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Physical Activity Is the Key Determinant of Skeletal Muscle Mitochondrial Function in Type 2 Diabetes - 'exercise reversed mitochondrial dysfynction in diabetics' perhaps exercise would reverse mitochondrial dysfunction in HIV+: from Jules
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The Journal of Clinical Endocrinology & Metabolism July 16, 2012

"In summary, our most important findings in skeletal muscle of prediabetic and insulin-treated T2DM subjects are that 1) mitochondrial dysfunction is apparent only in inactive longstanding T2DM patients, which indicates that mitochondrial function and insulin resistance do not depend on each other, and 2) mitochondrial dysfunction in longstanding T2DM patients using exogenous insulin therapy can, at least partly, be reversed by prolonged endurance- and resistance-type exercise training."

"To study the long-term effects, eight longstanding T2DM patients completed a 1-yr training protocol. This intervention resulted in increased muscle strength, greater submaximal aerobic capacity, and improved in vivo and ex vivo mitochondrial functioning......Training also improved blood lipid profiles of T2DM subjects (Supplemental Table 3), because high-density lipoprotein and low-density lipoprotein cholesterol levels were, respectively, significantly increased and decreased after 1 yr of exercise training.....gene expression analysis indicated reduced muscle wasting and increased muscle regeneration, especially for type I muscle fibers, which possibly contributes to increased fatty acid oxidation. Exercise training may, therefore, reverse the loss of oxidative fibers in metabolic syndrome and T2DM patients (40)."

Training Procedures

All T2DM patients followed the same one year supervised exercise protocol with 5 months of progressive resistance type exercise training (PRT), supplemented with high-intensity interval exercise training (HIT) of 4-8 cycling bouts of 30/60 s at 50-60% (mean SD) Wmax (De Feyter, Praet et al. 2007). Thereafter, exercise was shifted towards more endurance type exercise training with an average intensity of 79±5% (mean SD) of maximum heart rate frequency and an average duration of 30±6 min per session. The latter was supplemented with 29±6 min (mean SD) of PRT per session. This consisted of 212 repetitions, at 65±6% (mean SD) of 1 repetition maximum strength (1RM) (Reynolds, Gordon et al. 2006), targeting 5-7 major muscle groups of the upper and lower limbs.

All T2DM were on exogenous insulin treatment and had been on a stable medication regimen over the last 3 months prior to being recruited. Seven of the 11 T2DM patients were treated with short (Novorapid,n=6) or rapid acting insulin (Humulin ,n=1) prior to each meal either in combination with NPH insulin (Insulatard,n=5), premixed biphasic insophane insulin (Mixtard 30/70 in combination with metformin, n=1), or a very long-acting insulin analogue (insulin glargine, n=1), all administered before bedtime. Three subjects were treated with premixed biphasic insophane insulin (Mixtard 30/70) twice a day in combination with metformin. One patient used NPH insulin (Humulin NPH) once a day before breakfast in combination with metformin and a sulphonylurea (Glimepiride). None of the subjects used thiazolidinediones or beta- blockers (<6 months).


Conflicting data exist on mitochondrial function and physical activity in type 2 diabetes mellitus (T2DM) development.

Objective: The aim was to assess mitochondrial function at different stages during T2DM development in combination with physical exercise in longstanding T2DM patients.

Design and Methods: We performed cross-sectional analysis of skeletal muscle from 12 prediabetic 11 longstanding T2DM male subjects and 12 male controls matched by age and body mass index.

Intervention: One-year intrasubject controlled supervised exercise training intervention was done in longstanding T2DM patients.

Main Outcome Measurements: Extensive ex vivo analyses of mitochondrial quality, quantity, and function were collected and combined with global gene expression analysis and in vivo ATP production capacity after 1 yr of training.

Results: Mitochondrial density, complex I activity, and the expression of Krebs cycle and oxidative phosphorylation system-related genes were lower in longstanding T2DM subjects but not in prediabetic subjects compared with controls. This indicated a reduced capacity to generate ATP in longstanding T2DM patients only. Gene expression analysis in prediabetic subjects suggested a switch from carbohydrate toward lipid as an energy source. One year of exercise training raised in vivo skeletal muscle ATP production capacity by 21±2% with an increased trend in mitochondrial density and complex I activity. In addition, expression levels of ß-oxidation, Krebs cycle, and oxidative phosphorylation system-related genes were higher after exercise training.

Conclusions: Mitochondrial dysfunction is apparent only in inactive longstanding T2DM patients, which suggests that mitochondrial function and insulin resistance do not depend on each other. Prolonged exercise training can, at least partly, reverse the mitochondrial impairments associated with the longstanding diabetic state.

Type 2 diabetes mellitus (T2DM) is characterized by peripheral insulin resistance and impairments in pancreatic insulin secretion. Skeletal muscle is the critical organ, accounting for approximately 75% of insulin-mediated glucose disposal (1). The majority of ATP is generated by oxidative phosphorylation in the mitochondria, and alterations in skeletal muscle mitochondrial quality and quantity have been observed in T2DM patients (2, 3). However, other studies have failed to confirm such impairments (4, 5). Similarly, in vivo and ex vivo measurements of ATP production capacity have been reported to be reduced in skeletal muscle of T2DM patients compared with age- and body mass index (BMI)-matched controls in some (6, 7) but not in all studies (4, 8). These inconsistencies could be (partly) explained by different patient characteristics, lifestyle, and/or analysis methods.

Mitochondrial function is negatively affected by the sedentary lifestyle many T2DM patients have adopted (9). The lack of sufficient physical activity reduces the expression of genes involved in mitochondrial biogenesis and metabolism (10, 11). Reconditioning by endurance and/ or resistance-type exercise training has proven an effective therapeutic strategy in T2DM patients, improving glycemic control, lowering blood pressure, and reducing oxidative stress (12). Physical performance capacity of T2DM patients is strongly associated with their disease status. T2DM patients with complications, such as polyneuropathy, generally display muscle weakness (13), impaired physical performance (9), poor glycemic contro, land a high cardiovascular risk profile (14). These subjects are generally not advised to participate in more intense exercise intervention programs because insufficient data are available on the clinical benefits and potential health risks of such interventions. Nevertheless, prolonged resistance-and interval-type exercise training has been shown to augment maximal workload capacity, reduce resting blood pressure, and attenuate the progressive increase in exogenous insulin (EI) requirements in longstanding, insulin-treated T2DM patients with comorbidities (15).

Our study analyzed mitochondrial quality and quantity and global gene expression profiles in skeletal muscle from prediabetic and longstanding T2DM patients compared with normoglycemic age- and BMI-matched controls. Furthermore, we determined the capacity of prolonged exercise training as a means to attenuate or even reverse the progression of the T2DM disease in longstanding insulin- treated T2DM patients.

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