Muscle Lipid and Insulin Resistance in the Elderly

This project will provide novel information concerning the ability of exercise to enhance the capacity for oxidative metabolism of fatty acids and improve insulin resistance in older adults who are at high risk for the development of type 2 diabetes. Ultimately this may help identify mechanisms and therapeutic targets implicated in skeletal muscle metabolic dysregulation. The proposed study is to conduct a randomized controlled exercise training intervention trial in older men and women. In addition, the response to exercise in these subjects will be compared to those of highly endurance-trained, age-matched athletes.

Hypothesis and Specific Aims:

1. To determine whether aerobic exercise improves both skeletal muscle fat distribution and insulin sensitivity of older men and women. We will test two hypotheses.

   i. Physical exercise in older adults will decrease the amount of fat interspersed within muscle, specifically the fat between muscle groups (intermuscular adipose tissue) as well as decrease specific lipid metabolites within muscle cells, compared to controls.

   ii. Exercise-induced improvements in insulin sensitivity of older men and women will be related to the changes in muscle fat content independent of changes in total body fat or visceral abdominal adipose tissue.
2. To determine whether increased capacity for oxidative fatty acid metabolism within muscle results in improved insulin sensitivity in older adults. We will test two hypotheses.

   i. Exercise training will increase the capacity of muscle to oxidize fatty acids assessed both in vitro and in vivo.

   ii. Improved capacity for oxidative fatty acid metabolism will predict improvements in insulin sensitivity.

Eligibility Criteria:
Inclusion Criteria:

* 60 - 70 years of age
* No weight gain/loss of \>10 lbs in 6 months
* Sedentary (No more than 1 continuous exercise/week) or Highly trained (\>5 exercise sessions/week for a duration of one year or more)
* Non-Smoker
* BMI 18-38.0
* Resting blood pressure less than 150mmHg systolic/95 mmHg diastolic
* Normal glucose tolerance: Fasting glucose \< 100 mg/dl or 2 hour glucose from OGTT \< 140 mg/dl or impaired glucose tolerance (fasting glucose \> 100 mg/dl \< 126 mg/dl or 2 hour glucose from OGTT \> 140 mg/dl but less than 200 mg/dl
* Note from PCP/Cardiologist for exercise clearance if positive stress test symptoms were observed from GXT

Exclusion Criteria:

* Clinically significant CVD including h/o MI
* Peripheral Vascular Disease
* Hepatic, renal, muscular/neuromuscular, or active hematologic/oncologic disease
* Clinically diminished pulse
* Presence of bruits in lower extremities
* Previous history of pulmonary emboli
* Peripheral Neuropathy
* Currently not engaged in a regular program and have a V)2 max pre-training value \> 55 ml/kg-fat free mass-min., indicative of moderate fitness OR currently engaged in regular program and having a V)2 max value \< 55 ml/kg-fat free mass-min.
* Anemia (Hematocrit \< 34%)
* Any contraindications to moderate exercise
* Inability and/or willingness to comply with the protocol as written
* Active alcohol or substance abuse (Past 5 years)
* Total cholesterol \> 300 mg/dL
* Triglyceride \> 350 mg/dL
* ALT \> 80, AST \> 80, Alk Phos \> 240
* Proteinuria (defined as \> 1+ on routine dipstick) hypothyroidism (sTSH\>8)
* Therapeutic Doses of Nicotinic Acid
* Type 2 Diabetes: Fasting Glucose \> 126 mg/dl or 2 hour glucose \> 200 mg/dl
* Oral Glucocorticoids
* Females currently on hormone replacement therapy (HRT) less than 6 months
* Claustrophobia
* Previous difficulty with lidocaine or other local anesthetic
* Stress test symptoms:

  * Positive ECG (\>2mm ST segment depression) without PCP cardiologist permission to participate
  * Signs or symptoms of cardiovascular decomposition (hypotensive response to exercise
  * Onset of angina or angina like symptoms, shortness of breath, change in heart rhythm, signs of poor perfusion (light-headedness), tightness
  * Hypotension