenerative cell exhaustion' or RCE. We have designed a new test to quantify stem cells that are responsible for repair of blood vessels. We found that people living with T2D demonstrated: (1) an overproduction of stem cells that increase inflammation, and (2) a decrease in stem cells that repair damaged vessels. How T2D causes this imbalance remains unknown. Whether or not RCE can be reversed is an important unanswered question isince a reduction in RCE is expected to prevent CV complications in people with T2D. We beleive that RCE prevents vascular repair during T2D and the reversal of RCE will decrease the risk of developing CV diseases. Specific Aims 1. To study how regenerative cells responsible for repairing damaged blood vessels differ in numbers and behaviour in people with T2D versus non-T2D controls 2. To determine how high blood sugar levels modify regenerative cell production and growth. 3. To determine whether combination therapy with 2 new types of drugs used for T2D can reverse RCE. Impact These studies will establish RCE as a drugable target to prevent the development of CV diseases in people with T2D. We will show that combination drug therapy will reverse RCE in patients with T2D and reduce CV complications.