Insulin Resistance, DiabetesLIDDIANCT03314714
Duality of Lipids: the Athlete's Paradox
A study testing Acute bout of endurance exercise in people with Insulin Resistance, Diabetes and Lipid Metabolism Disorders, run by German Diabetes Center at 2 sites in 2 countries.
Trial summary
Accumulation of intramyocellular lipids (IMCLs) due to increased supply of fatty acids can induce defects in the insulin signaling cascade, causing skeletal muscle insulin resistance. However, the causes for muscle insulin resistance are not well understood. Read more about this study
- Who is it for?
- Ages 18 to 69 yearsHealthy volunteers can take part
- Conditions the study is for
- Insulin Resistance, Diabetes, Lipid Metabolism Disorders
- What is being tested?
- Acute bout of endurance exercise
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 100 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 3 Apr 2017to 1 Jun 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 69 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Insulin-resistant, non-athletic persons with a comparable content of IMCLs as the athletes
- Healthy, insulin-sensitive, normal-weight, non-athletic (BMI 18-25 kg / m2) individuals
- Endurance trained individuals (VO2max≥60 mL / kg / min ♂ and 45 mL / kg / min ♀)
- Male and female, age between ≥ 18 and ≤ 69 years
Who cannot join
- Acute infections / fever
- Immunosuppressive therapy
- Serious heart, kidney or liver disease: - New York Heart Association-Classification (NYHA) stage ≥ II - creatinine ≥ 1.6 mg / dl - Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ two-fold upper reference value - severe peripheral artery disease (PAD) (stage IV)
- autoimmune diseases
- Anemia (Hb <12g / l)
- Severe psychiatric illness or addiction
Show all 19Show fewer
- Malignant cancer
- Participation in another intervention study
- Blood clotting disorders or increased risk of thrombosis
- Pregnancy, lactation
- Cigarettes (or non-smokers <1 year)
- alcohol consumption (men> 30g / d, women> 20g / d)
- ECG changes (ST reductions or - elevations, high-grade rhythm disorders (salvage or polytope extrasystoles, ventricular tachycardia)
- Heart diseases (angina pectoris at rest or under light load, myocardial infarction, thromboembolic processes / pulmonary embolism or severe arteriosclerosis, acute myocarditis or pericarditis, cardiac wall aneurysms, cor pulmonale, aortic stenosis)
- Hypertension (> 220/120 mmHg)
- Pacemaker
- Metallic and magnetic implants (for example, mechanical heart valves, joint prostheses, clip after vascular surgery, middle and inner ear implants or fresh dental implants, penis implants)
- Waist circumference> 135cm
- Claustrophobia
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
Germany1 site
German Diabetes Center
Düsseldorf, North Rhine-Westphalia, 40225
About this study
Official title: The Dual Role of Intramyocellular Lipids in Mediating Insulin Resistance: Assessing the Mechanisms of the Athlete's Paradox
Accumulation of intramyocellular lipids (IMCLs) due to increased supply of fatty acids can induce defects in the insulin signaling cascade, causing skeletal muscle insulin resistance. However, the causes for muscle insulin resistance are not well understood. The association of elevated IMCLs and insulin resistance has been shown in obese humans and individuals with type 2 diabetes as well as several animal models of insulin resistance. Despite the strong relationship between IMCLs and insulin resistance, this suggested relationship disappears when well-trained endurance athletes are included into this consideration as this group is highly insulin sensitive. This metabolic enigma has been termed the 'athlete's paradox'. The aim of this project is to resolve the mechanisms contributing to the athlete's paradox.
Read the detailed description
Type 2 diabetes (T2D) is characterized by an increasing insensitivity of muscle, fat and liver cells to the hormone insulin. About 9% of the global population is affected by this condition and mortality risk is twice as high in individuals with diabetes compared to similar-aged people without diabetes.
