2Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
Keywords: Cardiorespiratory Fitness; Type 2 Diabetes; Oxygen Uptake Kinetics; Sedentary Lifestyle; Thiazolidinedione
However, patients with diabetes are often sedentary. According to a survey of the US population including 23,283 people in 2003, compared with 58% of adults without diabetes, only 39% of adults with diabetes were physically active, i.e., engaged in more than 30 min of moderate or vigorous physical activity at least three times a week . A UK study also revealed that two-thirds of patients with diabetes had not participated in any physical activity in the two weeks before the study . Among these "inactive" patients, younger (< 60 years) patients stated that a lack of spare time or local facilities were the main barriers to exercise. In addition, they were less likely to exercise if they were tired.
Gender (male=1, female=0)
Heart Rate Recovery
ß are standard coefficient of each independent variable.
R2 is the coefficient of determination.
Commitment to exercise by the medical staff, adequate space and equipment, or interesting and stimulating regional programs or interventions, are necessary elements for improving adherence to exercise in these unfit and unmotivated patients. More patients with type 2 diabetes will possibly undertake workouts if counseled to do so. However, counseling by the medical staff unfortunately does not seem to be sufficient. According to the National Health Interview Survey in 2010, 56% of adults with diabetes in the US had been recommended to commence or continue to perform exercise or physical activity by their physicians or other health professionals in the previous year . Although these patients were more likely to have been advised exercise than those patients who had other chronic diseases, such as hypertension, cardiovascular disease, and cancer, patients were still less likely to attempt exercise.
Regarding the potential pharmacological approaches used to augment cardiorespiratory fitness, thiazolidinedione (TZD), an insulin-sensitizing agent, is known to improve peak VO2 in the graded exercise test in patients with type 2 diabetes [32,33]. No human study regarding the effect of pioglitazone on cardiorespiratory fitness is available, although a few reports have shown that pioglitazone improved exercise capacity in diabetic mice . It has been reported that 4–8 mg/day of rosiglitazone administration increased peak VO2 by 4%–7% in patients with type 2 diabetes [32,33], although a few studies with a relatively short-term intervention period (4–12 weeks) concluded that there was no effect of rosiglitazone therapy on cardiorespiratory fitness [35,36]. Some mechanisms for TZDs and how these improve cardiorespiratory fitness have been suggested. First, TZDs stimulate the differentiation of adipocytes as an agonist for the nuclear hormone receptor proxisome proliferator-activated receptor γ (PPARγ) and for the storage of fatty acids mainly in the subcutaneous adipose tissue . These changes in the adipocyte consequently decrease the level of intramyocellular/ intrahepatic triglycerides and cellular lipotoxicity, which results in improvements in mitochondrial and endothelial functions. In addition, the differentiation of adipocytes increases the secretion of adiponectin, an adipocytokine known to ameliorate insulin resistance. Adiponectin is also known to induce the production of nitric oxide from arterial endothelial cells . Kadoglou et al. has demonstrated that the rosiglitazone-induced increase in cardiorespiratory fitness was closely associated with an increase in plasma adiponectin in patients with type 2 diabetes . Furthermore, TZDs as well as exercise are known to activate the skeletal muscle AMP-activated protein kinase (AMPK), which most likely results in an increase in cardiorespiratory fitness through enhanced fat oxidation and mitochondrial biogenesis in the skeletal muscle. However, it should be acknowledged that the administration of TZDs is only an option. Exercise or increased physical activity is a low-cost, simple intervention for the management of diabetes and should be given first priority in the strategy for improving cardiorespiratory fitness. Furthermore, the therapeutic approach using TZDs should be considered on a case-by-case based on the balance of the aforementioned advantages and potential side effects (including increasing serum LDL-cholesterol level and bone fracture) of the drugs as well as the existing patient co-morbidities.
It has been shown that metformin, another activator of AMPK, reduced peak VO2, peak heart rate, and exercise duration in the graded exercise test with healthy, normal-weight subjects . administration of metformin did not affect cardiorespiratory fitness . The inconsistency of TZD and metformin effects on cardiorespiratory fitness may be attributed to the difference in the mechanism of how these two insulin sensitizers activate AMPK. These two drugs share the process of indirect AMPK activation by inhibiting complex 1 of the mitochondrial respiratory chain and by consequently increasing AMP synthesis; specifically, TZDs activate AMPK through the effects of PPARγ to stimulate adiponectin secretion. It remains to be clarified whether the unfavorable effect of metformin on exercise capacity is the same for patients with diabetes or obesity, although a non-randomized, observational study concluded that metformin users with type 2 diabetes had no disadvantage in improving their cardiorespiratory fitness by aerobic or resistance training .
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