INSULIN AND SARCOPENIA IN THE ELDERLY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background: Muscle mass and strength progressively decline with aging. This process has been termed sarcopenia, and is associated with increased risk of falls and bone fracture, which increase the risk of admission in nursing homes. Further, decreases in muscle mass and strength can lead to a reduction in physical activity, which may have possible effects including weak bone, obesity, and diabetes. Hypothesis: Our general hypothesis is that older muscle does not respond properly to insulin, a hormone that is usually released in the blood during a meal and that normally helps to use blood sugar and, in young people, to grow muscle. We further hypothesize that this change occurs even in healthy seniors, and is not linked to diabetes. Specific Aims and Procedures (summary): 1. To compare the response of muscle (growth and loss) to insulin between healthy senior volunteers and younger controls. This will allow us to test the hypothesis that the response of muscle protein synthesis to insulin is impaired in the healthy seniors. 2. To compare the response of glucose and muscle protein turnover (synthesis and breakdown) to insulin between healthy younger volunteers and younger type 2 diabetic volunteers, and between healthy senior volunteers and senior type 2 diabetic volunteers. In this way we will test the hypothesis that the defect in the response of muscles to insulin is only age-dependent and unrelated to diabetes. Experimental Design (summary): Volunteers will be recruited by an institutional review board-approved advertisement that will be posted at the University of Texas Medical Branch, local newspapers, and social centers, and by word of mouth. The volunteers will be informed about the risks and the benefits of the studies and will be asked to sign an approved consent form. The volunteers will arrive fasted at the GCRC in the morning. We will check them for any diseases that would not allow them to participate in the study. They will be enrolled only if the screening tests show that they do not have any health problems that may prevent them from participating in the study. The volunteers will come back to the GCRC the night before the study. The nursing staff will measure weight, height, blood pressure, and they will draw blood to check blood count, clotting, and some other blood tests including electrolytes (salts). Should any of the tests show alterations that may prevent the participation to this experiment, the volunteer will not be allowed to continue. A DEXA scan will also be taken to measure the amount of bone, muscle and fat in the body. If a volunteer is assigned to a pilot study with exercise, after the DEXA scan (s)he will walk fast on the treadmill for 45 min. Thereafter, the volunteer will be given dinner, and will sleep at the GCRC. The volunteer will not be allowed to eat after a midnight snack. Water, iced water or caffeine free and sugar free drinks will be allowed at any time during the night and during the study. The next morning we will wake up the volunteer and place a catheter (small tube for drawing blood or putting fluids in the body) in a vein of each arm. We will also place one catheter in the femoral artery and one in the femoral vein of one leg (the vessels that bring blood in and out of the leg), at the top of the thigh, close to the groin fold. The femoral catheters will be placed using a sterile procedure to avoid infections, plus local anesthesia with lidocaine (numbing medicine) to eliminate pain. An ultrasound machine will be used to better visualize the blood vessels of the leg. After the catheters are placed, we will start to give stable isotopes through one of the arm catheters. This will go on until the end of the study, about 7-8 hours. In general, the stable isotopes of a material are very similar to the regular material, except that they are heavier, but not radioactive. An example of stable isotope is the "heavy water", which is just a stable isotope of water. Stable isotopes are natural compounds also present in very small quantities in our body. We will infuse an extra amount of stable isotopes of amino acids (the building blocks of proteins) and glucose (sugar) to increase the level of the naturally occurring isotopes by 2-5 %. The isotopes are tested in order to assure their sterility (absence of microorganisms, such as bacteria, that may give infections and fever). We will then be able, using highly sophisticated analytical instruments, to measure the small changes in the concentration of these substances in the blood and muscle. This will allow us to compute the rate of metabolism, exchange, or turnover of these substances in the body. During the study we will take 3 muscles biopsies, 3 hours apart from each other, from the same leg in which we placed the catheters. This procedure involves the taking of a small piece of muscle from the leg. The skin is cleaned and made sterile, and the skin and tissue below are injected with local anesthetic (numbing medicine) to eliminate pain. We will make a small incision at mid-thigh, through which a needle about the size of this letter "O" will be advanced into the muscle. A piece of the thigh muscle will then be removed with the needle, the skin closed with a steri-strip, and a light dressing applied. The last two biopsies will be taken from the same incision where the first one was taken. After the last biopsy the incision will be closed with one stitch. During the study, indocyanine green, which is a dye, will also be given in the artery of the leg to measure the blood flow. During the last three hours of the infusion study, we will give insulin into the leg through the arterial catheter. This method will allow us to expose the leg muscles to an amount of insulin much higher than the rest of the body, so that the blood sugar and blood amino acids (the building blocks of proteins) should not drop very much. The insulin will be diluted in sterile saline (diluted salted water). During the administration of insulin we will frequently draw very little amounts of blood (0.5-1 ml, approximately a few drops) to check that blood sugar remains normal. Should the blood sugar drop due to insulin we will give some extra sugar through one of the arm catheters to maintain the blood sugar normal. We will also occasionally draw some blood from the femoral catheters and one of the wrist catheters. Significance (summary): We hope to learn if the loss of muscle with aging is due to changes in the ability of insulin to grow muscle in senior citizens, and if this is related or not to diabetes. Insulin is a hormone produced by the body that regulates sugar utilization by the body as well as other body functions including muscle growth. We will test the effects of different amounts of insulin (low, medium, or high) on muscle growth in young and elderly people, with or without diabetes.