RECO1: Effect of Short-Term Exercise Training on ATP Synthesis in Relatives of Type 2 Diabetic Humans

Sponsor

Landsteiner Institut (Other)

Overall Status

Completed

CT.gov ID

NCT00710008

Collaborator

Mein Hanusch-Krankenhaus (Other), Karl-Landsteiner Institute for Endocrinology and Metabolism (Other), Medical University of Vienna (Other), Lund University Hospital (Other), Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy (Other)

Enrollment

Location

Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Other: exercise training	N/A

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

26 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Effect of Short-Term Exercise Training on ATP Synthesis in Relatives of Type 2 Diabetic Humans

Study Start Date :

Feb 1, 2006

Actual Primary Completion Date :

Jun 1, 2008

Actual Study Completion Date :

Jun 1, 2008

Outcome Measures

Primary Outcome Measures

ATP-Synthesis, liver lipid content, skeletal muscle lipid content []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

First degree relatives of type 2 diabetic patients
Age: 18-50 years
BMI <30 kg/m2 (due to limited MR diameter)
Normal routine lab tests (blood cell count, kidney, liver, pancreas, thyroid and neuromuscular function)
Availability within the local area throughout the study
Ability to understand and sign the consent forms