Grant: Operating Grant

Muscle is the principle tissue with high protein content in the body, so it plays a central role in the whole body's protein balance. Insulin is the main anabolic (tissue-building) hormone, and it affects protein metabolism during meal absorption and between meals. How it increases muscle synthesis and decreases muscle breakdown are not fully understood. Furthermore, a prominent feature of obesity is that tissue responses to insulin's effects are blunted. When this reaches the point that hypersecretion of insulin to overcome this insulin resistance can no longer occur, high blood sugar, i.e., type 2 diabetes develops. We have shown insulin resistance of protein metabolism in obesity. We wish to better understand this defect in obese persons, as the main objective of the proposed study. Specific amino acids from protein, especially leucine, also directly stimulate protein synthesis, and obesity may also have an as yet unrecognized defect at this level. To define these defects, we will use our method, the "hyperinsulinemic, hyperglycemic, hyperaminoacidemic clamp" test with studies of leg muscle. In this, we raise insulin, glucose and amino acids (protein) to levels found after meals by giving them intravenously for several hours. This simulates the situation after a meal, during which most anabolism takes place. This will be combined with measurements in needle biopsies of the muscle. The biopsies will give direct access to tissue so that we can assess its rates of protein accretion in response to insulin and amino acids. The most novel aspect of the work is that we will be able to learn more about what happens inside the muscle cell that controls its rates of protein metabolism, including using "gene-chip" technology. We expect that obese persons' muscle will be less responsive to the effects of insulin and amino acids. These studies can help not only basic understanding of obesity but also; to give insights into dietary requirements for treatment of obesity.