Anthony J. Muslin, M.D.
Project Overview:
Adult-onset type 2 diabetes mellitus is becoming increasingly prevalent and is frequently associated with cardiovascular disease. Type 2 diabetes mellitus is caused by the loss of responsiveness of skeletal muscle, adipose and cardiac tissue to insulin action. After release from the beta cells of the pancreas, insulin binds to cell surface receptors that activate an intracellular signaling cascade that includes the protein kinase Akt. Activation of this kinase leads to the translocation of glut4 containing vesicles to the cell surface, promoting glucose uptake by cells. TRB3 is an intracellular protein that binds to and inactivates Akt.
Polymorphisms in the TRB3 gene were discovered and our ongoing work suggests that the TRB3 genotype correlates with outcomes in patients with coronary artery disease. One polymorphism in the TRB3 gene (Q84R) results in a missense mutation that leads to the substitution of an arginine residue for a glutamine residue and results in a protein with increased ability to inhibit Akt. The Q84R polymorphism was found in a preliminary study by other investigators to be associated with an increased incidence of hypertriglyceridemia and also with an earlier age at first myocardial infarction (MI).
In our work over the past year, we investigated the Q84R TRB3 polymorphism in a population of patients from the INFORM trial who presented with acute MI or unstable angina. We found that the Q84R polymorphism was associated with a higher rate of re-hospitalization in the year following MI or unstable angina, and was also associated with increased responsiveness to β-blocker therapy in terms of hospitalization rates. In our planned studies, we will determine whether the Q84R SNP correlates with clinical outcomes, clinical responsiveness to β-blocker therapy, hyperglycemia, hypertriglyceridemia, and hypercholesterolemia in a second larger and completely separate population of patients from the TRIUMPH registry. In addition, we will determine whether the Q84R SNP is associated with an altered acute response to β-blocker therapy in healthy volunteers in a prospective clinical trial. These studies will help to establish the utility of genomic studies in the clinical management of patients with cardiovascular disease.
Final Report:
Type 2 diabetes mellitus is a common condition that is thought to be caused by insulin resistance in muscle, fat and other tissues. In response to feeding, pancreatic beta cells release insulin that binds to cell surface receptors, resulting in the activation of an intracellular signal transduction cascade that include the protein kinase Akt2. TRB3 is an inducible pseudokinase that binds to and inhibits Akt2 function. Polymorphisms in the TRB3 gene were identified several years ago. A major polymorphism in the TRB3 gene (Q84R) results in a missense mutation that encodes a protein with increased ability to inhibit Akt. The Q84R polymorphism was found in several studies by other investigators to be associated with an increased incidence of hypertriglyceridemia and myocardial infarction. In animal model work in our laboratory, we showed that TRB3 expression is murine heart cells and myocardium is increased in response to hyperglycemia, hyperlipidemia and ischemia. We also showed that overexpression of TRB3 in murine myocardium sensitized these animals to pathological cardiac remodeling after myocardial infarction. In clinical studies, we investigated the Q84R TRB3 polymorphism in a population of patients from the INFORM and TRIUMPH trials who presented with acute myocardial infarction (MI) or unstable angina. We found that the Q84R polymorphism was associated with a higher rate of re-hospitalization following MI or unstable angina, and was also associated with increased responsiveness to b-blocker therapy in terms of hospitalization rates. We also found that cardiac mortality was increased in the INFORM and TRIUMPH patients with Q84R TRB3 who were not treated with beta blockers. These studies suggest that patients with the Q84R TRB3 should be aggressively treated with beta blockers and also show the utility of genomic studies in the clinical management of patients with cardiovascular disease.
