Metabolic Phenotyping in Humans (MetPhe)

Metabolic Characterization of Type 2 Diabetic, Obese, Lean Sedentary and Endurance Trained Individuals in Vivo, ex Vivo and in Vitro

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.

Study Overview

• Status: Recruiting
• Conditions: Healthy; Obesity; Type 2 Diabetes Mellitus

Detailed Description

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 (Anticipated): 132

Contacts and Locations

• Study Contact: Name: Madeleen Bosma, M.S.; Phone Number: 31433884254; Email: m.bosma@maastrichtuniversity.nl
• Study Contact Backup: Name: Bram Brouwers, B.S.; Phone Number: 31433884258; Email: b.brouwers@maastrichtuniversity.nl

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6200MD
      • Recruiting
      • Maastricht University
      • Contact: Madeleen Bosma, M.S.; Phone Number: 31433884254; Email: m.bosma@maastrichtuniversity.nl
      • Principal Investigator: Lauren M Sparks, PhD
      • Principal Investigator: Madeleen Bosma, M.S.
      • Sub-Investigator: Vera Schrauwen-Hindeling, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

Study Population

Human volunteers from the surrounding area

Description

General Inclusion criteria:

• Male sex
• Generally healthy with specifically no known cardiovascular disease or gastric ulcers, which can affect the study parameters
• Stable dietary habits (no weight loss/gain > 3 kg in the last 6 months)

Group 1, type 2 diabetes participants:

• Ages 40-70 years
• BMI > 30 kg/m2
• Non-insulin dependent type 2 diabetes
• Must be on sulphonylurea (SU)-derivate or metformin therapy for at least six months with a constant dose for at least two months, or on dietary treatment for at least six months
• Well-controlled diabetes: HbA1c < 8%
• No diabetes related co-morbidities like cardiovascular diseases, diabetic foot, polyneuropathy, retinopathy

Group 2, obese healthy control participants:

• Ages 40-70 years
• BMI > 30 kg/m2
• A plasma glucose level lower than 6.1 mmol/L
• No family history of diabetes
• No medication use
• Sedentary lifestyle; No participation in any physical activity for at least 2 years

Group 3, endurance trained athletes:

• Ages 18-35 years
• BMI < 25 kg/m2
• No family history of diabetes
• No medication use
• VO2max > 55ml/kg/min
• Active in competitive endurance-exercise activities, 3 times a week for at least 2 years
• Stable level of training for at least 6 months

Group 4, lean healthy sedentary control participants:

• Ages 18-35 years
• BMI < 25 kg/m2
• No family history of diabetes
• No medication use
• VO2max < 55ml/kg/min
• Plasma glucose < 6.1 mmol/L
• Sedentary lifestyle; No participation in physical activity for more than 1 hour per week for at least 2 years

General Exclusion criteria:

• Regular smokers
• Participation in other studies
• Female sex
• Insulin dependent diabetic individuals
• Participants with diabetes related diseases (diabetic foot, diabetic polyneuropathy, diabetic retinopathy etc.)
• Use of Thiazolidines (glitazone/rosiglitazone/pioglitazone/troglitazone)
• Use of anti-coagulants (not thrombocyte-aggregation inhibitors)
• Aberrant ECG (with signs of ischemia or cardiac failure or arrythmias)
• Weight gain/loss > 3 kg in the last 6 months
• HbA1c < 7.8 in type 2 diabetic individuals

• Contraindications for MRS scans:

  • Electronic implants such as pacemakers or neurostimulator
  • Iron-containing foreign bodies in eyes or brain
  • Some hearing aids and artificial (heart) valves which are contraindicated for MRS
  • Claustrophobia
• Participants, who do not want to be informed about unexpected medical findings, or do not wish that their physician be informed, cannot participate in the study.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Euglycemic-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.	10 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	1.5 hours

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Investigators: Study Director: Patrick Schrauwen, PhD, Maastricht University; Principal Investigator: Lauren M Sparks, PhD, Maastricht University; Principal Investigator: Madeleen Bosma, M.S., Maastricht University

Publications and helpful links

General Publications

• Houzelle A, Jorgensen JA, Schaart G, Daemen S, van Polanen N, Fealy CE, Hesselink MKC, Schrauwen P, Hoeks J. Human skeletal muscle mitochondrial dynamics in relation to oxidative capacity and insulin sensitivity. Diabetologia. 2021 Feb;64(2):424-436. doi: 10.1007/s00125-020-05335-w. Epub 2020 Nov 30.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Anticipated): March 1, 2024
• Study Completion (Anticipated): March 1, 2024

Study Registration Dates

• First Submitted: February 16, 2011
• First Submitted That Met QC Criteria: February 16, 2011
• First Posted (Estimate): February 17, 2011

Study Record Updates

• Last Update Posted (Actual): September 19, 2022
• Last Update Submitted That Met QC Criteria: September 16, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Mitochondrial function; Lipid metabolism; Metabolic flexibility; Human primary myoblasts
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: NL35178.068.11