Impact of Aerobic Exercise Training on Insulin Sensitivity by jlhd32

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									                                                                                        IMPACT OF ENDURANCE EXERCISE ON INSULIN SENSITIVITY, PHYSICAL FITNESS AND
                                                                                            MUSCLE OXIDATIVE CAPACITY IN OFFSPRING OF TYPE 2 DIABETIC PATIENTS
                                                                                                                                             Torben Østergård 1, Kevin R Short 2, Bengt Saltin 3, KS Nair 2, Ole Schmitz 1
                                                                                                                                      1Medical
                                                                                                                                Dpt. M (Endocrinology and Diabetes), Aarhus University Hospital, Denmark;
                                                                                      2    Division of Endocrinology, Mayo Clinic and Foundation, Rochester, MN, USA; 3Copenhagen Muscle Research Center, Rigshospitalet, Denmark


             First-degree relatives of type 2 diabetic patients (FDR) are
                                                                                                                                                                                                                                                                                                                                                                                                                         r=0.06, P=0.76                                                                                                 r=0.57, P=0.01
             often employed when studying potentially early steps in the
                                                                                                                                                                                                                                                                                                                                                                                                               6                                                                                                       6




  1          development of type 2 diabetes. Insulin resistance and
                                                                                                                                   3                                                                                                                                                    Control
                                                                                                                                                                                                                                                                                                                                       5                                                                       4                                                                                                       4




                                                                                                                                                                                                                                                                                                                                                                                           ∆ISGU (mg/kg/min)




                                                                                                                                                                                                                                                                                                                                                                                                                                                                             ∆ISGU (mg/kg/min)
             impaired physical capacity (VO2max) are frequently                                                                                                                                                                    FDR                                                                                     p                                                                                   2                                                                                                       2

                                                                                                                                                                                                                                                                                        subjects
             demonstrated in healthy and normal glucose tolerant FDR.                                                                                                                                                                                                                                                                                                                                          0                                                                                                       0


                                                                                                                                                     N                                                                             29                                                   19
Background


                                                                                                                                                                                                                                                                                                                                                                                                               -2                                                                                               -2

             Both insulin sensitivity and VO2max are associated with
                                                                                                                                                     Gender (m/f)                                                                  19/10                                                14/5
             skeletal muscle oxidative capacity. Interestingly, evidence of
                                                                                                                                                                                                                                                                                                                                                                                                               -4                                                                                               -4
                                                                                                                                                                                                                                                                                                                                                                                                                    -5     0           5        10         15      20   25                                                         -5      0     5         10        15          20      25

                                                                                                                                                                                                                                                                                                                                                                                                                                       ∆VO2max (ml/kg/min)                                                                                       ∆VO2max (ml/kg/min)

             reduced muscle oxidative capacity and impaired                                                                                          Age (years)                                                                   33.3 ± 5.5                                           30.7 ± 5.5                         0.11
             mitochondrial function have recently been demonstrated in                                                                               BMI (kg/m 2)                                                                  26.3 ± 1.6                                           25.8 ± 3.0                         0.54
                                                                                                                                                                                                                                                                                                                                                                                                                                      Changes in insulin sensitivity and in VO2max were only
                                                                                                                                                                                                                                                                                                                                                                                                                                                    related in control subjects
             both patients with type 2 diabetes (1) as well as in healthy




                                                                                                                                  Subjects
             first-degree relatives of patients with type 2 diabetes (2).                                                                            Waist-hip ratio                                                               0.90 ± 0.05                                          0.89 ± 0.07                        0.31
                                                                                                                                                                                                                                                                                                                                                                                      70
                                                                                                                                                                                                                                                                                                                                                                                                                                    P=0.12
                                                                                                                                                                                                                                                                                                                                                                                                                                              P=0.32                                                                               50                              P=0.10




                                                                                                                                                                                                                                                                                                                                     Results
             Thus, as mitochondrial dysfunction might link insulin                                                                                   F-p-glucose (mM)                                                              5.3 ± 0.5                                            5.1 ± 0.3                          0.07                                                                                                                                                                                                                          P=0.07




                                                                                                                                                                                                                                                                                                                                                   COX enzyme activity (arb. units)
                                                                                                                                                                                                                                                                                                                                                                                      60




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 CS enzyme activity (arb. units)
             resistance and decreased VO2max we sought to explore
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   40
                                                                                                                                                                                                                                                                                                                                                                                      50                                                             *
                                                                                                                                                                                                                                                                                                                                                                                                                                *                                                                                                                                         *
             whether first-degree relatives differ in the ability to improve                                                                         F-s-insulin (pM)                                                              54 ± 29                                              55 ± 30                            0.98                                                       40                                                                                                                                           30                *

             skeletal muscle oxidative capacity, insulin sensitivity and




                                                                                                                                                                                                                                                                                                                                                                                                                                    Post-ex



                                                                                                                                                                                                                                                                                                                                                                                                                                                         Post-ex
                                                                                                                                                                                                                                                                                                                                                                                      30




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         Post-ex



                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               Post-ex
                                                                                                                                                                                                                                                                                                                                                                                                                         Pre-ex



                                                                                                                                                                                                                                                                                                                                                                                                                                               Pre-ex
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   20




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               Pre-ex



                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Pre-ex
                                                                                                                                                     F-C-peptide                                                                   646 ± 207                                            531 ± 150                          0.04*
             physical capacity compared with a group of age, gender and
                                                                                                                                                                                                                                                                                                                                                                                      20
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   10
                                                                                                                                                                                                                                                                                                                                                                                      10