Muscle is of particular importance for glucose homeostasis, since in healthy subjects it accounts for 80-90% of postprandial insulin-stimulated glucose disposal. After cellular uptake of glucose by the specialized glucose transporter 4 (GLUT4), glucose is phosphorylated and stored as glycogen. In individuals with obesity or T2D, the capacity for insulin to facilitate glucose uptake and glycogen synthesis is impaired. This reduced response of a given insulin concentration to exert its biological effect is termed insulin resistance. Subsequent diminished insulin secretion due to β-cell failure results in fasting hyperglycemia and overt diabetes. Importantly, muscle insulin resistance is the initial defect occurring in the development of T2D and precedes the clinical development of the disease by up to 20 years. Intracellular defects in glucose transport have been identified as the limiting step for insulin-mediated glucose uptake into skeletal muscle. Impaired muscle glucose transport activity is likely a consequence of ectopic lipid accumulation and subsequent dysregulation of intramyocellular fatty acid metabolism. Indeed, results from normal weight, nondiabetic adults suggest that intramyocellular triglyceride content is a strong predictor for muscle insulin resistance. Of note, the development of insulin resistance occurred without changes in intramyocellular triglyceride content, thus dissociating the amount of these neutral storage lipids from insulin resistance. Instead, the bioactive lipid species diacylglycerols (DAG) and ceramides have been implicated in interfering with insulin signaling and glucose homeostasis in obese and insulin resistant individuals and individuals with T2D by activating members of the protein kinase C (PKC) family while ceramides mediate an increase in protein phosphatase 2A (PP2A) and an association of PKCζ and protein kinase B (PKB)/Akt2. To add another layer of complexity, DAGs seem to exert their detrimental intracellular effects in a subspecies- (mostly C18:0, C18:1, or C18:2 DAGs) and stereo-selective manner (sn-1,2 stereoisomer DAG). Taken together, excessive amounts of bioactive intramyocellular lipids (IMCLs) contribute to defective insulin signaling in obese individuals and patients with T2D. Surprisingly, endurance athletes have comparable amounts of IMCLs, but remain highly insulin sensitive. This metabolic conundrum has been termed "athlete's paradox".
This study therefore aims at resolving this conundrum with mass-spectrometry based state-of-the-art methodology by analysing lipid subspecies in endurance-trained athletes, untrained healthy individuals and insulin-resistant individuals.
- Being tested
- Acute bout of endurance exercise
- Medical subject headings
- Insulin Resistance, Diabetes Mellitus, Lipid Metabolism Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Acute bout of endurance exerciseProcedure or surgery
Individuals will undergo an acute bout of endurance exercise for 90 min at 75% of maximal oxygen uptake.
| Study group | Role | What they receive |
|---|---|---|
| Acute bout of endurance exercise | Experimental | Intramyocellular lipid metabolism will be assessed in insulin resistant and healthy, sedentary individuals after an acute bout of endurance exercise. Receives: Procedure: Acute bout of endurance exercise |
What is being measured
The primary outcome is the main question the study is designed to answer.
Assessment of intramyocellular lipid content via magnetic resonance spectroscopy
Intramyocellular lipid content assessed via magnetic resonance spectroscopy (%lipid) in endurance-trained athletes and sedentary individuals
Measured: 2 years
Assessment of intramyocellular lipid composition via mass spectrometry
Detailed composition of intramyocellular lipids assessed via mass spectrometry (concentration of bioactive lipids) in endurance-trained athletes and sedentary individuals
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Oct 2017
- Study start3 Apr 2017
- Primary completion1 Jun 2023
- Study completion1 Jun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Insulin Resistance, DiabetesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 100 participants (actual)
Sponsor and investigators
- Lead sponsor
- German Diabetes Center
- Sponsor type
- University, hospital or other
- Collaborators
- Maastricht University
- Responsible party
- Sponsor
- Investigators
- Michael Roden, Prof., MD, Principal investigator, German Diabetes Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03314714
- Sponsor's protocol ID
- DDZ-LIDDIA01
- Acronym
- LIDDIA
- Status last verified
- Jun 2023
- First submitted
- 3 Apr 2017
- Last updated
- 13 Jun 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab. 2001 Dec;86(12):5755-61. doi: 10.1210/jcem.86.12.8075.
PubMed 11739435Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996 Jun 15;97(12):2859-65. doi: 10.1172/JCI118742.
PubMed 8675698Szendroedi J, Yoshimura T, Phielix E, Koliaki C, Marcucci M, Zhang D, Jelenik T, Muller J, Herder C, Nowotny P, Shulman GI, Roden M. Role of diacylglycerol activation of PKCtheta in lipid-induced muscle insulin resistance in humans. Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9597-602. doi: 10.1073/pnas.1409229111. Epub 2014 Jun 16.
