Targeting Hyaluronan Accumulation Through Exercise in T2DM

Hyaluronan accumulation (HA) in calf muscle will be assessed using 3D T1ρ and T2-weighted MR scans on a 3T whole-body clinical MRI scanner (Prisma, Siemens Healthcare, Erlangen, Germany) with a 15-channel knee coil (QED, Cleveland OH). The total scan time is expected to be 29 min, 30 s. The sequence acquisition parameters will be as follows: TR/TE = 1500 ms/3.78 ms, flip angle = 8°, field of view (FOV) = 140 mm2, spin-lock lengths (TSLs)=0,10ms, 20ms, 30ms, 40ms and 60ms, spin-lock frequency=500Hz matrix size 256 × 128 × 64, slice thickness = 2 m.

Calf muscle stiffness will measured using a previously validated device (FDA product classification: non-powered goniometer, 510K exempt). Briefly, subjects are positioned supine with the knee extended and their leg is secured by Velcro straps. Torques of 15, 20 and 25 Nm are applied using a hand-held force gauge (FDK 40, Wagner Instruments, Greenwich, CT) and resultant angular kinematics are measured using a digital inclinometer (Checkpoint Inc., Torrance, CA). Three cycles of testing are performed in ascending order of force application and resultant peak dorsiflexion range of motion is recorded at each force level. Calf muscle stiffness is calculated as the slope of the resultant curves over the 15 to 25 Nm intervals. This device has demonstrated high convergent validity compared to motion analysis (Intraclass correlation coefficient (ICC [2,k])> 0.95).

Passive ankle mobility will measured using a previously validated device (FDA product classification: non-powered goniometer, 510K exempt). Briefly, subjects are positioned supine with the knee extended and their leg is secured by Velcro straps. The axis of rotation of the device is then adjusted in the anteroposterior and supero-inferior directions to approximate the ankle axis of rotation determined by palpation of the distal tips of the medial and lateral malleoli. Torques of 15, 20 and 25 Nm are applied using a hand-held force gauge (FDK 40, Wagner Instruments, Greenwich, CT) and resultant angular kinematics are measured using a digital inclinometer (Checkpoint Inc., Torrance, CA). Three cycles of testing are performed in ascending order of force application and resultant peak dorsiflexion range of motion is recorded at each force level.

Calf muscle strength, quantified as peak plantarflexion torque. An isokinetic dynamometer (Biodex, Shirley, NY) will be used to quantify peak isokinetic torque of the calf muscle at 60 degrees per second in participants' available range of motion (FDA product classification: AC powered dynamometer, 510K exempt). All participants will be tested in the seated position. Three practice trials will be given, after which peak plantarflexion torque will be recorded from the highest of three trials. With these procedures, coefficient of variation of <10% has been reported in individuals with T2DM, indicating good repeatability.

The study will use a motion capture system to collect kinematic (marker) and kinetic (force plate and pressure plate) data as subjects walk barefoot at self-selected speed along a 10 m walkway. A minimum of five successful trials will be collected for each subject. A trial will be considered successful if the subject made clean force plate contact on the tested side without targeting. Stride length will be defined as the distance between consecutive initial contacts of the same limb and will be calculated using Visual3D software (C-motion Inc., USA).

The study will use a motion capture system to collect kinematic (marker) and kinetic (force plate and pressure plate) data as subjects walk barefoot at self-selected speed along a 10 m walkway. A minimum of five successful trials will be collected for each subject. A trial will be considered successful if the subject made clean force plate contact on the tested side without targeting. Walking speed will be defined as distance travelled in unit time and will be calculated using Visual3D software (C-motion Inc., USA).

This will be evaluated using Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function and Pain Interference scales. PROMIS is a computer adaptive testing outcomes instrument, generated after exhaustive review, and the application of item response theory to calibrate the individual items. The higher the score indicate higher levels of physical functioning. All PROMIS measures are scored using the final re-centered item response theory (IRT) item parameters and transformed to the T-score metric (mean=50, SD=10).

Glycemic control will be assessed with Hemoglobin A1c test. Participants will be asked to give 1 mL of blood at baseline and after intervention.

Physical activity will be assessed using a wrist-worn triaxial accelerometer (Actigraph). Step counts, and percent of time in sedentary, light and moderate / vigorous physical activity will be quantified for each participant. The actigraph will be worn for two weeks on the wrist, participants may take it off when bathing and sleeping.

Number of sessions attended will be calculated and used to calculate adherence. A systematic review of exercise training indicates attrition rates of <20% and adherence rates of >75% in individuals with T2DM.

The Michigan Neuropathy Screening Instrument will be used to screen for the presence of peripheral neuropathy. The Michigan Neuropathy Screening Instrument (MNSI) is used to assess distal symmetrical peripheral neuropathy in diabetes. It includes two separate assessments: a 15-item self-administered questionnaire and a lower extremity examination that includes inspection and assessment of vibratory sensation and ankle reflexes

Presence of knee osteoarthritis may affect levels of serum HA. American College of Rheumatology (ACR) Clinical Classification Criteria will be used to screen for the presence of knee osteoarthritis. History and physical examination will be used to screen for knee osteoarthritis using the following criteria: Pain in the knee and three of the following: 1) >50 years of age, 2) Less than 30 minutes of morning stiffness, 3) Crepitus on active motion, 4) Bony tenderness, 5) Bony enlargement, 6) No palpable warmth of synovium.