Restoration of Muscle Mitochondrial Function and Metabolic Flexibility in Type 2 Diabetes by Exercise Training Is Paralleled by Increased Myocellular Fat Storage and Improved Insulin Sensitivity

Abstract

OBJECTIVEMitochondrial dysfunction and fat accumulation in skeletal muscle (increased intramyocellular lipid [IMCL]) have been linked to development of type 2 diabetes. We examined whether exercise training could restore mitochondrial function and insulin sensitivity in patients with type 2 diabetes.RESEARCH DESIGN AND METHODSEighteen male type 2 diabetic and 20 healthy male control subjects of comparable body weight, BMI, age, and Vo2max participated in a 12-week combined progressive training program (three times per week and 45 min per session). In vivo mitochondrial function (assessed via magnetic resonance spectroscopy), insulin sensitivity (clamp), metabolic flexibility (indirect calorimetry), and IMCL content (histochemically) were measured before and after training.RESULTSMitochondrial function was lower in type 2 diabetic compared with control subjects (P = 0.03), improved by training in control subjects (28% increase; P = 0.02), and restored to control values in type 2 diabetic subjects (48% increase; P < 0.01). Insulin sensitivity tended to improve in control subjects (delta Rd 8% increase; P = 0.08) and improved significantly in type 2 diabetic subjects (delta Rd 63% increase; P < 0.01). Suppression of insulin-stimulated endogenous glucose production improved in both groups (−64%; P < 0.01 in control subjects and −52% in diabetic subjects; P < 0.01). After training, metabolic flexibility in type 2 diabetic subjects was restored (delta respiratory exchange ratio 63% increase; P = 0.01) but was unchanged in control subjects (delta respiratory exchange ratio 7% increase; P = 0.22). Starting with comparable pretraining IMCL levels, training tended to increase IMCL content in type 2 diabetic subjects (27% increase; P = 0.10), especially in type 2 muscle fibers.CONCLUSIONSExercise training restored in vivo mitochondrial function in type 2 diabetic subjects. Insulin-mediated glucose disposal and metabolic flexibility improved in type 2 diabetic subjects in the face of near–significantly increased IMCL content. This indicates that increased capacity to store IMCL and restoration of improved mitochondrial function contribute to improved muscle insulin sensitivity.

Effect of physical training on mitochondrial respiration and reactive oxygen species release in skeletal muscle in patients with obesity and type 2 diabetes

“…Training resulted in a large (about 63%) increase in muscle oxidative capacity shown by increased State3 respiration per kg muscle weight. These results are in accordance with a recent study showing that in vivo mitochondrial function increased in type 2 diabetic and control participants [26]. The present study expands on this finding by showing that the adaptation seems to be most pronounced in the mitochondrial ability to use complex I-supporting substrates, since the most significant adaptation was when pyruvate and glutamate were used as substrates (Fig.…”

“…2a). As suggested by Meex et al [26], an increase in muscle oxidative capacity is most likely to be caused by increased mitochondrial content and/or increased intrinsic mitochondrial activity. In the present study, CS activity, a marker of mitochondrial content, increased by ∼50% in the whole group.…”

“…The mechanism might be related to improved muscle oxidative capacity [25]. A recent study showed that physical training improves in vivo mitochondrial function concomitantly with increased insulin sensitivity in type 2 diabetes patients and control participants [26]. As suggested by the authors, the improved in vivo mitochondrial function may be due to increased mitochondrial content and/or increased functionality per mitochondrion (intrinsic) [26].…”

“…A recent study showed that physical training improves in vivo mitochondrial function concomitantly with increased insulin sensitivity in type 2 diabetes patients and control participants [26]. As suggested by the authors, the improved in vivo mitochondrial function may be due to increased mitochondrial content and/or increased functionality per mitochondrion (intrinsic) [26]. These results are in agreement with another study showing that changes in plasma glucose concentration and HbA 1c , induced by increased physical activity and weight-loss, were significantly associated with increased mitochondrial content [27].…”

Effect of exercise training on insulin sensitivity, mitochondria and computed tomography muscle attenuation in overweight women with and without polycystic ovary syndrome

“…In the present study, there was an unexpected differential response of muscle lipid content to exercise training, with PCOS women increasing and non-PCOS women decreasing lipid, while IR decreased in both groups. Another study in overweight and obese adults found that exercise-induced improvements in insulin sensitivity were accompanied by increases in IMCL [34,35]. Meex et al [35] demonstrated a trend to increased IMCL with exercise in male patients with type 2 diabetes, whose IR improved, but, in contrast with the present study, mitochondrial function also improved.…”