Lack of Improvement in Insulin Responsiveness in the Metabolic Syndrome after Resistance Training Only May Be Due to Fewer Muscle Slow-Twitch Fibers and Decreased Activation of AMPK Ten non-diabetic subjects (fi Ten non-diabetic subjects (five males, five females) with the Metabolic Syndrome underwent eight weeks of supervised strength training. Training consisted of five weekly sessions. A brief orientation period was followed by two blocks of progressively increasing intensity training. Nine control subjects were trained at the same time following the same protocols. At the completion of training, strength and VO[sub]2[/sub]max increased by 10% in both groups, but body composition and body weight had not changed. Insulin responsiveness, quantified using a three hour euglycemic clamp procedure, did not improve in the insulin resistant Metabolic Syndrome subjects, but increased significantly (13%) in the control group. Control subjects had significantly more slow-twitch muscle fibers at baseline (50% vs. 36%). The fiber composition was not changed in either group by training. Expression of GLUT4, the principle insulin-responsive glucose transporter, increased significantly in both groups (39% in Metabolic Syndrome subjects, 76% in the control group). The muscle mitochondrial biogenesis pathway reflected by AMPK total expression and activation, and the muscle hypertrophy pathway as indicated by mTOR expression and activation were increased in both groups. Even though total AMPK and total mTOR increased about 40% in both groups, the change in activated phospho-AMPK was greater in the control group (38% vs. 8%), and the activated phospho-mTOR increased more in the Metabolic Syndrome group (50% vs. 25%). Since AMPK is predominantly expressed in slow-twitch muscle fibers and mTOR is expressed at higher levels in fast-twitch fibers, these data may reflect the difference in fiber composition between the two groups. Strength training resulted in qualitatively similar effects on muscle remodeling in persons at low risk or high risk for diabetes, but greater activation of AMPK was associated with increased insulin responsiveness. In Metabolic Syndrome subjects, resistance training alone activated muscle hypertrophy pathways and increased muscle GLUT4 expression, but did not improve insulin responsiveness.