Lipid-induced Insulin Resistance
Conditions
Brief summary
Type 2 diabetes is the most common metabolic disease worldwide, characterized by hyperglycemia, decreased whole body insulin sensitivity, and white adipose tissue (WAT) dysfunction. A key factor in its development is chronic overnutrition, usually with a high-fat diet (HFD), leading to disturbances of glucose and lipid metabolism. However, the mechanism of short-term HFD-induced tissue-specific insulin resistance remains poorly understood. This project aims to further unravel the underlying mechanisms of short-term HFD overnutrition-mediated WAT insulin resistance. The model described here corresponds to a randomized, single- blinded parallel-grouped trial, consisting of two interventions: a macronutrient-balanced diet and or a hypercaloric diet over three weeks in order to investigate differences in interorgan fatty acid and glucose metabolism between the studied groups. Based on recent studies, the hypothesis is that 21-day hypercaloric HFD induces WAT insulin resistance via a diacylglycerol, novel protein kinase C-insulin receptor signaling model in both fasting and insulin-stimulated states.
Interventions
BEHAVIORALHigh-fat overnutrition
Overnutrition: 40% higher lipid consumption per day than required
BEHAVIORALNormocaloric macronutrient-balanced nutrition
Normocaloric, macronutrient-balanced nutrition: Calories requirement for weight maintenance \[(kcal/d) 55% carbohydrates, 15% proteins, 30% fat\]
Sponsors
Yale University
German Diabetes Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Age between 18 and 40 years * BMI \< 29 kg/m2 * Sport inactive (\<1x /week) * Capacity to consent
Exclusion criteria
* Diabetes mellitus disease * Acute coronary heart syndrome (myocardial infarction, unstable angina pectoris, stroke or transient ischemic attack in the last 3 months before study participation) * Acute infectious disease * Taking blood glucose-lowering drugs * Diseases or drugs affecting the immune system and allergies to drugs used in the study * Drugs with potential metabolic effects * Chronic liver disease (hepatitis, gallbladder disease, elevated liver enzymes (ALT \> 300 U/L)) * Chronic inflammatory bowel diseases * Rheumatic diseases * Hyper- or hypothyroidism of the thyroid gland * Renal insufficiency, administration of iodine-containing contrast media in the last 2 days * Chronic lung diseases * cancerous diseases * Addictive diseases, psychiatric diseases * Pregnancy, breastfeeding * Shift workers * Anemia (Hb \<12 g/dl) * Disorders of hemostasis * Regular use of antithrombotic drugs * Alcohol consumption, smoking * Conditions that do not permit an MRI examination
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Whole-body insulin sensitivity and WAT insulin sensitivity | 3 weeks intervention period each | Hyperinsulinemica-euglycemia clamp tests with deuterated glucose to measure fasting and insulin-stimulated whole-body insulin sensitivity and measurement of the index ADIPO-IR (fasting insulin x free fatty acid concentration) before and after dietary intervention period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| WAT insulin signaling pathways | 3 weeks intervention time | Adipose tissue biopsies are planned to be taken during the fasting and insulin-stimulated state before and after the dietary intervention period. DAG and ceramide subcellular fractionation assay is planned to be performed. Expressionanalyses for activation /membrane translocation of novel and atypical protein kinase C isoforms will be done. Determination of the degree of phosphorylation of various components of the insulin pathway via Western blot are planned. |
Countries
Germany
Contacts
Primary ContactTheresia Sarabhai, MD
Backup ContactSabine Kahl, MD
Outcome results
None listed