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

Ruth C R Meex, Vera B Schrauwen-Hinderling, Esther Moonen-Kornips, Gert Schaart, Marco Mensink, Esther Phielix, Tineke van de Weijer, Jean-Pierre Sels, Patrick Schrauwen, Matthijs K C Hesselink, Ruth C R Meex, Vera B Schrauwen-Hinderling, Esther Moonen-Kornips, Gert Schaart, Marco Mensink, Esther Phielix, Tineke van de Weijer, Jean-Pierre Sels, Patrick Schrauwen, Matthijs K C Hesselink

Abstract

Objective: Mitochondrial 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 methods: Eighteen 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.

Results: Mitochondrial 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.

Conclusions: Exercise 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.

Figures

FIG. 1.
FIG. 1.
In vivo mitochondrial function measured in vastus lateralis muscle expressed as the rate constant (s−1) before (black bars) and after (white bars) training. A high rate constant reflects high in vivo mitochondrial function. Data are expressed as means ± SE. Pre- and posttraining leg-extension exercise was performed at 0.5 Hz to an acoustic cue on an magnetic resonance–compatible ergometer and a weight corresponding to 60% of the predetermined maximum. Spectra were fitted in the time domain with the AMARES algorithm (22) in the jMRUI software (23). Five peaks were fitted with Gaussian curves (Pi, PCr, and three ATP peaks). The time course of the PCr amplitude [PCr(t)] during the last 20 sec of exercise (steady state) and during the recovery period was fitted as previously described (9), asssuming a monoexponential PCr recovery. Postexercise PCr resynthesis is driven almost purely oxidatively (24), and the resynthesis rate reflects in vivo mitochondrial function in health (25) and disease (rev. in 26,27). #Data for type 2 diabetic (T2D) subjects significantly different from that of the control (C) group. *Posttraining significantly different from pretraining.
FIG. 2.
FIG. 2.
IMCL content before (black bars) and after (white bars) training in all muscle fibers (A), in type 1 muscle fibers (B), and in type 2 muscle fibers (C). Data are expressed as means ± SE. Muscle fiber typing was performed using a monoclonal primary antibody against the slow isoform of myosin heavy chain 1 (MHC1), which was visualized using a secondary fluroscein isothiocyanate (FITC)-conjugated secondary antibody. Thus, MHC1-positive cells were considered type 1 muscle fibers, whereas MHC1-negative cells were considered type 2 muscle fibers. Immunolabeling of the basement membrane protein laminin was performed to identify the cellular border. Thus, we were able to identify the typology of individual muscle cells. Tresholding the Oil red O signal allowed us to compute the relative fraction of cell area containing lipid droplets per individual muscle fiber of either type. C, control subjects; T2D, type 2 diabetic subjects.
FIG. 3.
FIG. 3.
Metabolic flexibility, measured as the change in respiratory quotient (respiratory exchange ratio [RER]) from the fasted state to the insulin-stimulated state before (black bars) and after (white bars) training. Data are expressed as means ± SE. #Type 2 diabetic (T2D) group significantly different from control (C) group. *Posttraining significantly different from pretraining.

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