Mechanisms of Skeletal Muscle Insulin Resistance in Older Adults
Condition: Reduced Physical Activity
Study type: Interventional

Summary: 
      The over-65 population is not only increasing at an alarming rate, but because six out of 10
      will be managing more than one chronic condition by 2030, they will make up a much greater
      proportion of hospitalizations than ever before. Hospitalizations for disease, injury, and/or
      surgery in this group are likely to impair physical mobility and, therefore, the older adults
      capacity to be physically active both during hospitalization and beyond. The resulting
      sedentary lifestyle is likely to be accepted as the "new normal", ultimately increasing the
      risk of skeletal muscle and metabolic dysfunction (e.g. impaired glucose disposal, insulin
      resistance). These devastating outcomes are neither inevitable nor necessary if prevented
      with an appropriate mechanism-based intervention.

      A novel mechanism that may contribute to physical inactivity-induced insulin resistance is
      accumulation of inflammation and ceramide within skeletal muscle. Of interest, increased
      skeletal muscle inflammation and ceramide has been tied to various metabolic disturbances
      such as diabetes and insulin resistance. However, it is currently unknown if skeletal muscle
      inflammation and ceramide are a key mechanism associated with insulin resistance due to
      physical inactivity in older adults.
    

Detailed description: 
      The investigator team will recruit younger and older (N=8; 18-35y and 60-85 yrs) male and
      female adults recruited in the Salt Lake City area.

      The investigator team will then schedule separate visits for Strength, Power and Physical
      Function and the separate visits for Lean Mass and OGTT measurements (see description below).

        1. Lean Mass, oral glucose tolerance test , Strength, Power, Exercise Testing and Physical
           Function Measurements. Lean mass assessment via dual-energy X-ray absorptiometry (DXA),
           ultra sound and peripheral quantitative computed tomography (pQCT) will be assessed in
           the center for clinical and translational sciences (CCTS) while knee extensor isometric
           strength, power and physical function testing will be conducted in the Skeletal muscle
           exercise research facility (SMERF) laboratory (520 Wakara Way). These endpoints will be
           considered secondary objectives to determine relationships with insulin sensitivity and
           muscle cell signaling events. These tests will occur within one week before the reduced
           activity experiment and will be repeated after completing the reduced activity period
           and after exercise training. For lean mass assessment, subjects will be tested in the
           morning after an overnight fast prior to the DXA scan. Isometric strength will be
           assessed in both legs with a maximal voluntary isometric contraction effort (at a 600
           knee angle) developed by the knee extensors (quadriceps) and plantar/dorsi flexor
           muscles on a dynamometer. For lower extremity extension power testing a Nottingham power
           rig will be used. The following battery of functional performance tests will be used:
           Stair ascent/descent time, six-minute walk distance, 50 foot walk time, and the timed up
           and go test. All tests are tests that we frequently and safely perform in older
           individuals.

           Maximal oxygen consumption (exercise testing) will be measured by a metabolic cart
           during a graded maximal exercise test on a stationary cycle ergometer. This test will be
           performed in the CCTS under direct supervision of an exercise physiologist.

        2. Physical Activity Monitoring, Dietary Record. Subjects will be fitted with an ankle Step
           Activity Monitor in order to determine their daily level of physical activity over 7
           days period preceding the reduced physical activity study. Additionally, a 3-day daily
           dietary record will be self-reported before this period. The participant will be
           properly instructed by a research team member on how to conduct this reporting and how
           to wear the ankle activity monitor.

        3. Insulin Clamp Study, Metabolic Rate and Muscle Biopsies. On a separate day, participants
           will arrive at the CCTS fasted in the morning on Day 1 and a euglycemic-hyperinsulinemic
           clamp study will be performed as we have done previously. The research team physician
           will oversee the clamp procedure as he is very experienced using this method.

           Metabolic rate will be determined 30 minutes before the initiation of the insulin
           infusion and 30 minutes at the end of the insulin infusion period. Metabolic rate will
           be determined using a indirect calorimeter housed at the CCTS. To do so, the participant
           will be fitted with a canopy hood. The participant with breathe normally for 30 minutes
           during the procedure. The canopy will be removed then the first muscle biopsy will
           occur.

           A vastus lateralis muscle biopsy will be sampled before and 3h after the clamp combined
           with periodic blood sampling for measure of fasting and insulin-stimulated insulin,
           glucose, muscle cell signaling endpoints, and specific ceramide species. Biopsies will
           occur on opposite legs. Muscle biopsies were be performed by trained CCTS nurses as we
           have done routinely in our bed rest studies in older adults. Muscle samples will then be
           flash-frozen in liquid nitrogen and stored for later analysis. After the clamp
           experiment, subjects will begin the reduced physical inactivity study which will take
           place at the participant home.

           On Day 14, the participant again will return to the CCTS following an overnight fast and
           the insulin clamp study will be repeated in order to make comparisons to the pre insulin
           clamp study (Day 1).

        4. Reduced Physical inactivity experiment. After completion of the first insulin clamp
           experiment (Day 1), subjects will adhere to 14-days of reduced physical activity at
           their home as has been conduced before. The goal will be for the participant to maintain
           no more than ~2000 steps/day as determined by a monitor that the subject will be able to
           see and record. The investigators will inform the participant that their normal diet
           should remain the same. As mentioned above, on day 7, the participant will return for a
           DXA scan, OGTT's and thigh muscle biopsies. Also mentioned above, on Day 14, after an
           overnight fast, a second insulin clamp study coupled with muscle biopsies will be
           conducted as detailed above in the CCTS. Lean mass, strength, power, and physical
           function measurements will be re-assessed on a later day following the reduced activity
           study.
    

Intervention name(s): Reduced activity
Intervention type(s): Procedure
Intervention description(s): Participants will reduced their physical activity level to approximately 2000 steps or 75% of their normal activity levels.
Intervention model: Single Group Assignment
Intervention model description: 2 weeks of physical inactivity
Masking: None (Open Label)
Primary purpose: Treatment