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

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.