Effect of Short-Term Exercise Training on ATP Synthesis in Relatives of Type 2 Diabetic Humans
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      First degree relatives of type 2 diabetic patients (T2DM) suffer an increased risk of
      developing this disease themselves, starting with impaired insulin sensitivity. This risk can
      be minimized by lifestyle interventions such as regular exercise training. Until this day,
      little is known about the short-term effects of exercise training on insulin sensitivity and
      the lipid content of the liver and skeletal muscle.
    

Detailed description: 
      Life style intervention including diet and exercise is the recommended strategy for the
      prevention of type 2 diabetes mellitus (T2DM). First-degree relatives of patients with type 2
      diabetes mellitus (T2DM) have an increased risk of insulin resistance and T2DM. According to
      the current paradigm, inherited and environmental factors cause insulin resistance by
      increasing intramyocellular lipid metabolites and stimulation of inflammatory pathways which
      both interfere with insulin signal transduction leading to an impaired rise of
      glucose-6-phosphate (G6P) upon insulin stimulation indicating impaired glucose
      transport/phosphorylation. In sedentary humans, these alterations can coexist with excessive
      storage of triglycerides as intramyocellular or hepatocellular lipids (IMCL, HCL). This
      indicates reduction of the muscles´ oxidative capacity which has been confirmed by
      demonstration of decreased mitochondrial function and/or number in insulin resistant states
      such as aging, increased availability of plasma free fatty acids (FFA) and overt T2DM.
      Likewise, severely insulin resistant, but nondiabetic relatives present with elevated FFA,
      IMCL and HCL along with impaired mitochondrial ATP synthesis which most likely results from
      reduced mitochondrial contents. However, it is unclear whether these alterations are only due
      to inherited abnormalities of mitochondrial biogenesis or secondary to chronically impaired
      glucose tolerance, increased lipid availability or inflammatory processes which are
      controlled by cytokines such as adiponectin, visfatin and retinol binding protein-4 (RBP4).

      Likewise it remains uncertain to which extent such abnormalities are reversible by physical
      exercise stimulation and/or occur independently of effects on insulin action.

      Long-term endurance exercise training increases insulin sensitivity in sedentary young and
      elderly healthy, first degree relatives of type 2 diabetic patients, glucose intolerant and
      obese nondiabetic or type 2 diabetic humans. Exercise training for at least 4 weeks also
      enhances fat oxidation along with increased size, number and enzyme activities of
      mitochondria. However, little is known on the time course and onset of exercise-induced
      changes in glucose and energy metabolism independently of the acute exercise effects
      occurring within the first 24 hours. At 48 hours after one bout of aerobic exercise,
      insulin-stimulated glucose disposal and IMCL can be increased or unchanged. Effects of
      short-term exercise on the underlying energy generating pathways have not yet been reported
      in vivo in humans. Flux of inorganic phosphate (Pi) to ATP through ATP synthase (fATPase)
      provides a measure of mitochondrial ATP synthesis.

      We use multinuclear magnetic resonance spectroscopy (MRS) to simultaneously measure fATP as
      well as G6P, IMCL and HCL before and after three bouts of cycling training. We will test the
      hypotheses that short-term exercise training simultaneously increases fATPase and insulin
      sensitivity in healthy humans (control) and in relatives. Furthermore, we will investigate
      whether baseline fATPase reflects whole-body oxidative capacity and whether post-exercise
      fATPase is influenced by lipid availability due to alterations in IMCL, HCL or circulating
      triglycerides or FFA.
    

Intervention name(s): exercise training
Intervention type(s): Other
Intervention description(s): 3 bouts of exercise at 90%RCP during one week
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: type 2 diabetes,; exercise training,; ATP-synthesis,; intramyocellular lipids,; hepatocellular lipids; first degree relatives of; patients