PubMed 24979806Pesta D, Anadol-Schmitz E, Sarabhai T, Op den Kamp Y, Gancheva S, Trinks N, Zaharia OP, Mastrototaro L, Lyu K, Habets I, Op den Kamp-Bruls YMH, Dewidar B, Weiss J, Schrauwen-Hinderling V, Zhang D, Gaspar RC, Strassburger K, Kupriyanova Y, Al-Hasani H, Szendroedi J, Schrauwen P, Phielix E, Shulman GI, Roden M. Determinants of increased muscle insulin sensitivity of exercise-trained versus sedentary normal weight and overweight individuals. Sci Adv. 2025 Jan 3;11(1):eadr8849. doi: 10.1126/sciadv.adr8849. Epub 2025 Jan 1.
PubMed 39742483
Study at a glance
From the registry record, last updated by the sponsor on 13 Jun 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Dual Role of Intramyocellular Lipids in Mediating Insulin Resistance: Assessing the Mechanisms of the Athlete's Paradox
- ClinicalTrials.gov ID
- NCT03314714
- Acronym / sponsor ID
- LIDDIA / DDZ-LIDDIA01
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 100 participants (actual)
- Lead sponsor
- German Diabetes CenterUniversity, hospital or other
- Collaborators
- Maastricht University
- Study start
- 3 Apr 2017 (actual)
- Primary completion
- 1 Jun 2023 (actual)
- Study completion
- 1 Jun 2023 (actual)
- First posted
- 19 Oct 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Accumulation of intramyocellular lipids (IMCLs) due to increased supply of fatty acids can induce defects in the insulin signaling cascade, causing skeletal muscle insulin resistance. However, the causes for muscle insulin resistance are not well understood. The association of elevated IMCLs and insulin resistance has been shown in obese humans and individuals with type 2 diabetes as well as several animal models of insulin resistance. Despite the strong relationship between IMCLs and insulin resistance, this suggested relationship disappears when well-trained endurance athletes are included into this consideration as this group is highly insulin sensitive. This metabolic enigma has been termed the 'athlete's paradox'. The aim of this project is to resolve the mechanisms contributing to the athlete's paradox.
Detailed description
Type 2 diabetes (T2D) is characterized by an increasing insensitivity of muscle, fat and liver cells to the hormone insulin. About 9% of the global population is affected by this condition and mortality risk is twice as high in individuals with diabetes compared to similar-aged people without diabetes.
Muscle is of particular importance for glucose homeostasis, since in healthy subjects it accounts for 80-90% of postprandial insulin-stimulated glucose disposal. After cellular uptake of glucose by the specialized glucose transporter 4 (GLUT4), glucose is phosphorylated and stored as glycogen. In individuals with obesity or T2D, the capacity for insulin to facilitate glucose uptake and glycogen synthesis is impaired. This reduced response of a given insulin concentration to exert its biological effect is termed insulin resistance. Subsequent diminished insulin secretion due to β-cell failure results in fasting hyperglycemia and overt diabetes. Importantly, muscle insulin resistance is the initial defect occurring in the development of T2D and precedes the clinical development of the disease by up to 20 years. Intracellular defects in glucose transport have been identified as the limiting step for insulin-mediated glucose uptake into skeletal muscle. Impaired muscle glucose transport activity is likely a consequence of ectopic lipid accumulation and subsequent dysregulation of intramyocellular fatty acid metabolism. Indeed, results from normal weight, nondiabetic adults suggest that intramyocellular triglyceride content is a strong predictor for muscle insulin resistance. Of note, the development of insulin resistance occurred without changes in intramyocellular triglyceride content, thus dissociating the amount of these neutral storage lipids from insulin resistance. Instead, the bioactive lipid species diacylglycerols (DAG) and ceramides have been implicated in interfering with insulin signaling and glucose homeostasis in obese and insulin resistant individuals and individuals with T2D by activating members of the protein kinase C (PKC) family while ceramides mediate an increase in protein phosphatase 2A (PP2A) and an association of PKCζ and protein kinase B (PKB)/Akt2. To add another layer of complexity, DAGs seem to exert their detrimental intracellular effects in a subspecies- (mostly C18:0, C18:1, or C18:2 DAGs) and stereo-selective manner (sn-1,2 stereoisomer DAG). Taken together, excessive amounts of bioactive intramyocellular lipids (IMCLs) contribute to defective insulin signaling in obese individuals and patients with T2D. Surprisingly, endurance athletes have comparable amounts of IMCLs, but remain highly insulin sensitive. This metabolic conundrum has been termed "athlete's paradox".