             BMI matched control group.                                                                                                              VO2 max (ml/kg/min)                                                           38.0 ± 6.5                                           40.8 ± 6.1                         0.14                                                       0
                                                                                                                                                                                                                                                                                                                                                                                                                               Offspring             Controls
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    0
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Offspring               Controls

             1. Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2                             Insulin sensitivity, M
             diabetes. Diabetes 2002; 51(10):2944-2950.                                                                                                                                                                            5.5 ± 1.9                                            7.2 ± 2.6                          0.01*                                                                         At baseline COX and CS enzyme activities in skeletal muscle tended to be
             2. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant                      (mg/kg/min)
             offspring of patients with type 2 diabetes. N Engl J Med 2004; 350(7):664-671.
                                                                                                                                                                                                                                                                                                                                                                                                       reduced in first-degree relatives. Exercise increased enzyme activities in both
                                                                                                                                                                                                                                                                                                                                                                                                       groups (* P < 0.001). The magnitude of these changes did not differ between
                                                                                                                                                                                                                                                                                                                                                                                                                             first-degree relatives and controls.




             Inclusion criterias:                                                                                                                                                                                                                                                                                                                  In conclusion:
             •Sedentary (VO2max ≤ 50 ml/kg/min)                                                                                                                                                     r=0.009, P=0.96
                                                                                                                                                                                                                                                                                                                                                   In conclusion, this study shows that first-degree
                                                                                                                                                                                 16                                                                                     16
                                                                                                                                                                                                                                                                                        r=0.67, P=0.002




                                                                                                                                                                                                                                                                                                                                     Conclusions
2                                                                                                                                 4
                                                                                                                                                                                 14                                                                                     14

             •Age 20-50 years                                                                                                                                                                                                                                                                                                                      relatives of type 2 diabetic patients are able to




                                                                                                                                                         ISGU (mg/kgLBM/min)




                                                                                                                                                                                                                                                  ISGU (mg/kgLBM/min)
                                                                                                                                                                                 12                                                                                     12


             •BMI ≤ 30 kg/m2                                                                                                                                                     10                                                                                     10
                                                                                                                                                                                                                                                                                                                                                   respond adequately to endurance training in terms
             •Normal glucose tolerance                                                                                                                                               8                                                                                         8



             •Offspring: at least two relatives diagnosed with type 2                                                                                                                6                                                                                         6                                                                   of changes in VO2max and insulin sensitivity.
             diabetes (at least one parent)
                                                                                                                                                                                     4                                                                                         4
                                                                                                                                                                                                                                                                                                                                                   However, contrasting that of the control group we
                                                                                                                                                                                                                                                                                                                                                   found a lack of a significant correlation between the
                                                                                                                                                                                     2                                                                                         2

             •Control subjects: no relatives diagnosed with type 2                                                                                                                            35      40     45      50     55

                                                                                                                                                                                                              VO2max (ml/kgLBM/min)
                                                                                                                                                                                                                                   60   65   70                                    35     40      45       50   55    60

                                                                                                                                                                                                                                                                                                   VO2max (ml/kgLBM/min)
                                                                                                                                                                                                                                                                                                                           65   70




             diabetes                                                                                                                                                                               At baseline insulin sensitivity and VO2max did only correlate in controls
                                                                                                                                                                                                                                                                                                                                                   increased VO2max and insulin sensitivity. In
             Exercise-protocol:                                                                                                                                                                                                                                                                                                                    accordance with previous studies we found
             10 weeks of cycle-ergometer training, 3 times per week, 45
                                                                                                                                                                                                                                                                                                                                                   indications of reduced oxidative capacity (citrate
                                                                                                                                  Results
                                                                                                                                                                                               55                                                                                  10
Design




             minutes each session at 70% of VO2max.                                                                                                                                            50
                                                                                                                                                                                                                                                                                   9                                                               synthase and cytochrome c oxidase activities) in
                                                                                                                                                                                                                                                                                                                                                   first-degree relatives of type 2 diabetic patients.
                                                                                                                                                                         VO2max (ml/kg/min)




                                                                                                                                                                                                                                                            ISGU (mg/kg/min)
             Before and after the training period:
                                                                                                                                                                                                                                                                                   8


                                                                                                                                                                                                                                                                                                                                                   Whether these observations are interrelated cannot
                                                                                                                                                                                               45


             •Hyperinsulinemic (1 mU/kg/min), euglycemic (5 mmol/l)
                                                                                                                                                                                                                                                                                   7



             glucose clamp for 150 minutes (M-value).
                                                                                                                                                                                               40
                                                                                                                                                                                                                                                                                   6                                                               be determined by this study. Nonetheless, in the
                                                                                                                                                                                               35
                                                                                                                                                                                                                                                                                   5                                                               light of previous reports documenting reduced
             •Incremental maximal exercise test (bicycle ergometer test)                                                                                                                                   Pre-ex vs. post-ex: P<0.001                                                         Pre-ex vs. post-ex: P<0.05
                                                                                                                                                                                               30                                                                                  4                                                               oxidative capacity in type 2 diabetic subjects and
                                                                                                                                                                                                                                                                                                                                                   their offspring we consider it to be a very tempting
                                                                                                                                                                                                            Week 0        Week 5   Week 10                                                        Pre-ex        Post-ex
             •Skeletal muscle citrate synthase (CS) and cytochrome c
             oxidase (COX) activites                                                                                                                                                                       VO2max and insulin sensitivity were improved equally in both
                                                                                                                                                                                                                                                                                                                                                   hypothesis.
                                                                                                                                                                                                               first-degree relatives (●) and control subjects (o)

								
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