Skeletal Muscle Lipid and Insulin Resistance: Effects of Physical Activity and Weight Loss (SHELL)

102 late- life adults at risk for developing type 2 diabetes mellitus, will be randomized to one of three interventions designed to improve insulin sensitivity thereby potentially preventing future progression of type 2 diabetes. The investigators predict that insulin sensitivity will improve equally following either weight loss or exercise, while there will be additive effects from combined intervention. The investigators hypothesize that weight loss will decrease intermuscular adipose tissue, intramyocellular lipid, and visceral abdominal adipose tissue.

The primary objective of this project will be to examine the role of skeletal muscle lipid and capacity for fat oxidation in insulin resistance in older adults who either are at high risk for the development of type 2 diabetes mellitus (T2DM) or who are untreated newly diagnosed T2DM. A randomized intervention trial will be conducted to examine the effects of physical activity and weight loss, alone or in combination, on intramyocellular lipid (IMCL), intermuscular adipose tissue (IMAT) and abdominal AT (adipose tissue), oxidative capacity and insulin resistance. The first aim is to examine the effects of weight loss without exercise on AT distribution, intramyocellular lipid (IMCL) and oxidative capacity of skeletal muscle in conjunction with improvements in insulin sensitivity. We will test the hypotheses that weight loss without exercise will: 1) Improve insulin sensitivity, decrease the lipid interspersed within muscle (intermuscular AT), intramyocellular lipid (IMCL), as well as visceral abdominal AT (VAT); and 2) Will have no effects on either skeletal muscle oxidative capacity determined in vitro or in vivo. A second aim is to examine the effects of exercise without weight loss on AT, IMCL, oxidative capacity and insulin resistance. We will test the hypotheses that exercise without weight loss will: 1) Increase the oxidative enzyme capacity of muscle; 2) Increase IMCL despite having little effect on AT distribution within muscle (intermuscular AT) or visceral AT; 3) Improve insulin sensitivity to a similar degree as weight loss without exercise. A third aim will be to examine the combined effects of exercise and weight loss on insulin resistance. Our third hypotheses are that combining weight loss and exercise will 1) Decrease IMAT, VAT and have little overall effect on IMCL 2) Improve the oxidative capacity of skeletal muscle; 3) Confer synergistic improvements in insulin sensitivity through the combined actions on AT and skeletal muscle capacity for oxidation. A fourth aim will be to examine the combined effects of exercise and weight loss on subjects with newly diagnosed but untreated T2DM. Our final hypotheses are that exercise and weight loss will have similar effects in subjects with newly diagnosed T2DM compared to those at risk for developing T2DM with regards to improved insulin sensitivity, body composition and oxidative capacity of skeletal muscle.

16 week intervention; 6 exercise sessions weekly w 3 supervised exercise sessions weekly utilizing cycling or walking/jogging. Participants maintain exercise diaries: wks 1-4; 30 minutes at 60-70% MHR, wks 5-8; 40 minutes at 60-70% MHR, weeks 9-16; 40 minutes at 75% MHR

Exercise: 16 week intervention; 6 exercise sessions weekly w 3 supervised exercise sessions weekly utilizing cycling or walking/jogging. Participants maintain exercise diaries: wks 1-4; 30 minutes at 60-70% MHR, wks 5-8; 40 minutes at 60-70% MHR, weeks 9-16; 40 minutes at 75% MHR. Weight Loss: Reduction of kcal/day through implementation of a low fat diet.

Effects of physical activity and weight loss, alone or in combination, on intramyocellular lipid, intermuscular adipose tissue and abdominal AT, oxidative capacity and insulin resistance.

Inclusion Criteria: 60-75 years of age Stable weight (No Gain/Loss of > 10 lbs in 6 months) Impaired Glucose Tolerance or Newly, untreated, undiagnosed type 2 diabetes Sedentary Non-smoker BMI 25.0-38.0 KG/M2 Resting Blood Pressure ≤ 150mmHg systolic and ≤ 95 mmHg diastolic IGT: Fasting Glucose > 100, < 126 2-Hour OGTT > 140 but < 200 T2D: Fasting Glucose > 126 < 2000 2-Hour OGTT > 200 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 VO2 max pre-training value > 55 ml/kg-fat free mass-min., indicative of moderate fitness. Anemia (Hematocrit < 34%) Any contraindications to moderate exercise (Please specify) Inability and/ or unwillingness 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 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

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