This study therefore aims at resolving this conundrum with mass-spectrometry based state-of-the-art methodology by analysing lipid subspecies in endurance-trained athletes, untrained healthy individuals and insulin-resistant individuals.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Acute bout of endurance exercise | Experimental | Procedure: Acute bout of endurance exerciseIntramyocellular lipid metabolism will be assessed in insulin resistant and healthy, sedentary individuals after an acute bout of endurance exercise. |
Who may qualify
- Ages
- 18 to 69 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Insulin-resistant, non-athletic persons with a comparable content of IMCLs as the athletes
- Healthy, insulin-sensitive, normal-weight, non-athletic (BMI 18-25 kg / m2) individuals
- Endurance trained individuals (VO2max≥60 mL / kg / min ♂ and 45 mL / kg / min ♀)
- Male and female, age between ≥ 18 and ≤ 69 years
Key exclusion criteria (19 listed)
- Acute infections / fever
- Immunosuppressive therapy
- Serious heart, kidney or liver disease: - New York Heart Association-Classification (NYHA) stage ≥ II - creatinine ≥ 1.6 mg / dl - Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ two-fold upper reference value - severe peripheral artery disease (PAD) (stage IV)
- autoimmune diseases
- Anemia (Hb <12g / l)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Acute bout of endurance exerciseIndividuals will undergo an acute bout of endurance exercise for 90 min at 75% of maximal oxygen uptake. | Procedure or surgery | Acute bout of endurance exercise |
Primary outcome
Assessment of intramyocellular lipid content via magnetic resonance spectroscopy
Time frame: 2 years
Intramyocellular lipid content assessed via magnetic resonance spectroscopy (%lipid) in endurance-trained athletes and sedentary individuals
Assessment of intramyocellular lipid composition via mass spectrometry
Time frame: 2 years
Detailed composition of intramyocellular lipids assessed via mass spectrometry (concentration of bioactive lipids) in endurance-trained athletes and sedentary individuals
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jun 2023.
- Background: PubMed 11739435Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab. 2001 Dec;86(12):5755-61. doi: 10.1210/jcem.86.12.8075.
- Background: PubMed 8675698Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996 Jun 15;97(12):2859-65. doi: 10.1172/JCI118742.
- Background: PubMed 24979806Szendroedi J, Yoshimura T, Phielix E, Koliaki C, Marcucci M, Zhang D, Jelenik T, Muller J, Herder C, Nowotny P, Shulman GI, Roden M. Role of diacylglycerol activation of PKCtheta in lipid-induced muscle insulin resistance in humans. Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9597-602. doi: 10.1073/pnas.1409229111. Epub 2014 Jun 16.
- Derived from this study: PubMed 39742483Pesta D, Anadol-Schmitz E, Sarabhai T, Op den Kamp Y, Gancheva S, Trinks N, Zaharia OP, Mastrototaro L, Lyu K, Habets I, Op den Kamp-Bruls YMH, Dewidar B, Weiss J, Schrauwen-Hinderling V, Zhang D, Gaspar RC, Strassburger K, Kupriyanova Y, Al-Hasani H, Szendroedi J, Schrauwen P, Phielix E, Shulman GI, Roden M. Determinants of increased muscle insulin sensitivity of exercise-trained versus sedentary normal weight and overweight individuals. Sci Adv. 2025 Jan 3;11(1):eadr8849. doi: 10.1126/sciadv.adr8849. Epub 2025 Jan 1.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael Roden, Prof., MD principal investigator
German Diabetes Center
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Acute bout of endurance exercise in people with Insulin Resistance, Diabetes and Lipid Metabolism Disorders, run by German Diabetes Center at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Germany, Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Assessment of intramyocellular lipid content via magnetic resonance spectroscopy (time frame: 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03314714, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jun 2023.