Type 2 diabetes (T2D) is a global burden disease affecting almost 200 million people and is expected to nearly double by 2030 (1). It is imperative that this disease is kept under control, and that we begin to reverse the direction of its incidence. We propose to start by identifying the physiological and molecular aspects of the problem in all spectrums of the disease (ie from insulin sensitive athletes to sedentary lean and obese individuals and further to overt type 2 diabetics), and focus our efforts on examining the differences and identifying the stages of progression for possible targets of future intervention. The proposed study "Metabolic Phenotyping" is novel in its target populations and innovative in its use of state-of-the-art techniques. We hypothesize that the in vivo differences in metabolic flexibility and mitochondrial function between endurance athletes and type 2 diabetics and their lean and obese controls are retained in vitro and will offer a new model in which to study the underlying mechanisms of the progression of T2D.
The aim of the present research proposal is to metabolically phenotype endurance trained athletes, lean and obese sedentary and type 2 diabetic individuals with the following objectives: 1. assess metabolic flexibility as measured by a euglycemic-hyperinsulinemic clamp 2. measure in vivo mitochondrial function by MRS of phosphocreatine (PCr) recovery 3. establish primary myoblast cell lines to correlate with the above in vivo measurements, as well as further explore dietary, pharmacological and genetic manipulations in vitro 4. quantify intramyocellular lipid (IMCL) and acetylcarnitine in vivo by MRS Study population: A total of 132 male participants (18-70 years) will participate in this study. The first group of 33 participants will be lean endurance-trained athletes, the second group will be lean sedentary control participants, the third group will be sedentary type 2 diabetic participants, and the last group of 33 participants will be obese, non-diabetic sedentary control participants. It is preferred to use male participants in order to minimize variation in the measurements by avoiding confounding factors such as hormones. Main study parameters/endpoints: The main study parameters are differences in metabolic flexibility as measured by euglycemic-hyperinsulinemic clamp, PCr recovery, IMCL and acetylcarnitines as measured by MRS and establishment of primary myoblast cell lines for future use.
Study Type
OBSERVATIONAL
Enrollment
132
Maastricht University
Maastricht, Limburg, Netherlands
RECRUITINGEuglycemic-hyperinsulinemic clamp for measurement of insulin sensitivity and metabolic flexibility
After taking fasting blood samples, a primed constant infusion of glucose is initiated. Plasma glucose levels are clamped at \~5 mmol/L by variable co-infusion of 20% glucose. Every 5 minutes, blood is sampled for immediate determination of plasma glucose concentration. Glucose infusion rate is adjusted to obtain plasma glucose levels of \~5 mmol/L (euglycemia). A bolus of insulin is then infused. Before and during steady state, substrate oxidation is measured using an indirect calorimeter, which determines metabolic flexibility.
Time frame: 10 hours
Evaluating mitochondrial function through measurement of phosphocreatine (PCr) recovery by phosphorus magnetic resonance spectroscopy (31P-MRS) within the skeletal muscle
The quantification of energy metabolites (Pi, PCr and ATP) in skeletal muscle will be performed in the v. lateralis at rest, during submaximal knee-extension exercise and during recovery. The rate at which PCr concentration is restored after exercise is an excellent in vivo measure of skeletal muscle mitochondrial oxidative capacity.
Time frame: 1.5 hours
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