We observed no abnormality in mitochondrial function in people with well-controlled type 2 diabetes compared with physical activity–, age-, and weight-matched control subjects. There was no relationship between basal (fasted) and maximal (recovery from exercise) ATP synthesis, suggesting that the factors influencing basal and maximal ATP synthesis are different. The physical activity intervention markedly increased the number of steps taken per day during the 8-week intervention. Fasting lipid oxidation was increased, but there was no change in ATP turnover or maximal ATP production.
The observation of no abnormality in basal ATP flux contrasts with recent studies. The seminal study (2
) indicating the possible importance of mitochondrial function in development of type 2 diabetes observed basal ATP flux in extreme phenotypes of insulin sensitivity. From 150 screened subjects, the most and least insulin-sensitive people underwent assessment of basal ATP flux and IMCL using magnetic resonance techniques. The 14 least insulin-sensitive subjects (with a family history of diabetes) had lower basal ATP flux and higher intramuscular lipid levels than the 10 most insulin-sensitive people. It was suggested that impaired mitochondrial function reduces the ability to oxidize lipids, with accumulation of intramuscular lipid impeding insulin signaling (5
), forming a pathway from impaired mitochondrial function to the development of type 2 diabetes. A further study (3
) demonstrated impaired ATP flux in people with type 2 diabetes, but the control subjects were unmatched for habitual physical activity. The present data agree with a recent study (9
) reporting no difference in basal ATP use between age-, weight-, and physical activity–matched subjects with and without type 2 diabetes using saturation transfer magnetic resonance. This study was only able to demonstrate differences in ATP flux in people with type 2 diabetes under insulin-stimulated conditions. The observation of no abnormality in basal ATP flux in diabetes implies that abnormal basal mitochondrial function is unlikely to be a primary causative factor in type 2 diabetes.
In contrast to basal ATP synthesis rates, which are primarily influenced by steady-state energy demand, the recovery of PCr from exercise is a robust measure of maximal oxidative ATP turnover (19
). This also reflects the recovery from muscular activity that happens frequently throughout the waking day, and any abnormality could bring about marked differences in muscle metabolism that may be associated with type 2 diabetes. The present data show no differences in the recovery of PCr from exercise between people with and without type 2 diabetes when controlled for habitual physical activity, weight, and age. To our knowledge, the present study is the first report to include both measures of basal and maximal ATP turnover in people with or without diabetes. No correlation was found between the basal and maximal ATP turnover rates. The lack of relationship between basal and maximal ATP turnover supports the concept that ATP turnover in these tests is determined by different factors. In the fasted, nonexercise state, the level of insulin-stimulated glucose uptake is likely to dominate requirement for ATP synthesis. This suggestion is based on studies that show a robust relationship between ATP synthesis and insulin-stimulated glucose uptake in skeletal muscle (9
). In the postexercise stimulated state, the ability to supply and use oxygen is likely to dominate the rate of ATP turnover. The lack of correlation between the basal and maximal measures of ATP synthesis highlights the importance of examining separately these differing states.
A previous study (3
) reported maximal ATP turnover to be reduced in people with type 2 diabetes compared with a BMI-matched control group. However, this study did not objectively control for differences in habitual physical activity, a factor that can influence mitochondrial function (13
). People with type 2 diabetes tend to be less physically active than people without diabetes (11
). Indeed, the reported PCr recovery data postexercise of people with type 2 diabetes (3
) are comparable with both the type 2 diabetes and control groups in the present study, raising the likelihood that the differences in maximal ATP turnover may lay in differences in habitual physical activity. Recent support has also been given to the idea that type 2 diabetes is not necessarily associated with impaired mitochondrial function but may reflect differences in mitochondrial volume. Direct analyses of mitochondria from biopsies taken from people with type 2 diabetes show that any apparent defect in mitochondrial ATP production disappears when corrected for mitochondrial density (10
). The reduced oxidative capacity accompanying type 2 diabetes may be the result of a deconditioning phenomenon (24
The present study shows that walking an extra 45 min per day over an 8-week period is an insufficient stimulus to induce detectable mitochondrial biogenesis. The physical activity was deliberately chosen to be of low intensity, as walking has been shown to be achievable and sustainable by people with type 2 diabetes (15
). More intensive and prolonged physical activity and diet does change mitochondrial density and aerobic capacity (14
). These changes correlate well with improvements in long-term glucose control and fasting insulin sensitivity. Other biopsy data suggest that the beneficial effect of exercise and moderate weight loss upon mitochondrial density is modest (26
). However, the in vitro function of mitochondria is improved, with a disproportionate increase in electron transfer chain activity following intervention. The improvements of mitochondrial function accompanying exercise are not replicated by weight loss alone (27
), stressing the importance of exercise in modifying oxidative capacity and maintaining metabolic flexibility. Further work is required to define the long-term effects of practically sustainable physical activity on mitochondrial function in muscle.
In type 2 diabetes changes in mitochondrial capacity are intertwined with changes in lipid oxidation (7
). The present data demonstrate physical activity–induced enhancement of resting lipid oxidation, independent of intramuscular lipid levels. Type 2 diabetes is characterized by both abnormal lipid storage and oxidation, with glucose control commonly reported to be negatively related to intramuscular lipid content (2
) via an effect on insulin action (5
). Walking for an extra 45 min each day increases skeletal muscle mRNA expression of genes implicated in glucose and lipid metabolism (25
). The cumulative effect of a sustained increase in lipid oxidation and decrease in IMCL would be expected to improve blood glucose control (15
). The effects of increased physical activity upon circulating triglyceride turnover, and the consequential influence upon insulin action, remain to be determined.
An important aspect of this study is that people with type 2 diabetes were able to sustain a more physically active lifestyle without supervision, and this would be expected to influence metabolic risk and glucose control (29
). The study was not powered to detect changes in glucose control in the basal state, as this was not a primary objective. However, measures of glucose control were lower following increased physical activity. Other dynamic testing methods may have been more sensitive to changes in insulin sensitivity than homeostasis model assessment. These data are in line with larger, better powered studies of walking interventions (12
). No change in serum triglycerides occurred in either group (data not shown). It is also possible that the various motivations for taking part in this study produced differences in the physical activity behavior. It is notable that the diabetic individuals sustained the level of physical activity better than the nondiabetic control group. The challenge ahead is to better understand how we can engage people with type 2 diabetes in reducing sedentary periods as well as to define how the underlying physiological mechanisms produce these benefits.
The magnetic resonance methods applied here, and previously (2
), are not without limitation. As the mitochondria are not isolated, ATP production may be limited by external factors, such as the supply of oxygen or ATP demand. However, with these limitations noted, it is clear that these noninvasive techniques provide a patient-friendly methodology that can be applied serially and complements more detailed in vitro techniques.
In summary, resting and maximal ATP turnover are not impaired in people with well-controlled type 2 diabetes, when compared with control subjects matched for physical activity as well as age and weight. Increased daily physical activity in the form of walking is sustainable and improves lipid oxidation independent of mitochondrial activity in people with type 2 diabetes.