Clinical Trials Logo

Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03314714
Other study ID # DDZ-LIDDIA01
Secondary ID
Status Completed
Phase N/A
First received
Last updated
Start date April 3, 2017
Est. completion date June 1, 2023

Study information

Verified date June 2023
Source German Diabetes Center
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical 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. 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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 100
Est. completion date June 1, 2023
Est. primary completion date June 1, 2023
Accepts healthy volunteers Accepts Healthy Volunteers
Gender All
Age group 18 Years to 69 Years
Eligibility Inclusion criteria - 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 Exclusion criteria - 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 - 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

Study Design


Intervention

Procedure:
Acute bout of endurance exercise
Individuals will undergo an acute bout of endurance exercise for 90 min at 75% of maximal oxygen uptake.

Locations

Country Name City State
Germany German Diabetes Center Düsseldorf NRW
Netherlands Maastricht University Maastricht

Sponsors (2)

Lead Sponsor Collaborator
German Diabetes Center Maastricht University

Countries where clinical trial is conducted

Germany,  Netherlands, 

References & Publications (3)

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. — View Citation

Roden 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. — View Citation

Szendroedi 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. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary 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 2 years
Primary 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 2 years
See also
  Status Clinical Trial Phase
Completed NCT04896619 - Cholesterol Effects of Kori-tofu Proteins N/A
Completed NCT01737164 - Effect of Age on Glucose and Lipid Metabolism N/A
Completed NCT05629403 - Exclusive Breastfeeding Improves Puerperal Glucose Metabolism in Pregnant Women With Gestational Diabetes Mellitus and Links to Lipids Composition
Withdrawn NCT03047538 - Fixed Combination for Lipid and Blood Pressure Control Phase 4
Withdrawn NCT02270164 - The Impact of Artichoke Leaf Extract on Blood Cholesterol: Primary Study N/A
Completed NCT01968720 - Pilot Study To Assess CAT-2003 in Patients With Severe Hypertriglyceridemia Phase 2
Completed NCT01435382 - A Pharmacokinetic and Pharmacodynamic Study of PF-04950615 (RN316) in Subjects With Hypercholesterolemia Phase 1
Completed NCT00707746 - Safety and Efficacy Study of ISIS 301012 (Mipomersen) Administration in High Risk Statin Intolerant Subjects Phase 2
Active, not recruiting NCT01803776 - The Physical Activity and Nutrition in Children (PANIC) Study N/A
Active, not recruiting NCT05618756 - CBD, Nutrient Metabolism and Energy Intake N/A
Completed NCT05558488 - The Effect of a Meatless,Keto Restrictive Diet on Body Composition,Strength Capacity,Oxidative Stress,Immune Response N/A
Recruiting NCT04948008 - Evaluate the Efficacy and Safety of IBI306 in Subjects With Homozygous Familial Hypercholesterolemia Phase 2/Phase 3
Completed NCT03898505 - Clinical Investigation on the Safety of Avocado Pulp Lipids Early Phase 1
Completed NCT01311375 - Omega 3 in Intervention Spinal Cord Injured People Phase 2/Phase 3
Terminated NCT01963650 - Natural History Study of Children With Metachromatic Leukodystrophy
Active, not recruiting NCT06448052 - Umbilical Cord Mesenchymal Stem Cell for Aging-related Low-grade Inflammation Phase 1/Phase 2
Not yet recruiting NCT06060886 - Multidisciplinary Design to Optimize Schizophrenia Treatment Based on Multi-omics Data and Systems Biology Analysis Phase 4
Completed NCT03976479 - Body Composition, Nutritional and Cardiovascular Status and Lifestyle Factors of Adults Who Are on Plant-Based Diet
Completed NCT02243969 - Alpha-linolenic Acid and Blood Pressure N/A
Completed NCT01874132 - Study of the Long-term Effects of Exercise on Heath Indicators in Older People N/A