Mitochondrial dysfunction has been reported in type 2 diabetic patients (4
) and in young, lean, insulin-resistant offspring of parents with type 2 diabetes (2
), although not all studies support this (34
). The present study confirms our previous observation of compromised mitochondrial function measured in vivo in patients with type 2 diabetes (9
). Importantly, exercise training in patients with type 2 diabetes completely restored mitochondrial function toward values observed in control subjects after training. In patients with type 2 diabetes, restoration of mitochondrial function was paralleled by improved (but not restored) insulin-stimulated glucose disposal and by complete restoration of metabolic flexibility and insulin-stimulated substrate oxidation toward control values—both in the face of a near-significant increase in IMCL content. In control subjects, training also improved mitochondrial function, while insulin-stimulated glucose disposal increased only marginally and metabolic flexibility and IMCL content remained unaltered.
The ability of patients with type 2 diabetes to increase mitochondrial function indicates that despite aberrations in the transcriptional control of mitochondrial biogenesis (5
), a lifestyle intervention comprising physical exercise is potent enough to overcome these apparent defects. Increased mitochondrial content and improved function have previously been observed in type 2 diabetic patients following a combined dietary exercise intervention targeting >7% of body weight loss (13
). Here, we show that exercise training, even without substantial loss of body mass, not only improves mitochondrial function but even results in complete restoration toward the control values observed in age- and BMI-matched normoglycemic control subjects. The observation of compromised mitochondrial function in patients with type 2 diabetes compared with that of control subjects, despite comparable mitochondrial density (as indicated by measurement of the protein content of five structural components in the electron-transport chain), supports previous findings of intrinsic defects in mitochondria of patients with type 2 diabetes (10
). Interestingly, mitochondrial protein content markedly increased after exercise training, suggesting that at least a major part of the restoration of mitochondrial function after training is due to increased mitochondrial biogenesis. Although it remains to be established whether exercise training also improves intrinsic mitochondrial function, it is of interest to note that protein expression of UCP3, a protein with a putative role in ameliorating lipotoxicity and oxidative stress via mild uncoupling (37
), was significantly lower in type 2 diabetic patients compared with that in control subjects, confirming previous work (30
). UCP3 content restored to control values after training in type 2 diabetic subjects even after adjustment for the increase in structural components of the electron-transport chain. This may indicate that exercise training in patients with type 2 diabetes not only improves mitochondrial content but also results in adaptive responses within mitochondria to cope better with the myocellular metabolic stress in the insulin-resistant state.
Part of the metabolic stress in type 2 diabetes may originate from myocellular fat storage. IMCL content correlates negatively with insulin sensitivity in untrained subjects (11
). On the other hand, endurance-trained athletes also have high levels of IMCL (11
) while being insulin sensitive. It has thus been suggested that low fat oxidative capacity and a concomitant increase in fatty acid metabolites induces insulin resistance rather than IMCL levels per se (11
). Our present study confirms previous findings of reduced mitochondrial function in type 2 diabetes with IMCL content similar between control subjects and type 2 diabetic patients (9
). This suggests that high IMCL levels combined with compromised mitochondrial function may contribute to impeded insulin sensitivity. This notion is substantiated by our observation that exercise training improved mitochondrial function and alleviated muscular insulin resistance in patients with type 2 diabetes even though IMCL levels increased posttraining.
Training-induced increases in IMCL content may originate from improved partitioning of fatty acids in IMCL due to exercise-induced increases in diacylglycerol-acyl transferase (DGAT1) (42
), the rate-limiting enzyme in IMCL synthesis. Indeed, enhancing IMCL storage capacity by overexpression of DGAT1 improved insulin sensitivity (42
). These findings support the idea that the capacity to effectively store fatty acids as IMCL along with appropriate mitochondrial function are major determinants of myocellular insulin sensitivity. We observed increased IMCL content in type 2 diabetic patients after combined endurance and resistance training in glycolytic type 2 muscle fibers, which in human possess lower IMCL levels than the more oxidative type 1 fibers. It could therefore be suggested that, due to the resistance exercise, previously inactive type 2 fibers were now recruited and increased their storage capacity for fatty acids as IMCL, thereby contributing to the insulin-sensitizing effect of training. This implies that it might be of added value for insulin-sensitizing training interventions to also include exercise at an intensity that requires recruitment of type 2 muscle fibers.
Metabolic inflexibility is another characteristic of insulin-resistant muscles (44
), possibly reflecting a reduced ability of mitochondria to shift fuel selection. Metabolic inflexibility in insulin resistance may reflect reduced insulin-stimulated glucose uptake, thereby reducing the availability of glucose for oxidation, rather than a mitochondrial defect in substrate selection (45
). The present study partly supports this notion. Impaired metabolic flexibility in type 2 diabetes before training was indeed accompanied by a reduced insulin-stimulated rate of glucose disappearance. Moreover, upon training, insulin-stimulated glucose disposal improved in the type 2 diabetic subjects in conjunction with improved metabolic flexibility. Although the improvement in insulin-stimulated glucose disposal completely matched the restoration of metabolic flexibility, restoration of mitochondrial function may be needed to facilitate this. In control subjects, training did not alter metabolic flexibility and also only marginally improved insulin-stimulated glucose disposal. It thus seems that after training, insulin-stimulated glucose oxidation was working at its maximal capacity in both control and type 2 diabetic subjects. Very interestingly, despite a restoration of metabolic flexibility, mitochondrial function, and insulin-stimulated glucose oxidation, insulin-stimulated glucose disposal was still lower in type 2 diabetic than in control subjects. This was completely accounted for by a lower nonoxidative glucose disposal. Thus, upon exercise training the oxidative component of insulin-stimulated glucose disposal is fully restored—in contrast to nonoxidative glucose disposal. Compromised nonoxidative glucose disposal in type 2 diabetes has previousl been reported (46
), and treating insulin-resistant first-degree relatives of type 2 diabetic patients with metformin normalizes nonoxidative glucose disposal (47
), supporting the notion that restoring nonoxidative glucose disposal may be crucial for normalizing insulin sensitivity and possibly plasma glucose in type 2 diabetes.
In a model of one-legged exercise training, nonoxidative glucose disposal improved along with increased fractional velocity of glycogen synthase (48
). The different training regimes applied (one vs. two-legged exercise six times per week vs. three times per week and aerobic exercise solely vs. a combination of aerobic and resistance exercise) in the one-legged exercise study vs. the present study are likely to explain the differences. It should be noted that also in the present study nonoxidative glucose disposal improved in ~30% of patients with type 2 diabetes (albeit nonsignificantly) but was still lower than that of the control group. More recently, restoration of nonoxidative glucose disposal upon exercise training in type 2 diabetic patients has been reported (49
). In that study, however, nonoxidative glucose disposal was measured as the residual of glucose disposal rate minus oxidative glucose disposal and may therefore be biased by hepatic glucose production; thus, the results are hard to compare with the data from the present study. Future studies are needed to identify the mechanism(s) underlying the defective nonoxidative glucose disposal in patients with type 2 diabetes and how to reinstate these defects before full restoration of insulin-stimulated glucose disposal can occur.
While skeletal muscle insulin resistance is a hallmark of type 2 diabetes, insulin resistance of liver and adipose tissue also contributes to the pathogenesis of type 2 diabetes. In this respect, it is relevant to note that exercise training also resulted in beneficial adaptations beyond those reported for muscle. Likewise, we observed that under hyperinsulinemic clamp conditions plasma FFA levels were significantly lower post- than pretraining, possibly reflecting improved antilipolytic activity of insulin in adipose tissue. In addition, exercise training in type 2 diabetic patients improved the ability of insulin to inhibit hepatic glucose output. At present, the routes or mechanisms responsible for these beneficial training-mediated multiple organ adaptations are unknown and warrant further study.
In conclusion, restoration of mitochondrial dysfunction in type 2 diabetes by physical exercise improves insulin-mediated glucose disposal in the presence of increased IMCL storage. Restoration of mitochondrial function and metabolic flexibility in type 2 diabetes by exercise is at least partly accounted for by increased mitochondrial content and possibly by intrinsic mitochondrial adaptations. The insulin-sensitizing effect of exercise training occurs in the absence of major changes in body mass and is not restricted to improved muscle insulin sensitivity but extends to improved hepatic and adipose tissue insulin sensitivity.